Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([OH:20])[CH:11]=2)=[CH:4][N:3]=1.[CH2:21](Br)[CH:22]=[CH2:23]>>[CH2:21]([O:20][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([O:16][CH3:17])[C:13]=1[O:18][CH3:19])[CH2:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1)[CH:22]=[CH2:23]
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(O)c1OC
Reactant: C=CCBr
Product: C=CCOc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC

Procedure:
The title compound was prepared from 2,4-diamino-5-(3-hydroxy-4,5-dimethoxybenzyl)pyrimidine (20.0 g, 72.4 mmol) and allyl bromide by the procedure of Example 1A. Recrystallization from 95% ethanol gave title compound as white crystals (14.9 g); mp 160°-162°. Anal. Calcd for C16H20N4O3 : C, 60.74; H, 6.37; N, 17.71. Found: C, 60.94; H, 6.45; N, 17.62.
Reaction SMILES: [F:1][CH:2]([F:34])[C:3]1[C:7]([C:8]2[N:9](O)[C:10]3[C:16]4[CH:17]=[CH:18][N:19]=[CH:20][C:15]=4[NH:14][C:13]4[N:21]=[CH:22][CH:23]=[CH:24][C:12]=4[C:11]=3[N:25]=2)=[C:6]([CH3:27])[N:5]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[N:4]=1.CN(C)C(=O)C.P(OC(C)C)(OC(C)C)OC(C)C>O>[F:34][CH:2]([F:1])[C:3]1[C:7]([C:8]2[NH:9][C:10]3[C:16]4[CH:17]=[CH:18][N:19]=[CH:20][C:15]=4[NH:14][C:13]4[N:21]=[CH:22][CH:23]=[CH:24][C:12]=4[C:11]=3[N:25]=2)=[C:6]([CH3:27])[N:5]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[N:4]=1
Reactant: Cc1c(-c2nc3c(n2O)-c2ccncc2Nc2ncccc2-3)c(C(F)F)nn1C1CCCCO1
Agent: CC(C)OP(OC(C)C)OC(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1c(-c2nc3c([nH]2)-c2ccncc2Nc2ncccc2-3)c(C(F)F)nn1C1CCCCO1

Procedure:
A solution of 2-[3-(difluoromethyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]imidazo[4,5-d]dipyrido[2,3-b:4′,3′-f]azepin-3 (8H)-ol (1.94 g, 4.17 mmol) in N,N-dimethylacetamide (30 mL, 0.3226 mol) was heated at 160° C. for 2.5 hours with triisopropyl phosphite (4.0 mL, 0.0174 mol). The reaction was allowed to cool and then poured into 50 mL water. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The reaction was chromatographed on silica gel using 3% Et3N with ethyl acetate, and 3% MeOH/ethyl acetate to give the desired product. 1H NMR (CDCl3): δ 9.52 and 9.45 (brs, 1H), 7.87-8.11 (m, 4H), 6.74-7.61 (m, 3H), 6.10 and 6.13 (br s, 1H), 5.40 (dd, 1H), 4.11 (m, 1H), 3.71 (m, 1H), 2.80 (s, 3H), 2.44 (m, 1H), 2.17 (m, 1H), 1.95 (m, 1H), 1.60-1.80 (m, 3H). Mass spec(EI) m/z=450 (M+1).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([OH:17])=O)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH2:20]([O:22][C:23]([C:25]1[N:26]([CH2:37][CH3:38])[C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([N+:34]([O-])=O)=[CH:29][CH:28]=2)=[O:24])[CH3:21].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:20]([O:22][C:23]([C:25]1[N:26]([CH2:37][CH3:38])[C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([NH:34][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:17])=[CH:29][CH:28]=2)=[O:24])[CH3:21]
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2n1CC
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2n1CC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.4 %

Procedure:
4′-Trifluoromethyl-biphenyl-2-carboxylic acid (5.04 g, 18.95 mmol) and 1-ethyl-5-nitro-1H-indole-2-carboxylic acid ethyl ester (4.00 g, 17.23 mmol) were dissolved in DCM (100 mL). DIEA (8 g, 61.8 mmol) was added to the above mixture and the mixture was stirred at room temperature for 5 minutes. PyBroP (9.63 g, 20.67 mmol) was added to the above solution in one portion. The reaction mixture was stirred for another 3 hours. The precipitate was filtered off and washed with cold DCM to provide the title compound (4.59, 54.4%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH2:23]Br)=[CH:18][N:17]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1([CH3:35])[O:31][C:30](=[O:32])[CH:29]([CH3:33])[C:28](=[O:34])[O:27]1.C(N(CC)CC)C.O>CS(C)=O>[C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][C:29]2([CH3:33])[C:28](=[O:34])[O:27][C:26]([CH3:25])([CH3:35])[O:31][C:30]2=[O:32])=[CH:18][N:17]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(CBr)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC1C(=O)OC(C)(C)OC1=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(CC2(C)C(=O)OC(C)(C)OC2=O)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 107.6 %

Procedure:
2-[N,N-bis(tert-Butoxycarbonyl)amino]-5-bromomethyl-3-methyl-pyridin (1.6 g, 4.0 mmol) was added to a solution of 2,2,5-trimethyl-1,3-dioxane-4,6-dione (630 mg, 4.0 mmol) and triethylamine (0.58 mL, 4.2 mmol) in dimethyl sulfoxide (40 mL). The reaction mixture was stirred overnight and water (100 mL) was added. The mixture was extracted with EtOAc, the combined organic phases washed with water and brine and dried. Concentration under reduced pressure gave crude 2-[N,N-bis(tert-butoxycarbonyl)amino]-3-methyl-5-(2,2,5-trimethyl-4,6-dioxo-[1,3]dioxan-5-ylmethyl)-pyridin (2.06 g)
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2CC#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([OH:25])(=[O:24])[CH3:23].S(=O)(=O)(O)O.O>O>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:8]=2[CH2:23][C:22]([OH:25])=[O:24])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCc1c(-c2ccccc2)cccc1-c1ccccc1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1c(-c2ccccc2)cccc1-c1ccccc1
Yield: 76 %

Procedure:
A mixture of [1,1′;3′,1″]terphenyl-2′-yl-acetonitrile (0.78 g, 2.9 mmol) in 28 mL of 10:3:1 acetic acid/sulfuric acid/water was refluxed for 2 days The reaction mixture was cooled and diluted with water. The aqueous was extracted with diethyl ether, dried over magnesium sulfate and concentrated to give 1,1′:3′,1″-terphenyl-2′-ylacetic acid as a tan solid (0.64 g, 76%): MS (ESI) m/z 287.1 (M−H); MS (ESI) m/z 575.2 (2M−H); MS (ESI) m/z 333 (M+FA−H); HRMS calcd for C20H16O2, 288.1150. Found (ESI+), 289.12244; 1H NMR (DMSO-d6): δ 3.30 (s, 2H), 7.30-7.50 (m, 13H), 12.07 (br s, 1H); Anal. Calcd for C20H16O2: C, 83.31; H, 5.59. Found: C, 83.02; H, 5.35.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:53])[NH:19][CH2:20][C:21]([N:23]2[CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[CH:26]([S:35]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)(=[O:37])=[O:36])[CH2:25][CH:24]2[C:44](=[O:52])[NH:45][CH2:46][CH2:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:22])[CH:14]=[CH:15][CH:16]=1)=[O:10])C1C=CC=CC=1.C(O)C>[Pd].C(Cl)Cl.CO>[CH3:49][C:48]([CH3:51])([CH3:50])[CH2:47][CH2:46][NH:45][C:44]([CH:24]1[CH2:25][CH:26]([S:35]([N:38]2[CH2:39][CH2:40][O:41][CH2:42][CH2:43]2)(=[O:37])=[O:36])[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[N:23]1[C:21](=[O:22])[CH2:20][NH:19][C:18](=[O:53])[NH:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:9]([OH:10])=[O:8])=[O:52]
Reactant: CC(C)(C)CCNC(=O)C1CC(S(=O)(=O)N2CCOCC2)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(C(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)CCNC(=O)C1CC(S(=O)(=O)N2CCOCC2)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1
Yield: 83.3 %

Procedure:
A The process is performed as described in Example 2A, but starting with 3 g of (2RS,4SR,5RS)-1-{2-[3-(3-benzyloxycarbonylphenyl)ureido]acetyl}-5-(2-fluorophenyl)-4-morpholinosulphonyl-2-(3,3-dimethylbutyl)carbamoylpyrrolidine, 0.3 g of 10% palladium-on-charcoal and 100 cm3 of ethanol under a hydrogen atmosphere (130 kPa). After treatment, 2.2 g of (2RS,4SR,5RS)-3-(3-{2-[2-(3,3-dimethylbutyl)carbamoyl-5-(2-fluorophenyl)-4-morpholinosulphonyl-1-pyrrolidinyl]-2-oxoethyl}ureido)benzoic acid are obtained [Rf=0.25; eluent: methylene chloride/methanol (90/10)].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[C:12]([O:14][CH3:15])=[O:13].[C:16]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:16]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:21]=[CH:20][C:19]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][C:10]=2[Cl:11])[NH:7][CH:6]=[C:5]3[C:12]([O:14][CH3:15])=[O:13])=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(-c4ccccc4)cc3)cc12
Temperature: 110 °C
Yield: 32.4 %

Procedure:
A mixture of methyl 5-bromo-6-chloro-1H-indole-3-carboxylate (150 mg, 0.52 mmol), 4-biphenylboronic acid (113 mg, 0.57 mmol) and 2M aqueous potassium carbonate (2M, 1.04 mL, 2.08 mmol) in toluene (3.0 mL) and ethanol (1.0 mL) was degassed with nitrogen for 10 minutes. The reaction mixture was then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20.0 mg, 0.026 mmol) and heated at 110° C. for 2 h in a sealed reaction vessel, which caused the reaction to appear burnt orange. The reaction mixture was cooled to room temperature and poured into ethyl acetate and water. The layers were separated and the aqueous layer was back-extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The material was then dissolved in ethyl acetate and methanol then silica gel was added. The solvent was removed and the crude material adsorbed onto silica gel was added to a column of silica gel and eluted with ethyl acetate/heptanes (1:4 to 1:1) to give the desired product as a tan solid 61 mg (35% yield). MS (ES+) 362.5 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.53 (br. s., 1 H), 8.17 (s, 1H), 7.94 (d, J=2.15 Hz, 1H), 7.61-7.72 (m, 4H), 7.57 (d, J=6.05 Hz, 2H), 7.45 (t, J=7.61 Hz, 2H), 7.31-7.40 (m, 1H), 3.89 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:3]1.[CH2:12]([N:15]([CH2:24][CH2:25][CH3:26])[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1)[CH2:13][CH3:14].O>C1C=CC=CC=1>[CH2:24]([N:15]([CH2:12][CH2:13][CH3:14])[C:16]1[CH:17]=[CH:18][C:19]([CH:20]2[O:21][C:2]([CH3:1])([CH3:11])[N:3]=[C:4]2[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:22][CH:23]=1)[CH2:25][CH3:26]
Reactant: CC1(C)N=C1c1ccccc1
Reactant: CCCN(CCC)c1ccc(C=O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCN(CCC)c1ccc(C2OC(C)(C)N=C2c2ccccc2)cc1

Procedure:
10 g of 2,2-dimethyl-3-phenyl-2H-azirine and 10 g of 4-dipropylaminobenzaldehyde were exposed to light in 2 liters of benzene under an atmosphere of argon for 40 minutes with a mercury high-pressure lamp of 2000 watt in a ring-mantle vessel through an interposed filter fluid. The filter fluid contained 35 g of cupric sulfate pentahydrate per liter of water and had a layer thickness of 1 cm. Not only the reaction solution but also the filter solution were cooled during the exposure to light in that they circulated with aid of pumps through a heat-exchanger positioned outside the photoreactor. During the exposure to light the temperature of the reaction solution amounted to 26° C. measured outside the photoreactor.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]([OH:9])[C:6]2[O:10][CH:11]=[CH:12][C:5]=2[CH2:4]1)[CH3:2].[Br:13][C:14]1[C:15]([Cl:21])=[C:16](F)[CH:17]=[CH:18][CH:19]=1>>[Br:13][C:14]1[C:15]([Cl:21])=[C:16]([O:9][CH:7]2[CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][C:5]3[CH:12]=[CH:11][O:10][C:6]2=3)[CH:17]=[CH:18][CH:19]=1
Reactant: CCN1Cc2ccoc2C(O)C1
Reactant: Fc1cccc(Br)c1Cl
Product: CCN1Cc2ccoc2C(Oc2cccc(Br)c2Cl)C1

Procedure:
The same method as in Example 1 was conducted using 5-ethyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridin-7-ol (Reference Example 34) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-bromo-2-chloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [CH2:1]([C:8]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH2:30][OH:31])[CH2:9][O:10][CH2:11][C:12]1[CH:13]=[C:14]([C:26]([O:28]C)=[O:27])[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]#[N:25])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH2:1]([C:8]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH2:30][OH:31])[CH2:9][O:10][CH2:11][C:12]1[CH:13]=[C:14]([C:26]([OH:28])=[O:27])[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]#[N:25])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(COCC(CO)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(-c2ccccc2C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC(CO)(COCc1cc(C(=O)O)cc(-c2ccccc2C#N)c1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.4 %

Procedure:
To a solution of crude methyl 5-({2-benzyl-2-[(tert-butoxycarbonyl)-amino]-3-hydroxypropoxy}methyl)-2′-cyano-1,1′-biphenyl-3-carboxylate from step A (442 mg, 0.83 mmol) in 4 mL THF was added 1 N LiOH (1.25 mL, 1.25 mmol) and the reaction mixture was stirred at room temperature for 1.5 h. 1 N LiOH (1.25 mL, 1.25 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water, extracted with CH2Cl2 (3×), dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (90 g silica, 0->85% (0.5% HOAc in EtOAc)/hexanes) to provide 259 mg of 5-({2-benzyl-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropoxy}methyl)-2′-cyano-1,1′-biphenyl-3-carboxylic acid as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 8.13 (s, 1H), 7.84 (s, 1H), 7.81 (d, J=7.7 Hz, 1H), 7.70 (t, J=7.3 Hz, 1H), 7.57 (d, J=7.7 Hz, 1H), 7.51 (t, J=7.3 Hz, 1H), 7.30-7.16 (m, 5H), 4.98 (s, 1H), 4.69 (A of AB, d, J=12.0 Hz, 1H), 4.65 (B of AB, d, J=12.0 Hz, 1H), 3.77 (A of AB, d, J=12.0 Hz, 1H), 3.69 (B of AB, d, J=12.0 Hz, 1H), 3.59 (A of AB, d, J=9.3 Hz, 1H), 3.69 (B of AB, d, J=9.3 Hz, 1H), 3.17 (A of AB, d, J=13.8 Hz, 1H), 2.93 (B of AB, d, J=13.8 Hz, 1H), 1.44 (s, 9H).
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][C:10]([CH3:14])([OH:13])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:2]2[C:7]([C@H:8]3[CH2:12][CH2:11][C@:10]([OH:13])([CH3:14])[CH2:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:28][CH:27]=1)=[O:25]
Reactant: CC1(O)CCC(c2cccnc2F)C1
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: C[C@@]1(O)CC[C@H](c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)C1
Temperature: 180 °C

Procedure:
To a vial containing 3-(2-fluoropyridin-3-yl)-1-methylcyclopentanol (570 mg, 2.92 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (1043 mg, 4.38 mmol), and cesium carbonate (2378 mg, 7.30 mmol) was added NMP (5.389 mL) before sealing and purging the vessel of air with nitrogen. The reaction mixture was set to heated at 180° C. for 5 h with microwave irradiation. It was diluted with ethyl acetate and washed with 5 N NaOH. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to a brown oil. The crude mixture of diastereomers was purified by SFC to yield four compounds. MS (ESI, pos. ion) m/z: 414.2 (M+1). IC50 (uM) +++++.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][C:5]=1[CH2:17][S:18][C:19]([CH3:22])([CH3:21])[CH3:20].C([BH-](CC)CC)C.[Li+]>C1COCC1>[C:19]([S:18][CH2:17][C:5]1[CH:6]=[C:7]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=[CH:9][C:4]=1[CH2:3][OH:2])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=O)c1ccc(NC(=O)C(C)(C)C)cc1CSC(C)(C)C
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)SCc1cc(NC(=O)C(C)(C)C)ccc1CO
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To 2-tert-butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-benzoic acid methyl ester (3.83 g, 10.9 mmol) in THF (100 mL) at −10° C. was added lithium triethylborohydride (1M in THF; 24 mL, 24.0 mmol) slowly via syringe. The reaction was allowed to warm to room temperature and stirred for 45 minutes. Analytical LCMS indicated that starting material still remained, so the mixture was cooled to 0° C., and additional lithium triethylborohydride (1M in THF; 12 mL, 12.0 mmol) was added. The reaction was warmed to room temperature, but analytical LCMS indicated that starting material still remained. The mixture was cooled to 0° C. and additional lithium triethylborohydride (1M in THF; 5 mL, 5.0 mmol) was added. The reaction was stirred at room temperature for 1.5 hours, and then the mixture was worked-up and purified to give the title compound.
Reaction SMILES: [OH-].[Na+].O.C([O:6][C:7]([C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]=[C:11]2[N:21]=[C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)[S:23][C:10]=12)=[O:8])C>O1CCOCC1>[F:31][C:27]1([F:30])[CH2:28][CH2:29][N:24]([C:22]2[S:23][C:10]3[C:11]([N:21]=2)=[N:12][C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:14][C:9]=3[C:7]([OH:8])=[O:6])[CH2:25][CH2:26]1
Reactant: CCOC(=O)c1cc(-c2ccccc2)nc2nc(N3CCC(F)(F)CC3)sc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(-c2ccccc2)nc2nc(N3CCC(F)(F)CC3)sc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
An aqueous solution of 4 mol/L sodium hydroxide (1.55 mL, 6.20 mmol) and water (1 mL) were added to a solution of 2-(4,4-difluoropiperidino)-5-phenyl-7-thiazolo[4,5-b]pyridinecarboxylic acid ethyl ester (500 mg, 1.24 mmol) prepared above in 1,4-dioxane (5 mL), followed by stirring at room temperature for 3 hr. The reaction solution was concentrated, and a saturated aqueous solution of ammonium chloride was added to the residue. The precipitated crystals were collected by filtration, washed with water, and dried. The resulting crude crystals were subjected to recrystallization from acetic acid-water to obtain the title compound (442 mg, 1.18 mmol) as a yellow powder.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([NH:18][CH:19]=[N:20]2)=[C:16]([Cl:23])[N:15]=1.[C:24]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:29]=CC=C[CH:25]=1.C(O)(C)C>C1COCC1>[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:24]([CH3:29])[CH3:25])=[C:16]([Cl:23])[N:15]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
Add DEAD (4.7 g, 27.09 mmol) slowly to a solution of 2,6-dichloropurine (1, 5 g, 26.5 mmol), triphenylphosphine (11.75 g, 44.5 mmol) and isopropyl alcohol (2b, 10 ml) in THF (100 ml), and stir at room temperature for 24 hours. Concentrate the reaction mixture, dissolve the residue in DCM (20 ml) and filter to remove the unwanted solids. Load the filtrate onto a 90 gram silica gel column (Biotage), and elute with DCM/acetone (95:5). Concentrate the desired fractions to give 3.0 grams of 2,6-dichloro-9-isopropyl-9H-purine (3b).
Reaction SMILES: C([O:8][N:9]1[C@H:13]([CH:14]([CH3:16])[CH3:15])[CH2:12][C@@H:11]([N:17]([CH2:37][CH2:38][CH3:39])[S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:10]1=[O:40])C1C=CC=CC=1>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[OH:8][N:9]1[C@H:13]([CH:14]([CH3:16])[CH3:15])[CH2:12][C@@H:11]([N:17]([CH2:37][CH2:38][CH3:39])[S:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=3)=[CH:25][CH:26]=2)(=[O:20])=[O:19])[C:10]1=[O:40]
Reactant: CCCN([C@@H]1C[C@@H](C(C)C)N(OCc2ccccc2)C1=O)S(=O)(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: CCCN([C@@H]1C[C@@H](C(C)C)N(O)C1=O)S(=O)(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 98 %

Procedure:
N-[(3R,5S)-1-(Benzyloxy)-5-isopropyl-2-oxopyrrolidinyl]-N-propyl-4′-(trifluoromethyl)[1,1′-biphenyl]-4-sulfonamide (0.023 g, 0.040 mmoles, Example 28a) in 5.0 mL methanol was hydrogenated on 5% Pd/BaSO4 (0.005 g) at 1 atm H2 and 22° C. After 6 hours the solution was filtered through Celite and concentrated by rotary evaporation to afford 0.019 g (98% yield) of the title compound as a white solid. LC-MS (APCI) n/z 485 (M+1). 1H NMR (DMSO-d6) δ 9.90 (br s, 1H), 8.04 (d, J=8 Hz, 2H), 7.99 (d, J=8 Hz, 2H), 7.97 (d, J=8 Hz, 2H), 7.88 (d, J=8 Hz, 2H), 4.53 (dd, J1=8 Hz, J2=10 Hz, 1H), 3.62 (dt, J1=3 Hz, J2=9 Hz, 1H), 3.08–2.90 (sym m, 2H), 2.14–2.02 (sym m, 2H), 1.87 (ddd, J1=8 Hz, J2=9 Hz, J3=14 Hz, 1H), 1.67–1.49 (sym m, 2H), 0.86 (d, J=7 Hz, 3H), 0.80 (t, J=7 Hz, 3H) and 0.77 (d, J=7 Hz, 3H) ppm.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:8]=[CH:7][N:6]([C:9]2[CH:18]=[C:17]3[C:12]([NH:13][C:14](=[O:24])[CH:15]([C:19]([O:21]CC)=[O:20])[NH:16]3)=[CH:11][C:10]=2[Cl:25])[CH:5]=1.[C:26]1([N:36]=[C:37]=[O:38])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>>[Cl:25][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[N:6]1[CH:7]=[CH:8][C:4]([CH2:3][NH:2][C:37]([NH:36][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][CH:27]=3)=[O:38])=[CH:5]1)[N:16]=[C:15]([C:19]([OH:21])=[O:20])[C:14](=[O:24])[NH:13]2
Reactant: CCOC(=O)C1Nc2cc(-n3ccc(CN)c3)c(Cl)cc2NC1=O
Reactant: O=C=Nc1cccc2ccccc12
Agent: Cl
Product: O=C(NCc1ccn(-c2cc3nc(C(=O)O)c(=O)[nH]c3cc2Cl)c1)Nc1cccc2ccccc12
Yield: 22.5 %

Procedure:
Using the compound (200 mg, 519 μmol) of Example 5 and 1-naphthyl isocyanate (89.4 μl, 622 μmol) and through the process similar to Example 38, 57.1 mg of title compound were obtained as yellowish brown powder. Yield 22%.
Reaction SMILES: [BH4-].[Na+].[CH3:3][S:4]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11])(=[O:6])=[O:5].O>C(O)C>[CH3:3][S:4]([C:7]1[CH:8]=[C:9]([CH2:10][OH:11])[CH:12]=[CH:13][CH:14]=1)(=[O:5])=[O:6]
Reactant: CS(=O)(=O)c1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaBH4 is added to a solution of 750 mg (4.08 mmol) 3-methanesulphonyl-benzaldehyde in 20 ml ethanol (see P. L. Ornstein, T. J. Bleisch, M. B. Arnold, R. A. Wright, B. G. Johnson, J. P. Tizzano, D. R. Helton, M. J. Kallman, D. D. Schoepp, M. Herin, J. Med. Chem. 1998, 41(3), 358-378 or B. Eistert, W. Schade, H. Selzer, Ber. 1964, 97(5), 1470-81). The reaction mixture is stirred at room temperature for 1 h. The reaction mixture is poured into water and extracted three times with ethyl acetate. The combined organic layers are washed with water and brine, dried, filtered and concentrated in vacuo to afford the title compound, used in the next step without further purification.