Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3].C(O)(=O)C(O)=O.[CH2:25]1[C:28]2([CH2:31][NH:30][CH2:29]2)[CH2:27][O:26]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:25]1[C:28]2([CH2:31][N:30]([S:2]([C:5]3[CH:6]=[C:7]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=3)[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3])[CH2:29]2)[CH2:27][O:26]1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)Cl)c1
Reactant: C1NCC12COC2
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CC3(COC3)C2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of methyl 3-(chlorosulfonyl)-5-(trifluoromethyl)benzoate (1 g, 1.33 mmol, Buttpark Ltd.) in CH2Cl2 (10 mL) was added N,N-ethyldiisopropylamine (1.28 g, 1.73 mL, 9.91 mmol, Eq: 3) and 2-oxa-6-aza-spiro[3.3]heptane oxalate (524 mg, 1.82 mmol). The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was poured on 30 mL 10% aqueous NaHCO3 solution and 30 mL CH2Cl2 and the layers were separated. The aqueous layer was extracted a second time with 30 mL CH2Cl2. The organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 30:70). Colorless solid (460 mg, 38.1%). MS (ESI): m/z=365 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.Cl[C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH2:23][CH:24]2[CH2:26][CH2:25]2)=[C:16]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:15]=1.CC1(C)C(C)(C)OB([C:41]2[CH:42]=[N:43][C:44]([NH2:47])=[N:45][CH:46]=2)O1>C(OCC)(=O)C.O>[CH:24]1([CH2:23][N:20]2[CH:19]=[N:18][C:17]3[C:21]2=[N:22][C:14]([C:41]2[CH:42]=[N:43][C:44]([NH2:47])=[N:45][CH:46]=2)=[N:15][C:16]=3[N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH2:26][CH2:25]1
Reactant: Clc1nc(N2CCOCC2)c2ncn(CC3CC3)c2n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CC4CC4)c3n2)cn1
Yield: 101 %

Procedure:
Sodium carbonate (3.25 g, 30.6 mmol) and tetrakis triphenylphosphine palladium (0.59 g, 0.51 mmol) were added to a 1,4-dioxane (60.0 ml)-water (30.0 ml) mixture solution of 2-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purine (3.0 g, 10.2 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (2.5 g, 11.2 mmol) at room temperature and the resulting mixture was heated to reflux for 3 hours in an argon atmosphere. The reaction mixture was left standing to cool and then poured into water, and ethyl acetate was added to separate the layers. The solid precipitated in the aqueous layer was collected by filtration, washed with water, and dried at 50° C. under reduced pressure to give the title compound (3.63 g, 100%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]([O:11]C)=[O:10])=[C:6]([N:13]([CH3:15])[CH3:14])[N:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[O:25])=[CH:19][CH:18]=2)[N:3]=1.[OH-].[Na+].O>C1COCC1.CCCCCC>[Cl:1][C:2]1[C:7]([CH2:8][C:9]([OH:11])=[O:10])=[C:6]([N:13]([CH3:15])[CH3:14])[N:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[O:25])=[CH:19][CH:18]=2)[N:3]=1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)c1nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc(Cl)c1CC(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 40 %

Procedure:
The thus obtained methyl {4-chloro-6-(dimethylamino)-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetate was dissolved in THF (1 mL) and treated with 1N NaOH (0.5 mL). The resulting biphasic mixture was stirred at room temperature for 14 hours at which time it was poured into water. The separated aqueous phase was washed with EtOAc and then acidified with 1N HCl and back extracted with EtOAc. The combined organic extracts was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product thus obtained was dissolved in a minimum volume of THF to which n-hexane was added. The separated precipitate was collected by suction, rinsed with n-hexane, and dried under vacuum to give {4-chloro-6-(dimethylamino)-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetic acid (0.038 g, 40% yield) as a white powder.
Reaction SMILES: Cl[C:2]([S:4]Cl)=[O:3].[NH2:6]/[C:7](/[CH3:11])=[CH:8]\[C:9]#[N:10]>O1CCCC1>[C:9]([C:8]1[S:4][C:2](=[O:3])[NH:6][C:7]=1[CH3:11])#[N:10]
Reactant: O=C(Cl)SCl
Reactant: C/C(N)=C/C#N
Solvent: C1CCOC1
Product: Cc1[nH]c(=O)sc1C#N
Temperature: 140 °C
Yield: 72.6 %

Procedure:
40 g of chlorocarbonylsulfenyl chloride were added to a mixture of 25 g of 3-amino-crotononitrile in 700 ml of tetrahydrofuran and the mixture was refluxed for 3 hours after which the solvent was distilled off under reduced pressure. The residue was heated at 140°C for 10 minutes and cooled and then 1N sodium hydroxide was added thereto. The aqueous solution was washed with ethylacetate, acidified with hydrochloric and extracted with ethylacetate. The organic extracts were dried, concentrated to dryness and isopropyl ether was added to obtain 31 g of 5-cyano-4-methyl-4-thiazoline-2-one melting at 180° to 181°C.
Reaction SMILES: O=[C:2]1[CH2:22][CH2:21][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.C([O-])(=O)C.[NH4+:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CO.C(Cl)Cl>[NH2:27][CH:2]1[CH2:22][CH2:21][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1
Reactant: O=C1CCC2(CC1)CCN(C(=O)OCc1ccccc1)CC2
Reactant: [NH4+]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CO
Product: NC1CCC2(CC1)CCN(C(=O)OCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 110.5 %

Procedure:
Benzyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (230 mg) was dissolved in methanol (4.5 mL) and methylene chloride (1.5 mL), and ammonium acetate (1.47 g) was added thereto, followed by stirring at room temperature for 10 minutes. Subsequently, sodium triacetoxyborohydride (323 mg) was added thereto, followed by stirring at room temperature overnight. To the reaction solution was added saturated aqueous sodium bicarbonate, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain benzyl 9-amino-3-azaspiro[5.5]undecane-3-carboxylate (255 mg).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH:16]=[CH:17][C:18]=3[C:5]=2[N:4]=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31]([N:35]([CH2:39][CH2:40][CH2:41][CH3:42])[C:36](Cl)=[O:37])[CH2:32][CH2:33][CH3:34].O1CCCC1>C(OCC)(=O)C.O>[CH2:31]([N:35]([C:36]([O:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH:16]=[CH:17][C:18]=3[C:5]=2[N:4]=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:37])[CH2:39][CH2:40][CH2:41][CH3:42])[CH2:32][CH2:33][CH3:34]
Reactant: CCCCN(CCCC)C(=O)Cl
Reactant: On1c(-c2ccccc2)nc2c3ccc4ccccc4c3ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCN(CCCC)C(=O)On1c(-c2ccccc2)nc2c3ccc4ccccc4c3ccc21

Procedure:
10 parts of 1-hydroxy-2-phenylphenanthroimidazole, 8 parts of anhydrous potassium carbonate and 6.7 parts of N,N-dibutylcarbamyl chloride in 100 parts of tetrahydrofuran are refluxed for 5 hours. 100 parts of water and 200 parts of ethyl acetate are then added. The organic phase is washed with water, dried over sodium sulfate and evaporated down under reduced pressure. When the residue is left to stand, 6.6 parts of a solid which has a melting point of 120° C. and is pure according to thin layer chromatography are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([C:11]#[N:12])[CH:3]=1.[CH2:13]([C:15]1[CH:16]=[C:17]([CH3:27])[C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:19][CH:20]=1)[CH3:14]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:18]3[C:17]([CH3:27])=[CH:16][C:15]([CH2:13][CH3:14])=[CH:20][N:19]=3)[CH2:22][CH2:23]2)=[O:8])=[C:4]([CH:3]=1)[C:11]#[N:12]
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Reactant: N#Cc1cc(Br)ccc1C(=O)O
Product: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Yield: 90.4 %

Procedure:
Using 4-bromo-2-cyanobenzoic acid (4.55 g) described in Preparation Example 76 and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (4.13 g) described in Preparation Example 81 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (7.52 g) was obtained.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][N:4]([C:11]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)[C:5](=[O:10])C(Cl)(Cl)Cl.C([O-])(=O)C.[NH4+:32]>C(O)C>[F:1][C:2]([F:27])([F:26])[CH2:3][N:4]1[C:11]2[C:12](=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:32][C:5]1=[O:10]
Reactant: [NH4+]
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1N(CC(F)(F)F)C(=O)C(Cl)(Cl)Cl
Agent: CC(=O)[O-]
Solvent: CCO
Product: O=c1nc(-c2ccccc2)c2cc(Cl)ccc2n1CC(F)(F)F

Procedure:
To a solution of 2.8 g of 2-[N-(2,2,2-trifluoroethyl)-trichloroacetamido]-5-chlorobenzophenone in 50 ml. of ethanol was added 4.6 g of ammonium acetate. The mixture was stirred and heated under reflux for 10 hours. Then the solvent was removed under reduced pressure. The residue was triturated with ether, filtered, washed with water and dried to give 1-(2,2,2-trifluoroethyl)-4-phenyl-6-chloro-2(1H)-quinazolinone. Recrystallization from ethanol gave pale yellow crystals, m.p. 185.0°-186° C.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1>C(Cl)Cl.CO>[NH2:8][C:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:12])[N:4]([CH3:11])[CH:5]=1
Reactant: Cn1cc([N+](=O)[O-])cc(F)c1=O
Solvent: ClCCl
Solvent: CO
Product: Cn1cc(N)cc(F)c1=O

Procedure:
The title compound was prepared in analogy to the procedure described in Step 5.2 using 3-fluoro-1-methyl-5-nitropyridin-2(1H)-one (Step 14.1). tR: 0.22 min (LC-MS 2); ESI-MS: 143 [M+H]+ (LC-MS 2); Rf=0.25 (CH2Cl2/MeOH 9:1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1.[NH:11]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]1>>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:11]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]2)[N:7]=1)[CH3:10]
Reactant: OC1CCNC1
Reactant: CCOc1ccnc(Cl)n1
Product: CCOc1ccnc(N2CCC(O)C2)n1

Procedure:
The title compound was prepared as described in Example 555, Step 2 using 2-chloro-4-ethoxypyrimidine (2.4 g, 15 mol) and pyrrolidin-3-ol (1.6 g, 18 mmol) as the starting materials.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]([OH:22])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1.[CH3:34][C:35]1[CH:36]=[C:37]([N:41]=[C:42]=[O:43])[CH:38]=[CH:39][CH:40]=1>C(Cl)Cl>[CH3:15][C:14]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:22][C:42](=[O:43])[N:41]([C:37]2[CH:36]=[C:35]([CH3:34])[CH:40]=[CH:39][CH:38]=2)[CH2:12][CH2:13]1
Reactant: Cc1cccc(N=C=O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(O)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cccc(N2CCC(C)(c3ccccc3)OC2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxy-3-phenylbutyl 4-methylbenzenesulfonate (1 g, 3.12 mmol) and DBU (1.4 g, 9.26 mmol) in CH2Cl2 (15 mL) was added a solution of 3-methylphenyl isocyanate (623 mg, 4.68 mmol) in CH2Cl2 (5 mL) at 0° C. over 0.5 h. The mixture was stirred at rt overnight. The mixture was concentrated to give the crude product, which was purified by column chromatography and then by preparative HPLC to afford 6-methyl-6-phenyl-3-m-tolyl-1,3-oxazinan-2-one. LC-MS Method 2, tR=2.706 min, m/z=282. 1H NMR (CDCl3) 1.75 (s, 3H), 2.30 (s, 3H), 2.35-2.50 (m, 2H), 3.30 (m, 1H), 3.50 (m, 1H), 6.95 (m, 2H), 7.05 (m, 1H), 7.20-7.30 (m, 1H), 7.35 (m, 1H), 7.42-7.50 (m, 4H).
Reaction SMILES: Br.[CH2:2]([N:5]([CH2:20][CH2:21][CH3:22])[CH:6]1[CH2:15][C:14]2[CH:13]=[C:12]([NH:16]C(=O)C)[CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7]1)[CH2:3][CH3:4]>O.[OH-].[Na+]>[CH2:20]([N:5]([CH2:2][CH2:3][CH3:4])[CH:6]1[CH2:7][CH2:8][C:9]2[C:14](=[CH:13][C:12]([NH2:16])=[CH:11][CH:10]=2)[CH2:15]1)[CH2:21][CH3:22]
Reactant: CCCN(CCC)C1CCc2ccc(NC(C)=O)cc2C1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCN(CCC)C1CCc2ccc(N)cc2C1
Yield: 88.2 %

Procedure:
A suspension of N-[7-(dipropylamino)-5,6,7,8-tetrahydro-2-naphthalenyl]-acetamide hydrobromide (3.0 g, 8.1 mmoles) in water was treated in 1N sodium hydroxide (100 ml) and the resulting free base was extracted in benzene. The solvent was evaporated and the residue was heated at reflux in 2N hydrochloric acid (37 ml) for 2 hr. After cooling, the solution was basified with 1N sodium hydroxide and extracted three times with benzene. The organic extracts were dried (MgSO4) and concentrated to afford a red oil (1.76 g) of 1,2,3,4-tetrahydro-N2, N2 -dipropyl-2,7-naphthalenediamine: NMR (CDCl3) δ 0.85 (t, 6H), 1.42 (m, 6H), 2.42 (t, 4H), 2.70 (m, 4H), 6.35 (m, 2H) and 6.80 (d, 1H). The di-(Z)-2-butenedioate salt was prepared in acetone and diethyl ether, and crystallized from methanol-diethyl ether: mp 124°-126° C. and Anal. Calcd for C 16 H26N2.2C4H4O2 : C, 60.23%; H, 7.16%, N, 5.85%; and Found: C, 60.45%; H, 7.21%; N, 5.88%.
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([C@H:16]([CH2:28][OH:29])[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C(=C)CC5[C@]4(C)CCCC5)[C@@H]2C3)C)O1.C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@H](CO)C5[C@]4(C)CCCC5)[C@@H]2C3)C)O1>>[CH2:11]1[CH2:10][O:9][C:8]23[O:13][CH2:14][CH2:1][O:2][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([C@@H:16]([CH2:28][OH:29])[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:12]1
Reactant: C[C@]12CCCCC1C[C@@H](CO)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Agent: C=C1CC2CCCC[C@]2(C)[C@H]2CC[C@@]3(C)[C@@H](CC45OCCOC43OCCO5)[C@H]12
Agent: C[C@]12CCCCC1[C@@H](CO)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCCCC1C[C@H](CO)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Yield: 70 %

Procedure:
17,17-bis(ethylendioxy)-7α-hydroxymethylandrostane and 3,3:17,17-bis(ethylendioxy)-7β-hydroxymethylandrostane were prepared in 10% and 70% yield, respectively, from 3,3:17,17-bis(ethylendioxy)-7-methyleneandrostane (Prepn. 33, 2.9 g) by the procedure described above for the preparation of 3,3:17,17-bis(ethylendioxy)-6α-hydroxymethyl-androstane (Prepn. 14). The residue was purified by flash chromatography (SiO2, n-hexane/EtOAc 60/40). 3,3:17,17-bis(ethylendioxy)-7α-hydroxymethylandrostane 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.85-3.75 (8H, m), 3.67 (2H, m), 3.34 (1H, t), 2.00-0.90 (21H, m), 0.87 (3H, s), 0.81 (3H, s) 3,3:17,17-bis(ethylendioxy)-7β-hydroxymethylandrostane 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.90-3.75 (8H, m), 3.58 (2H, m), 3.31 (1H, t), 2.00-1.10 (21H, m), 0.84 (3H, s), 0.81 (3H, s).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1.[CH3:36][C:37]([CH3:42])([CH2:40]O)[CH2:38][OH:39]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:36][C:37]1([CH3:42])[CH2:38][O:39][C:32]2([CH2:31][CH2:30][CH:29]([N:3]3[C:2](=[O:1])[C:7]([CH2:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]5[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:13][CH:14]=4)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]4[N:26]=[CH:27][N:28]=[C:4]34)[CH2:34][CH2:33]2)[O:35][CH2:40]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCC(C)(C)CO3)c2ncnn12
Temperature: 110 °C
Reaction time: 3 h
Yield: 111.4 %

Procedure:
A mixture of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.5 g), 2,2-dimethylpropane-1,3-diol (0.22 g), p-toluenesulfonic acid monohydrate (0.002 g) and toluene (20 mL) was subjected to an azeotropic dehydration reaction by stirring at 110° C. for 3 hr in a reaction vessel equipped with a Dean-stark trap. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.66 g, 100%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=1.Cl[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24]>CN(C)C=O.O.C(OCC)(=O)C>[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH:13][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[N+:23]([O-:25])=[O:24])=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: NCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cnccc1NCc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
Sodium carbonate (3.20 g, 30.27 mmol) and 4-fluorobenzylamine (2.14 ml, 18.92 mmol) were added to a solution of 4-chloro-3-nitropyridine (3.0 g, 18.92 mmol) prepared in Step 1 of Preparation 1 in 30 ml of anhydrous N,N-dimethylformamide and then the reaction mixture was stirred for 1 hour at 80° C. The reaction mixture was diluted with a mixture of water (10 ml) and ethyl acetate (100 ml) and then washed with water (100 ml) twice. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure to give the titled compound as a yellow solid (3.01 g, 83.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:7]([C:12](=O)[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[C:21]([O:27][CH3:28])(=[O:26])[CH2:22][C:23]([CH3:25])=O.Cl.C(=O)([O-])O.[Na+]>C(O)(=O)C>[Cl:19][C:15]1[CH:14]=[C:13]([C:12]2[C:7]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:9]([O:10][CH3:11])[CH:8]=3)[N:6]=[C:23]([CH3:25])[C:22]=2[C:21]([O:27][CH3:28])=[O:26])[CH:18]=[CH:17][N:16]=1
Reactant: COc1cc(N)c(C(=O)c2ccnc(Cl)c2)cc1OC
Reactant: COC(=O)CC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1c(C)nc2cc(OC)c(OC)cc2c1-c1ccnc(Cl)c1
Temperature: 25 °C

Procedure:
A mixture of 3,4-dimethoxy-6-(2-chloroisonicotinoyl)aniline (2.93 g), methyl acetoacetate (2.16 ml), conc. hydrochloric acid (0.1 ml) and acetic acid (30 ml) is heated under reflux for two hours. The reaction mixture is cooled to room temperature, and thereto is added an aqueous sodium hydrogen carbonate solution. The mixture is extracted with ethyl acetate, and the extract is washed, dried, and concentrated. The residue is purified by silica gel column chromatography (solvent; chloroform:ethyl acetate=9:1) to give 2-chloro-4-(6,7-dimethoxy-3-methoxycarbonyl-2-methylquinolin-4-yl)pyridine (3.0 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:15][C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[C:8](=[O:16])[C:7]=2[CH:17]=1.[CH3:18][N:19](C)C=O.[C-]#N.[Na+]>O>[C:18]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:15][C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[C:8](=[O:16])[C:7]=2[CH:17]=1)#[N:19]
Reactant: CN(C)C=O
Reactant: O=c1c2cc(CBr)ccc2oc2ncccc12
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#CCc1ccc2oc3ncccc3c(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 25 g of 7-bromomethyl-5-oxo-5H-[1]benzopyrano-[2,3-b]pyridine and 175 ml of dimethylformamide is added 5.1 g of sodium cyanide under ice cooling. The mixture is stirred at room temperature for 2 hours, and then 300 ml of water is added to the reaction mixture. The resulting crystalline precipitate is filtered off, washed with water, and recrystallized from dioxane to give 17 g of 7-cyanomethyl-5-oxo-5H-[1]-benzopyrano[2,3-b]pyridine melting at 198°-201°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])=[CH:4][C:3]=1[OH:20].[N+:21]([O-])([OH:23])=[O:22]>>[Cl:1][C:2]1[C:3]([OH:20])=[C:4]([N+:21]([O-:23])=[O:22])[C:5]([N:9]2[C:10](=[O:19])[C:11]3=[CH:18][CH:17]=[CH:16][CH:15]=[C:12]3[C:13]2=[O:14])=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=C1c2ccccc2C(=O)N1c1cc(O)c(Cl)cc1F
Product: O=C1c2ccccc2C(=O)N1c1c(F)cc(Cl)c(O)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
2-Chloro-4-fluoro-5-(phthalimido)phenol (5.0 g, 17.1 mmol) was slowly added with stirring to con. nitric acid (50 ml) at −10° C. Solution was then warned to ambient temperature. and allowed to stir for 0.5 hr. Addition to ice-water resulted in a light yellow precipitate which was separated by filtration to afford the title compound (5.5 g); 1H NMR (CDCl3+CD3OD, 300 MHz) 4.36 (H, br s), 7.61 (1H, d, J=8.6 Hz), 7.88 (2H, dd, J=3.0, 5.5 Hz), 7.99 (2H, dd, J=3.0, 5.5 Hz) ppm.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.[CH3:29][OH:30].[BH4-].[Li+].Cl>O1CCCC1.O>[O:28]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH2:20][C:21]3[CH:22]=[CH:29][O:30][CH:23]=3)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CO
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1NCc1ccoc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.103 g, 0.23 mmol) in tetrahydrofuran (4 mL) and methanol (0.030 mL, 0.8 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.200 mL, 0.4 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 2% methanol in chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 4.08 (s, 2 H) 6.59 (s, 1 H) 6.95 (s, 1 H) 7.32 (d, J=5.15 Hz, 1 H) 7.58 (m, 3 H) 7.66 (d, J=8.09 Hz, 1 H) 7.79 (t, J=8.46 Hz, 1 H) 7.93 (d, J=7.72 Hz, 1 H) 8.24 (d, J=5.52 Hz, 1 H) 14.21 (s, 1 H) 14.83 (s, 1 H). MS (ESI−) m/z 441 (M−H)−.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]#[C:33][CH3:34])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[CH2:31]([O:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([C:6]2([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][CH:18]=3)[CH2:8][CH2:7]2)(=[O:22])=[O:23])=[CH:25][CH:26]=1)[C:32]#[C:33][CH3:34]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(C#N)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(C#N)cc3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4-carboxylic acid ethyl ester (4 g, 8.3 mmol) dissolved in THF:Methanol (60:30 ml) and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 1.8 g (48%); off white solid; MS: 441.9 (M+H)+.