Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[CH3:7][C:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[N:20]=[C:21]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[O:22][C:23]=1[CH3:24])([CH3:11])[C:9]#[N:10]>CN(C)C=O>[CH3:11][C:8]([C:9]1[NH:10][N:3]=[N:2][N:1]=1)([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[N:20]=[C:21]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[O:22][C:23]=1[CH3:24])[CH3:7]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(-c2nc(CCCCCCOC(C)(C)C#N)c(C)o2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc(CCCCCCOC(C)(C)c3nnn[nH]3)c(C)o2)cc1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 55.6 %

Procedure:
Sodium azide (4.12 g) and 2.97 g of ammonium chloride were added to 27 ml of a solution of 2.70 g of 2-methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexyloxy}-propiononitrile in N,N-dimethylformamide, and stirred for 1.5 hours at 120° C. To the reaction solution was added ice-cold water, and extracted with ethyl acetate, washed with water and brine sequentially, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, chloroform: methanol=100:1 to 50:1) and recrystallized from isopropyl ether to provide 1.69 g of the objective compound as colorless crystals. M.p. 87° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[C:16]([C:32]([O:34]CC)=O)[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[CH3:37][N:38]([CH3:44])[CH2:39][CH2:40][CH2:41][CH2:42][NH2:43]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[C:16]([C:32]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][N:38]([CH3:44])[CH3:37])=[O:34])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=4)[C:19]=3[CH3:20])=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CN(C)CCCCN
Reactant: CCOC(=O)c1cc(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cc(C(=O)NCCCCN(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Yield: 58 %

Procedure:
Intermediate A and N,N-dimethylbutane-1,4-diamine were reacted together using an analogous method to that described in Step 1 of Example 1 to afford 5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-N-[4-(dimethylamino)butyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (139 mg, 58%) as a white solid; 1H NMR (500 MHz, DMSO) δ 1.40 (4H, dq), 1.74 (3H, s), 2.06 (6H, s), 2.15 (2H, t), 3.24 (2H, q), 6.72 (1H, d), 7.67-7.64 (2H, m), 7.71 (1H, d), 7.88-7.81 (2H, m), 7.95-7.89 (4H, m), 8.06 (1H, s), 9.30 (1H, t); APCI-MSm/z: 563[MH+]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([NH:26][C:27](=O)[O:28]C4C=CC=CC=4)[CH2:24][C:23]([CH3:37])([CH3:36])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.[NH2:38][NH2:39]>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([NH:26][C:27]([NH:38][NH2:39])=[O:28])[CH2:24][C:23]([CH3:37])([CH3:36])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:6][CH:7]=1
Reactant: CC1(C)CC(NC(=O)Oc2ccccc2)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Reactant: NN
Solvent: CCO
Product: CC1(C)CC(NC(=O)NN)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1

Procedure:
A solution of the product of Step A (77 mg, 0.14 mmol) and hydrazine (8.7 μL, 0.28 mmol) in 5.0 mL of EtOH was refluxed for 3 h. The reaction mixture was then concentrated to give the product, which was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:9][C:10]([CH2:12][NH:13][C:14]([C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[NH:26][C:27]([N:29]1[CH2:32][CH2:31][CH2:30]1)=[O:28])=[O:15])=[O:11])[C@@H:4]([OH:8])[CH2:5][CH2:6][CH3:7].[CH3:33][C:34]([CH3:38])([CH3:37])[CH:35]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:33][C:34]([CH3:38])([CH3:37])[CH2:35][NH:1][CH2:2][C@H:3]([NH:9][C:10]([CH2:12][NH:13][C:14]([C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[NH:26][C:27]([N:29]1[CH2:32][CH2:31][CH2:30]1)=[O:28])=[O:15])=[O:11])[C@@H:4]([OH:8])[CH2:5][CH2:6][CH3:7]
Reactant: CCC[C@H](O)[C@H](CN)NC(=O)CNC(=O)c1cc(C(F)(F)F)ccc1NC(=O)N1CCC1
Reactant: CC(C)(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCC[C@H](O)[C@H](CNCC(C)(C)C)NC(=O)CNC(=O)c1cc(C(F)(F)F)ccc1NC(=O)N1CCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.9 %

Procedure:
Azetidine-1-carboxylic acid (1S,2S)-(2-{[(1-aminomethyl-2-hydroxy-pentylcarbamoyl)-methyl]-carbamoyl}-4-trifluoromethyl-phenyl)-amide (165 mg, 0.35 mmol, see procedure 1b) was dissolved in dichloroethane (4 mL). The resultant solution was charged sequentially with trimethylacetaldehyde (20.5 mg, 0.2 mmol) and sodium triacetoxyborohydride (148 mg, 0.7 mmol), stirred for 3 h at RT, quenched with sat. NaHCO3, and extracted twice with EtOAc. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by reverse-phase HPLC to afford the title compound (55 mg) as a white powder after lyopholization. MS found: (M+H)+=530.5.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][CH:13]([CH2:16]OS(C4C=CC(C)=CC=4)(=O)=O)[O:12][C:8]3=2)[N:3]=1.[F:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32]2[C@@H:38]1[CH2:43][CH2:42][C@H:41]([NH2:44])[CH2:40][CH2:39]1>>[F:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32]2[C@@H:38]1[CH2:43][CH2:42][C@H:41]([NH:44][CH2:16][C@@H:13]2[O:12][C:8]3=[C:9]4[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14]2)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]4)[CH2:40][CH2:39]1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc4nc(C)ccc4c3O2)cc1
Reactant: N[C@H]1CC[C@@H](c2c[nH]c3ccc(F)cc32)CC1
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CN[C@H]1CC[C@@H](c2c[nH]c4ccc(F)cc42)CC1)O3

Procedure:
This compound was prepared in a manner similar to Example 1, using toluene-4-sulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.5 g, 1.29 mmol) and cis-4-(5-fluoro-1H-indol-3-yl)-cyclohexylamine (0.4 g, 1.72 mmol) to give 0.116 g (20%) product as an oxalate salt: MS (ESI) m/z 446 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[S:24][C:14]=2[N:15]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-dichlorobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:5])[C@H:2]([CH3:4])O.S(Cl)([Cl:23])(=O)=O>CN(C)C=O>[Cl:23][C@H:2]([CH3:4])[C:1]([O:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: C[C@H](O)C(=O)OC(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: C[C@@H](Cl)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: -40 °C

Procedure:
In 11 ml of dimethylformamide was dissolved 2.16 g of benzhydryl L-lactate. After cooling the solution to -40° C., 0.8 ml of sulfuryl chloride was added thereto followed by stirring for an hour. Thereafter the reaction solution was extracted with ethyl acetate and a sodium bicarbonate aqueous solution. The organic phase was washed with water, dried and then concentrated to dryness to give 1.8 g of benzhydryl (2R)-2-chloropropionate. This ester was reacted with 3.1 g of allyl (Z)-2-hydroxyimino-2-(2-tritylaminothiazol-4-yl)acetate prepared in a manner similar to the description of Published Unexamined Japanese Patent Application No. 149289/80 in 16 ml of dimethylsulfoxide overnight at room temperature in the presence of 1.8 g of potassium carbonate. The reaction solution was partitioned with ice water and ethyl acetate. The organic phase was washed with water, dried and concentrated. The residue was dissolved in 30 ml of methylene chloride. To the solution were added 182 mg of triphenylphosphine and 34 mg of tetrakistriphenylphosphine palladium. The mixture was stirred at room temperature for 30 minutes. Then, a solution of 1.26 g of potassium 2-ethylhexanoate in ethyl acetate. After stirring at room temperature for 2 hours, 45 ml of isopropyl ether was added and the mixture was allowed to stand overnight at 0° C. The obtained precipitates were partitioned in ethyl acetate-acidic water (pH 2.8). The organic phase was washed with water, dried and concentrated to give 2.13 g of 2-(2-tritylamino-thiazol-4-yl)-2-{(1S)-1-diphenylmethoxycarbonylethoxyimino}acetic acid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:23])[N:6]=1.[F:24][C:25]([F:40])([F:39])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1>>[F:24][C:25]([F:39])([F:40])[C:26]1[CH:27]=[C:28]([C:2]2[S:3][CH:4]=[C:5]([CH2:7][N:8]3[C:16]4[C:11](=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=4)[CH:10]=[C:9]3[CH3:23])[N:6]=2)[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1csc(Br)n1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1csc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 310D using 1-[(2-bromo-1,3-thiazol-4-yl)methyl]-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 311B) and [3,5-bis(trifluoromethyl)phenyl]boronic acid: MS (ES) m/z 534 (M+1).
Reaction SMILES: [O:1]1[C@H:3]([CH3:4])[CH2:2]1.[CH2:5]([Mg]Br)[CH2:6][CH2:7][CH:8]=[CH2:9]>C1COCC1>[CH3:4][C@@H:3]([OH:1])[CH2:2][CH2:9][CH2:8][CH2:7][CH:6]=[CH2:5]
Reactant: C[C@@H]1CO1
Reactant: C=CCCC[Mg]Br
Solvent: C1CCOC1
Product: C=CCCCC[C@@H](C)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.4 %

Procedure:
(R)-(+)-1,2-epoxypropane (1.12 ml, 16.0 mmol) is dissolved in dry THF (23 ml) and CuBr (230 mg, 1.6 mmol) is added therein, after which the temperature is reduced −78° C. The 1M 4-pentenylmagnesium bromide solution (23 ml, 23.5 mmol) prepared in the reaction (1) is added to reaction mixture. The temperature is gradually increased to a room temperature and the mixture is stirred for 4 hours. The reaction is finished with saturated NH4 Cl solution (10 ml). An obtained product is extracted with Et2O (20 ml×2) and it is washed by water (10 ml). An organic layer is dried using anhydrous MgSO4. The solution is vacuum concentrated, and then the compound (III) (1.3 g, 65%) is isolated using flash column chromatography (Et2O/n-pentene, 5:1, v/v):
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH-].[NH4+:14]>>[NH2:14][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1ncnc2ccc(I)cc12

Procedure:
500 mg of 4-chloro-6-iodo-quinazoline are treated with 30 ml of aqueous ammonium hydroxide solution and heated to reflux for 2 hours. After cooling the precipitated title compound is filtered and dried.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].[Br:17]Br>>[OH:1][C:2]1[C:6]([Br:17])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1O
Reactant: BrBr
Product: COC(=O)c1sc(-c2ccccc2)c(Br)c1O
Yield: 60.8 %

Procedure:
Prepared by the method described in Example 4 from methyl 3-hydroxy-5-phenyl-2-thiophenecarboxylate (5.0 g, 21 mmoles) and bromine (3.4 g, 21 mmoles). Recrystallization from methanol gave the product (4.0 g); mp 85°-87° C.
Reaction SMILES: [CH2:1]1[N:11]2[C:12]3[C:8]([C@H:9]4[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13][C@H:10]42)=[CH:7][CH:6]=[CH:5][C:4]=3[S:3](=[O:24])[CH2:2]1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:1]1[N:11]2[C:12]3[C:8]([C@H:9]4[CH2:16][NH:15][CH2:14][CH2:13][C@H:10]42)=[CH:7][CH:6]=[CH:5][C:4]=3[S:3](=[O:24])[CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cccc3c1N2CCS3=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S1CCN2c3c(cccc31)[C@H]1CNCC[C@H]12
Yield: 35.7 %

Procedure:
The title compound (28 mg, 17%) was prepared by treatment of tert-butyl(6bS,10aR)-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate 3-oxide (110 mg) with excess TFA in CH2Cl2 at 0 C. followed by treatment with 1 N aq. NaOH. 1H NMR (300 MHz, CDCl3) 1.79-1.99 (m, 1H), 2.10 (d, 1H, J=12.2 Hz), 2.39-2.57 (m, 1H), 2.72-3.01 (m, 3H), 3.01-3.22 (m, 2H), 3.22-3.51 (m, 3H), 3.61-3.72 (m, 1H), 6.69-6.89 (m, 1H), 7.17 (d, 1H, J=7.0 Hz), 7.42 (d, 1H, J=9.6 Hz) ppm; CI MS m/z=249 [C13H16N2OS+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH:20]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[CH:20]1([C:25]([NH:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([B:10]([OH:12])[OH:11])=[CH:8][CH:9]=2)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NCc1ccc(B(O)O)cc1
Reactant: O=C(Cl)C1CCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(B(O)O)cc1)C1CCCC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 83.4 %

Procedure:
Dissolve 4-aminomethylphenyl boronic acid hydrochloride (1.0 g, 5.34 mmol) in DCM (50 mL), add triethylamine (1.64 mL, 11.74 mmol) and cool the mixture to 0° C. Add cyclopentanecarbonyl chloride (778 mg, 5.78 mmol) and warm to room temperature. Stir the reaction mixture for 18 h, filter and wash the solid with DCM (10 mL) to give the title compound as a fine white powder (1.1 g, 83%).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:10]([NH:12][CH:13]1[N:19]=[C:18]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH3:30])[C:14]1=[O:31])=[O:11])=O)(C)(C)C.Cl>C(OCC)(=O)C>[NH2:8][C@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:10]([NH:12][C@@H:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH3:30])[C:14]1=[O:31])=[O:11]
Reactant: CN1C(=O)C(NC(=O)[C@@H](Cc2ccccc2)NC(=O)OC(C)(C)C)N=C(C2CCCCC2)c2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: CN1C(=O)[C@H](NC(=O)[C@H](N)Cc2ccccc2)N=C(C2CCCCC2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
3(R,S)-[2(R)-(tert-Butyloxycarbonyl)amino-3-phenylpropio nylamino]-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiaze pin-2-one (4.7 g, 9.1 mmol) was dissolved in ethyl acetate (20 ml) and cooled to 0° C. This solution was then saturated with hydrogen chloride gas. After 1 h 30 min, the resulting precipitate (which was shown to be the undesired diastereoisomer, Rf =0.04 ethyl acetate), was removed by filtration and the filtrate evaporated. The solid residue was partitioned between ethyl acetate (25m1) and 10% sodium carbonate solution (20 ml). The 25 organic phase was separated and the aqueous extracted with ethyl acetate (2×25 ml). The combined organic phases were dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica using a gradient elution of 0-20% methanol in ethyl acetate to afford the title compound (1.66 g, 44%, Rf =0.13 ethyl acetate) as a pale yellow solid. mp 100-103° C. 1H NMR (360 MHz, CDCl3) δ1.00-1,39 (4H, m), 1.50-1.72 (4H, m), 1.84-1.92 (1H, m), 2.00-2.07 (1H, m), 2.72-2.84 (1H, m), 2.79 (1H, dd, J=13.8 and 9.8 Hz), 3.28 (1H, dd, J=13.8 and 4.0 Hz), 3.40 (3H, s), 3.69 (1H, dd, J=9.8 and 4.1 Hz), 5.36 (1H, d, J=8.3 Hz), 7.21-7.36 (7H, m), 7.47-7.58 (2H, m), 8.66 (1H, d, J=8.3 Hz). [α]23 D +32.7°(c=0.58,CH3OH).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]([F:40])([F:39])[CH2:28][O:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1>CCCCCCC.CCOC(C)=O>[CH3:25][N:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[C:35]1[C:30]([O:29][CH2:28][C:27]([F:39])([F:26])[F:40])=[N:31][CH:32]=[CH:33][CH:34]=1)[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: OB(O)c1cccnc1OCC(F)(F)F
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1I
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1cccnc1OCC(F)(F)F

Procedure:
The title compound was prepared in analogy to example 72, from N-(4-iodo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 98, intermediate a) and 2-(2,2,2-trifluoroethoxy)pyridin-3-ylboronic acid (Combi-Blocks Inc.) and using a gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Colorless solid (58%). MS (ESI): m/z=524.103 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][Cl:7].[S:8](Cl)(Cl)(=[O:10])=[O:9]>N1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][N:4]([CH2:5][CH2:6][Cl:7])[SH:8](=[O:10])=[O:9]
Reactant: ClCCNCCCl
Reactant: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Product: O=[SH](=O)N(CCCl)CCCl

Procedure:
N,N-bis(2-chloroethyl)arylsulfonamide can be prepared from bis(2-chloroethyl)amine (10 mmol) and the corresponding sulfonyl chloride (10 mmole) in 50 ml dry pyridine at ambient temperature for 2 hours. Pyridine can be removed and the mixture can be extracted with EtOAc and water. The organic layer can be acidified with 0.1 N HCl, washed with water and dried. The desired N,N-bis(2-chloroethyl)sulfonamide is obtained in the form of an oil.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][NH:4][C:3]=1[CH2:9][O:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=1)[C:14]#[N:15].[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH3:1][C:2]1[C:7](=[O:8])[C:6]2[C:5](=[CH:1][CH:2]=[CH:3][CH:9]=2)[NH:4][C:3]=1[CH2:9][O:10][C:11]1[CH:12]=[C:13]([C:14]2[NH:29][N:28]=[N:27][N:15]=2)[CH:16]=[C:17]([O:19][CH2:20][CH:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[CH:18]=1
Reactant: Cc1c(COc2cc(C#N)cc(OCC3CCOCC3)c2)[nH]ccc1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(COc2cc(OCC3CCOCC3)cc(-c3nnn[nH]3)c2)[nH]c2ccccc2c1=O
Temperature: 100 °C
Reaction time: 24 h
Yield: 58.6 %

Procedure:
To a solution of 3-[(3-methyl-4-oxo-1,4-dihydropyridin-2-yl)methoxy]-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzonitrile (100 mg) in DMF (2 mL) were added sodium azide (18 mg) and ammonium chloride (15 mg), followed by stirring at 100° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a 1M aqueous sodium hydroxide solution and washed with diethyl ether. The aqueous layer was adjusted to a pH of 2 by adding 1M hydrochloric acid, followed by extraction with chloroform and a mixed solvent of chloroform-methanol (5:1). The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer chromatography (developer: chloroform/methanol=6/1) and washed with ethyl acetate to obtain 3-methyl-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)-5-(1H-tetrazol-5-yl)phenoxy]methyl}quinolin-4(1H)-one (37 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[CH:12]=2)[C:7]([CH2:18][CH3:19])=[N:6]1.[OH-].[K+:26]>C(O)C>[Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([O-:17])=[O:16])[CH:12]=2)[C:7]([CH2:18][CH3:19])=[N:6]1.[K+:26]
Reactant: CCc1nn(Cc2c(Cl)cccc2Cl)c2cc(CC(=O)O)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCc1nn(Cc2c(Cl)cccc2Cl)c2cc(CC(=O)[O-])ccc12

Procedure:
To a solution of the compound [140] (42 mg) in ethanol (1 mL) was added an aqueous solution of 1N-potassium hydroxide (116 μL) at room temperature, and the solution was concentrated under reduced pressure to give the titled compound (110 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10](=[O:12])[CH3:11].C[O-].[Na+].[C:16](OC)(=[O:21])[C:17]([O:19][CH3:20])=[O:18]>CO>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10](=[O:12])/[CH:11]=[C:16](\[OH:21])/[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)c1c(F)ccc(C)c1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)/C(O)=C/C(=O)c1c(F)ccc(C)c1Cl
Reaction time: 0.5 h

Procedure:
2′-chloro-6′-fluoro-3′-methylacetophenone (1.00 g, 5.36 mmol) was dissolved in 2.0 mL anhydrous methanol under N2 and subjected to the addition of 25% sodium methoxide in methanol (2.2 equiv, 11.8 mmol, 2.7 mL) via syringe. The nearly colorless solution was stirred for 30 min and then dimethyl oxalate (2.2 equiv, 11.8 mmol, 1.39 g) was added. The cloudy white mixture was stirred at 30° C. After 15 h, the cloudy white mixture was quenched with 2.0 mL 2 M HCl(aq) and extracted with 3×10 mL EtOAc. The light yellow organics were washed with 10 mL saturated brine solution, dried over anhydrous MgSO4 for 5 min, filtered, and concentrated in vacuo to afford a light yellow solid. Silica gel chromatography followed by recrystallization from hot hexanes/dichloromethane (ca. 5:1) afforded the desired product as analytically pure white needles (688 mg, 47% yield).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:19]=[C:12]2[N:13]=[C:14](Cl)[C:15]([CH3:17])=[CH:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O-:21].[Na+]>>[CH2:1]([S:8][C:9]1[N:19]=[C:12]2[N:13]=[C:14]([O:21][CH3:20])[C:15]([CH3:17])=[CH:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Cc1cn2nc(SCc3ccccc3)nc2nc1Cl
Agent: [Na+]
Product: COc1nc2nc(SCc3ccccc3)nn2cc1C
Yield: 64 %

Procedure:
This material was prepared in 64% yield by reaction of 2-benzylthio-5-chloro-6-methyl-1,2,4-triazolo[1,5-a]pyrimidine with sodium methoxide following the general procedure described in Example 22. The desired product was isolated as a solid, m.p. 145°-146° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH3:12].C1C(=O)N([Br:20])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:9])([F:10])[F:11])[C:3]=1[CH2:12][Br:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Br)cccc1C(F)(F)F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1cccc(Br)c1CBr
Temperature: 25 °C
Yield: 99 %

Procedure:
To a solution of 1-bromo-2-methyl-3-(trifluoromethyl)benzene (CXXVII) (5.7 g, 23.86 mmol) in CCl4 (50 mL) was added NBS (4.24 g, 23.86 mmol) and a catalytic amount of benzoyl peroxide. The reaction mixture was gently refluxed for 1 h. The reaction mixture was cooled to room temperature and the precipitate was removed by filtration. The solution was concentrated under reduced pressure and the crude product was dissolved in hexane and additional precipitate was removed by filtration. The filtrate was concentrated to dryness to give 1-bromo-2-(bromomethyl)-3-(trifluoromethyl)benzene (CXXVIII) as an orange oil (7.51 g, 23.62 mmol). 1H NMR (DMSO-d6) δ ppm 4.73 (s, 2H), 7.4 (dd, J=8 Hz, J=8 Hz, 1H), 7.80 (d, J=8 Hz, 1H), 8.02 (d, J=8 Hz, 1H); 19F NMR (DMSO-d6) δ ppm −57.85 (s, 3F). The crude product was used without further purification for step 2.