Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:20](=[O:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][C:28]([CH3:48])([CH3:47])[CH2:29][CH2:30][N:31]1[C:36]2[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=2[C:34]([CH2:44][CH3:45])([CH2:42][CH3:43])[O:33][C:32]1=[O:46].[BH4-].[Li+]>C1COCC1.O.ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:26])[CH2:21][NH:27][C:28]([CH3:48])([CH3:47])[CH2:29][CH2:30][N:31]2[C:36]3[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=3[C:34]([CH2:44][CH3:45])([CH2:42][CH3:43])[O:33][C:32]2=[O:46])[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(O)C(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Reactant: CCC1(CC)OC(=O)N(CCC(C)(C)N)c2cc(F)ccc21
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CCC1(CC)OC(=O)N(CCC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3c2OCC(=O)N3)c2cc(F)ccc21
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 232 mg (0.649 mmol) of 6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 200 mg (0.649 mmol) of 1-(3-amino-3-methylbutyl)-4,4-diethyl-7-fluoro-1,4-dihydrobenzo[d][1,3]oxazin-2-one in absolute THF (5 mL) is stirred for 2.5 hours at RT. The mixture is cooled to 5° C., combined with 60 mg (2.755 mmol) lithium borohydride, heated to RT, and stirred for 1 hour. The mixture is again cooled to 5° C. and slowly diluted with 15 mL of water and 20 mL of dichloromethane. The phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried with sodium sulfate and concentrated by evaporation in vacuo. The residue is purified by column chromatography (silica gel, dichloromethane/MeOH 95:5). Yield: 257 mg (65%); HPLC-MS: Rt=16.5 min. (method A).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20]CC3C=CC=CC=3C)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:7]([C:29]23[O:36][CH2:35][C:32]([CH3:37])([CH2:33][O:34]2)[CH2:31][O:30]3)[CH:6]1[CH3:38])=[O:4].[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[CH3:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:7]([C:29]23[O:36][CH2:35][C:32]([CH3:37])([CH2:31][O:30]2)[CH2:33][O:34]3)[CH:6]1[CH3:38])=[O:4]
Reactant: CNC(=O)N1CCN(S(=O)(=O)c2ccc(OCc3ccccc3C)cc2)C(C23OCC(C)(CO2)CO3)C1C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CNC(=O)N1CCN(S(=O)(=O)c2ccc(O)cc2)C(C23OCC(C)(CO2)CO3)C1C
Yield: 100.9 %

Procedure:
To an ethanol (15 ml) solution of 4-[4-(2-methyl-benzyloxy)-benzenesulfonyl]-2-methyl-3-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-piperazine-1-carboxylic acid methylamide (1.9 g, 3.48 mmol) was added 10% palladium hydroxide on carbon (370 mg). The mixture was shaken under about 20 psi hydrogen gas for about 1.5 hours. The resulting mixture was filtered through Celite® and concentrated in vacuo to give 1.55 g of the title compound (compound of formula XLV).
Reaction SMILES: [N:1]#[C:2]Br.[C:4]1([CH:10]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][NH:14][CH2:13][CH2:12][NH:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[C:4]1([CH:10]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]([C:2]#[N:1])[CH2:13][CH2:12][NH:11]2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(C2NCCNCc3ccccc32)cc1
Reactant: N#CBr
Solvent: CO
Product: N#CN1CCNC(c2ccccc2)c2ccccc2C1
Reaction time: 3 h
Yield: 35.7 %

Procedure:
A solution of 6.87 g (63 mmol) of cyanogen bromide in 15 mL of methanol was added to a solution of 15 g (63 mmol) of 1,2,3,4,5,6-hexahydro-1-phenyl-2,5-benzodiazocine in 110 mL of methanol at 0°. The reaction was allowed to come to room temperature and stirred 3 hours. The reaction was stripped and the residue partitioned between ethyl acetate and water made slightly acidic with 6N HCl. The aqueous layer was made basic, extracted into ethyl acetate, dried, stripped and chromatographed on ten times its weight of silica gel, eluting with 1:9 ethyl acetate/dichloromethane. There was obtained 5.93 g of 6-phenyl-3,4,5,6-tetrahydro2,5-benzodiazocine-2(1H)-carbonitrile, mp 134°-135° from dichloromethane/ether/hexane.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]([OH:37])[CH2:21][NH:22][C:23]2([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[CH2:25][CH2:24]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]([OH:37])[CH2:21][NH:22][C:23]2([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)[CH2:25][CH2:24]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2
Reactant: O=c1ccc2c(C(O)CNC3(Cc4ccc(C(F)(F)F)cc4)CC3)ccc(OCc3ccccc3)c2[nH]1
Agent: [Pd]
Solvent: CO
Product: O=c1ccc2c(C(O)CNC3(Cc4ccc(C(F)(F)F)cc4)CC3)ccc(O)c2[nH]1

Procedure:
322 mg (0.63 mmol) 8-benzyloxy-5-{1-hydroxy-2-[1-(4-trifluoromethyl-benzyl)-cyclopropylamino]-ethyl}-1H-quinolin-2-one are dissolved in 10 mL methanol and hydrogenated in the presence of palladium on charcoal at 3 bar. The precipitated product is dissolved by adding methanol. The catalyst is separated off and the filtrate is evaporated down. The precipitated solid is filtered off and suspended in diethyl ether for further purification. Yield: 161 mg (61%); mass spectroscopy: [M+H]+=419.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([OH:11])[OH:10])=[CH:4][C:3]=1[F:13].C([O-])([O-])O[CH2:16][CH3:17].[C:20]1(C)C=CC=C[CH:21]=1>C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([O:10][CH2:16][CH3:17])[O:11][CH2:20][CH3:21])=[CH:4][C:3]=1[F:13]
Reactant: O=C(c1ccc(Br)c(F)c1)C(O)O
Reactant: CCOC([O-])[O-]
Reactant: Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: CCOC(OCC)C(=O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Yield: 93 %

Procedure:
To a solution of 1-(4-bromo-3-fluorophenyl)-2,2-dihydroxyethanone (3.5 g, 0.014 mol) in toluene (30 mL) was added ethyl orthoformate (5.8 mL, 0.035 mol) and p-toluenesulfonic acid (100 mg). The reaction was refluxed for 4 h. After cooled to RT, the mixture was diluted with ethyl acetate, washed with saturated NaHCO3 solution, water, and brine, dried over MgSO4, filtered and concentrated to give the product (4.0 g, 93%) which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH:25]3[CH3:30])[C:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]=3[N:23]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH2:31]1[CH2:35][O:34][CH2:33][CH2:32]1>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:16]3[CH2:17][CH2:18][N:19]([CH2:35][CH2:31][CH2:32][CH2:33][OH:34])[CH2:20][CH2:21][C:22]=3[N:23]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4C)n2)CCNCC3)cc1
Reactant: C1CCOC1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(CCCCO)CC3)cc1

Procedure:
During the synthesis of S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-d]azepin-2-yl)phenyl)urea (Step 3 of Example 286), the title compound sl (a white powder) was obtained as a by-product due to the oxidation of THF during long-term storage: 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J=8.6 Hz, 2H), 7.36 (d, J=8.7 Hz, 2H), 6.33 (s, 1H), 4.62 (m, 1H), 3.89-3.55 (m, 6H), 3.39-3.15 (m, 5H), 2.98-2.52 (m, 7H), 1.74 (m, 8H), 1.33-1.02 (m, 6H); LC-MS m/z=483 (M+H).
Reaction SMILES: [C:1]1([O:7][C:8](=[O:22])[NH:9][C:10]2[S:11][C:12]3[CH:18]=[C:17]([S:19][C:20]#[N:21])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:6]=CC=CC=1.[N:23]1(CCN)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[N:23]1([CH2:6][CH2:1][O:7][C:8](=[O:22])[NH:9][C:10]2[S:11][C:12]3[CH:18]=[C:17]([S:19][C:20]#[N:21])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: N#CSc1ccc2nc(NC(=O)Oc3ccccc3)sc2c1
Reactant: NCCN1CCOCC1
Product: N#CSc1ccc2nc(NC(=O)OCCN3CCOCC3)sc2c1

Procedure:
The 2-morpholin-4-ylethyl(6-thiocyanato-1,3-benzothiazol-2-yl)carbamate was prepared according to the method described in Example 9c, but using 654 mg of phenyl(6-thiocyanato-1,3-benzothiazol-2-yl)carbamate and 0.27 cm3 of 2-morpholin-4-ylethanamine. The residue obtained is chromatographed on an Analogix cartridge of 40 g of silica 15-40 μm, elution being carried out with a gradient of dichloromethane then 95/5 dichloromethane/methanol. 729 mg of 2-morpholin-4-ylethyl(6-thiocyanato-1,3-benzothiazol-2-yl)carbamate are thus obtained in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:13]=[C:14]3[CH:20]=[CH:19][NH:18][C:15]3=[N:16][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CC(N(C)C)=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:13]=[C:14]3[CH:20]=[CH:19][N:18]([S:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:31])=[O:30])[C:15]3=[N:16][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(c2cnc3[nH]ccc3c2)C1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 12.1 %

Procedure:
3-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-azetidine-1-carboxylic acid tert-butyl ester (56 mg, 0.2 mmol) was dissolved in DMA (2 ml) and cooled to 0° C. Sodium hydride (16 mg, 0.37 mmol, 55%) was added, and the reaction mixture was stirred for 30 minutes at 0° C. Benzenesulfonyl chloride (40 μl, 0.29 mmol) was added slowly to the reaction mixture. Stirring was continued for 3 hours. Water and ethyl acetate was added to the reaction mixture. The organic phase was extract three times with water. The organic phase was dried over magnesium sulphate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethylacetate:cylcohexane) to afford the title compound (10 mg, 12% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH:9]1[CH:14]=[N:13][CH:12]=[C:11]([CH2:15][OH:16])[CH:10]=1.[H-].[Na+]>O1CCOCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:16][CH2:15][C:11]2[CH:12]=[N:13][CH:14]=[CH:9][CH:10]=2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: OCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1cncc(OCc2cccnc2)n1

Procedure:
The title compound was prepared according to the procedure of example 4, step 1 starting from 2,6-dichloropyrazine (444 mg, 3.00 mmol), nicotinic alcohol (360 mg, 3.30 mmol) in dioxane (5 mL) and NaH (55% in oil, 144 mg, 3.30 mmol). The crude product, obtained as an oil (0.72 g), was used directly in the next step. MS m/z 221 (M)+.
Reaction SMILES: [CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19](CC(OC)=O)=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH2:27][CH3:28])[CH2:7][CH2:6]1)([CH3:3])[CH3:2].[OH-:29].[Na+].O.CC#N.[CH2:35]([OH:37])C>O1CCCC1>[CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([C:35]([OH:37])=[O:29])=[CH:20][CH:21]=3)=[CH:10][C:9]=2[CH2:27][CH3:28])[CH2:7][CH2:6]1)([CH3:2])[CH3:3]
Reactant: CCc1cc(C#Cc2ccc(CC(=O)OC)cc2)ccc1C1(OC(C)C)CC1
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: CCc1cc(C#Cc2ccc(C(=O)O)cc2)ccc1C1(OC(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
Using General Procedure I; a solution of methyl {4-[4-(1-isopropoxycyclopropyl)-3-ethyl-phenylethynyl]-phenyl}-acetate (Compound 96, 156.0 mg, 0.41 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up and isolation by HPLC (partisil 10-pac, 10% H2O/CH3CN) afforded 85.0 mg (57%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[N+:11]([O-])([O-:13])=[O:12].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=[N+]([O-])[O-]
Reactant: O=Cc1ccc(F)cc1Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=Cc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 0 °C
Yield: 89.7 %

Procedure:
A stirred solution of 2-chloro-4-fluorobenzaldehyde (1.0 g, 6.3 mmol) in conc. sulphuric acid (8 ml) at 0° C. under argon was treated portionwise with potassium nitrate (0.70 g, 6.9 mmol) and maintained at 0° C. for 30 minutes, before warming to room temperature over 1.5 hrs. The reaction mixture was added to well stirred ice/water (100 ml) and then extracted with ethyl acetate. The extract was dried and concentrated to leave the title compound as a pale yellow oil (1.15 g, 90%).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:31]([O:38][C:39](=[O:45])[C@H:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:31]([O:38][C:39](=[O:45])[CH:40]([NH:41][C:16]([C@@H:11]1[CH2:12][S:13][CH2:14][CH2:15][N:10]1[S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=1)(=[O:8])=[O:9])=[O:18])[CH:42]([CH3:44])[CH3:43])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)NC(C(=O)OCc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.8 %

Procedure:
0.301 g (1 mmol) of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.417 g (1.1 mmol) of L-valine benzyl ester p-toluenesulfonic acid salt, 0.227 g (1.2 mmol) of DCC and 0.122 g (1 mmol) of DMAP were dissolved in 30 mL of CH2Cl2, 0.2 ml (1.4 mmol) of TEA was added. The mixture was stirred for 24 h at room temperature. The solid was filtrated and the solvent was evaporated. The residual was dissolved in a suitable amount of ethyl acetate (20 ml) and then the mixture was filtered to remove insoluble substance. The ethyl acetate was added to 60 ml and then the liquid was washed with 10% NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. After the drying agent was removed and part of ethyl acetate was evaporated, the crude product was purified by flash column chromatography (eluent: CH2Cl2:CH3Cl=1:1) to obtain the product as a glassy solid (0.20 g).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:18]([CH3:21])[C:19]#[N:20])[CH:14]=[CH:15][C:16]=1[OH:17]>N1C=CC=CC=1>[C:1]([NH:10][C:11]1[CH:12]=[C:13]([CH:18]([CH3:21])[C:19]#[N:20])[CH:14]=[CH:15][C:16]=1[OH:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C#N)c1ccc(O)c(N)c1
Solvent: c1ccncc1
Product: CC(C#N)c1ccc(O)c(NC(=O)c2ccccc2)c1
Temperature: 100 °C

Procedure:
Benzoyl chloride (27.09 g., 0.19 mole.) was added, with cooling, during 20 minutes to a stirred solution of 2-(3-amino-4-hydroxyphenyl) propionitrile (28.35 g., 0.175 mole.) in dry pyridine (200 ml.) at 0°-3° C. After addition was complete, the mixture was heated at 100° C., for 1 hour. It was then evaporated under reduced pressure to yield crude 2-(3-benzamido-4-hydroxyphenyl) propionitrile as an oil.
Reaction SMILES: [CH3:1][C:2]12[C:8]([CH3:10])([CH3:9])[C:5]([C:11]([O:13][CH2:14][C@H:15]3[C@@H:17]([CH2:18][O:19][CH3:20])[C@@:16]3([CH3:35])[C:21]3[CH:30]=[CH:29][C:28]4[C:27]([CH3:32])([CH3:31])[CH2:26][CH2:25][C:24]([CH3:34])([CH3:33])[C:23]=4[CH:22]=3)=[O:12])([CH2:6][CH2:7]1)[O:4][C:3]2=[O:36].[CH3:37][C:38]12[C:44]([CH3:46])([CH3:45])[C:41]([C:47]([O:49][CH2:50][C@@H:51]3[C@H:53]([CH2:54][O:55][CH3:56])[C@:52]3([CH3:71])[C:57]3[CH:66]=[CH:65][C:64]4[C:63]([CH3:68])([CH3:67])[CH2:62][CH2:61][C:60]([CH3:70])([CH3:69])[C:59]=4[CH:58]=3)=[O:48])([CH2:42][CH2:43]1)[O:40][C:39]2=[O:72].[CH2:73](OCC1[C@H](CO)C1(C)C1C=CC2C(C)(C)CCC(C)(C)C=2C=1)C>>[CH3:1][C:2]12[C:8]([CH3:9])([CH3:10])[C:5]([C:11]([O:13][CH2:14][C@H:15]3[C@@H:17]([CH2:18][O:19][CH2:20][CH3:37])[C@@:16]3([CH3:35])[C:21]3[CH:30]=[CH:29][C:28]4[C:27]([CH3:32])([CH3:31])[CH2:26][CH2:25][C:24]([CH3:34])([CH3:33])[C:23]=4[CH:22]=3)=[O:12])([CH2:6][CH2:7]1)[O:4][C:3]2=[O:36].[CH3:37][C:38]12[C:44]([CH3:45])([CH3:46])[C:41]([C:47]([O:49][CH2:50][C@@H:51]3[C@H:53]([CH2:54][O:55][CH2:56][CH3:73])[C@:52]3([CH3:71])[C:57]3[CH:66]=[CH:65][C:64]4[C:63]([CH3:68])([CH3:67])[CH2:62][CH2:61][C:60]([CH3:70])([CH3:69])[C:59]=4[CH:58]=3)=[O:48])([CH2:42][CH2:43]1)[O:40][C:39]2=[O:72]
Reactant: COC[C@H]1[C@@H](COC(=O)C23CCC(C)(C(=O)O2)C3(C)C)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: COC[C@@H]1[C@H](COC(=O)C23CCC(C)(C(=O)O2)C3(C)C)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCOCC1[C@H](CO)C1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: CCOC[C@@H]1[C@H](COC(=O)C23CCC(C)(C(=O)O2)C3(C)C)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: CCOC[C@H]1[C@@H](COC(=O)C23CCC(C)(C(=O)O2)C3(C)C)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 50 %
Yield: 49 %

Procedure:
Following a procedure, similar to that for the preparations of Intermediates 8a and 9a but using Intermediate 6b as the starting material afforded Intermediate 8b (62 mg, 50% yield) and Intermediate 9b (60 mg, 49% yield) as colorless oils:
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C1(C)C=CC(S([N:28]=[N+:29]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[N+:28]=[N-:29])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CCOC(=O)Cc1ccc(S(=O)(=O)C2CC2)cc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(=[N+]=[N-])c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
Ethyl 2-(4-cyclopropylsulfonylphenyl)acetate [obtained as described in WO2004/072031 (40 g, 149.07 mmol)] was dissolved in dry acetonitrile (745 mL) under argon atmosphere. To the above solution para toluene sulfonyl azide (32.33 g, 163.97 mmol) was added, followed by DBU (33.40 mL, 223.6 mmol) in dropwise manner, and stirred for 30 min. Reaction mixture was poured in ice cold water (500 mL), solid obtained was filtered through buchner funnel and dried under vaccum which yielded ethyl 2-(4-cyclopropylsulfonylphenyl)-2-diazo-acetate (40 g).
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7][C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:19](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:20]>C(Cl)Cl>[C:1]([C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7][C:8]1[C:13]([N:14]=[C:19]=[S:20])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: CC(C)(C)c1ccccc1Oc1ncccc1N=C=S
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(2-tert-Butylphenoxy)-3-aminopyridine (Example 203b) (5.21 g, 21.5 mmol) and 1,1′-thiocarbonyldi-2(1H)-pyridone (5 g, 21.5 mmol) in DCM (100 mL) was stirred at rt for 18 h. The mixture was evaporated and the solid was dissolved in hexanes/DCM (50 mL, 9/1). The residual solid was removed by filtration and the solution was evaporated to provide the title compound as a brown solid. (M+H)+=285.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([C:13]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[C:9](F)=[N:10][CH:11]=1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([C:13]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[C:9]([NH:29][C:30]2[CH:35]=[N:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[N:10][CH:11]=1
Reactant: COc1ccc(N)cn1
Reactant: Cc1nc(-c2cc(C3OCCO3)cnc2F)c2ncn(C3CCCCO3)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Nc2ncc(C3OCCO3)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 77.8 %

Procedure:
6-(5-(1,3-Dioxolan-2-yl)-2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (4.557 g, 11.82 mmol) and 5-amino-2-methoxypyridine (1.507 g, 12.14 mmol) were dissolved in tetrahydrofuran (80 mL) and cooled in an ice water bath. Then, LiHMDS (Aldrich 1.0 M in THF, 36.0 mL, 36.0 mmol) was added via syringe over about 10 minutes. The reaction was stirred under nitrogen at 0° C. for 40 minutes, and then the reaction was treated with water (100 mL) and warmed to room temperature. The layers were separated, and the aqueous phase was extracted with DCM. The aqueous phase was diluted with brine and extraction with DCM was continued. The combined organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (600 mL fritted filter, about 3 inches of silica gel, 80:1 DCM/2N ammonia in MeOH to 50:1 DCM/2N ammonia in MeOH) to give 5-(1,3-dioxolan-2-yl)-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-amine (4.500 grams, 71% purity, 52% yield over two steps). MS MS (ESI pos. ion) m/z 446. Calculated exact mass for C23H23N7O3: 445 (M+—C2H4O). 1H NMR (CDCl3, 400 MHz) δ 12.69 (s, 1H), 9.91 (s, 1H), 8.44 (d, J=2.74 Hz, 1H), 8.41 (d, J=2.15 Hz, 1H), 8.29 (s, 1H), 8.23 (dd, J=8.80 Hz, 2.74 Hz, 1H), 6.79 (d, J=8.80 Hz, 1H), 5.94 (s, 1H), 5.87 (dd, J=10.56 Hz, 2.15 Hz, 1H), 4.24-4.17 (m, 3H), 4.12-4.05 (m, 2H), 3.96 (s, 3H), 3.88-3.79 (m, 1H), 2.91 (s, 3H), 2.19-2.00 (m, 3H), 1.93-1.77 (m, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]1[N:20]2[N:21]=[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[C:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[C:19]2[N:18]=[C:17]([CH3:38])[N:16]=1)=O)(C)(C)C.Cl.C(OCC)C>C(Cl)Cl.CO>[ClH:30].[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:22]1[C:23]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)=[C:19]2[N:18]=[C:17]([CH3:38])[N:16]=[C:15]([N:11]3[CH2:10][C@@H:9]4[CH2:14][C@H:12]3[CH2:13][NH:8]4)[N:20]2[N:21]=1
Reactant: Cc1nc(N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1nc(N2C[C@@H]3C[C@H]2CN3)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Reaction time: 8 h

Procedure:
To a solution of (1S,4S)-5-[7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (8A-1; 200 mg, 0.36 mmol) in methylene chloride (3 ml) and methanol (3 ml) was added 1M HCl in diethyl ether (1.8 ml, 1.8 mmol). After stirring overnight, the reaction was concentrated, in vacuo, and then triturated from diethyl ether to afford 9A-1 (180 mg, 96%) as a solid: +ESI MS (M+1) 451.3; 1H NMR (400 MHz, CD3OD) δ 7.48-7.36 (m, 4H), 7.32 (d, J=8.7 Hz, 2H), 7.26 (d, J=8.7 Hz, 2H), 4.64 (s, 1H), 3.68 (d, J=10.8 Hz, 1H), 3.55 (dd, J=10.8, 1.6 Hz, 1H), 2.58 (s, 3H), 2.41 br d, J=11.2 Hz, 1H), 2.18 (d, J=11.2 Hz, 1H).