Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH:10]([OH:16])[CH2:11][O:12][CH2:13][CH2:14][OH:15])[CH:8]=[CH:9][C:2]1=2.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.Cl.C(OCC)C>N1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH:10]([OH:16])[CH2:11][O:12][CH2:13][CH2:14][O:15][S:23]([C:20]3[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=3)(=[O:25])=[O:24])[CH:8]=[CH:9][C:2]1=2
Reactant: OCCOCC(O)c1ccc2sccc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCCOCC(O)c2ccc3sccc3c2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 51.9 %

Procedure:
In 54 ml of pyridine was dissolved 9.0 g of 1-(benzo[b]thiophen-5-yl)-2-(2-hydroxyethoxy)ethanol. To the solution was added, at -25° C., 7.2 g of p-toluenesulfonyl chloride. The mixture was allowed to stand at 0°-5° C. for 24 hours and further at room temperature for 4 hours. The reaction mixture was added to a mixture of 103 ml of 6N hydrochloric acid, 50 ml of ice water and 100 ml of diethyl ether. The resulting mixture was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with 30 ml of diethyl ether. The extract was combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=10/1) to obtain 7.7 g of colorless oily 1-(benzo[b]thiophen-5-yl)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethanol.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Br:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.BrC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([F:48])=[C:44]([NH:49][C:50]([CH3:53])([CH3:52])[CH3:51])[N:43]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(Cl)(Cl)Cl>[Br:20][C:14]1[C:15]([F:19])=[C:16]([F:18])[CH:17]=[C:12]2[C:13]=1[N:41]([C:42]1[CH:47]=[CH:46][C:45]([F:48])=[C:44]([NH:49][C:50]([CH3:53])([CH3:52])[CH3:51])[N:43]=1)[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]2=[O:22]
Reactant: CC(C)(C)Nc1nc(N)ccc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Br)c1F
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Br)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2ccc(F)c(NC(C)(C)C)n2)c2c(Br)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.42 h

Procedure:
To 1 ml of chloroform solution of ethyl 3-ethoxy-2-(3-bromo-2,4,5-trifluorobenzoyl)acrylate prepared from 0.65 g of ethyl 3-bromo-2,4,5-trifluorobenzoylacetate by normal process was added 0.3 g of 2-amino-6-(t-butylamino)-5-fluoropyridine. The solution was concentrated under reduced pressure to obtain yellowish orange solid residue. To this residue were added 0.4 g of anhydrous potassium carbonate and 2 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 25 minutes and allowed to cool. The solution was separated by adding 25 ml of chloroform and 400 ml of distilled water, and the chloroform layer was washed with 400 ml of distilled water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. After adding 2 ml of ethanol, the solution was and allowed to stand. The precipitate was dispersed in ethanol and collected by filtration, and washed with ethanol and diisopropylether successively to obtain 0.53 g of the title compound as a pale yellow powder.
Reaction SMILES: C(Cl)(=O)C.[Si]([O:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([P:20]([CH3:23])([CH3:22])=[O:21])[CH:19]=1)(C(C)(C)C)(C)C>CO>[CH3:23][P:20]([C:18]1[CH:19]=[C:14]([CH2:13][OH:12])[CH:15]=[N:16][CH:17]=1)([CH3:22])=[O:21]
Reactant: CC(C)(C)[Si](C)(C)OCc1cncc(P(C)(C)=O)c1
Solvent: CO
Solvent: CC(=O)Cl
Product: CP(C)(=O)c1cncc(CO)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (0.044 ml, 0.625 mmol) was added to 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-(dimethylphosphoryl)pyridine (170 mg, 0.568 mmol) stirred in MeOH (1 ml) at 0° C. and the mixture was stirred at 0° C. for 1 h. The reaction was concentrated and left on high vac pump to dry. [5-(dimethylphosphoryl)pyridin-3-yl]methanol was taken on to next reaction crude. MS: cal'd 186 (MH+), exp 186 (MH+).
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]([NH2:31])=[NH:30])(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[NH2:31][C:29](=[NH:30])[NH:28][S:25]([C:22]1[CH:21]=[CH:20][C:19]([NH:18][CH:4]=[C:5]2[C:16]3[C:8](=[CH:9][CH:10]=[C:11]4[C:15]=3[S:14][CH:13]=[N:12]4)[NH:7][C:6]2=[O:17])=[CH:24][CH:23]=1)(=[O:27])=[O:26]
Reactant: N=C(N)NS(=O)(=O)c1ccc(N)cc1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Product: N=C(N)NS(=O)(=O)c1ccc(NC=C2C(=O)Nc3ccc4ncsc4c32)cc1
Yield: 26 %

Procedure:
The title compound was prepared in 26% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 4-amino-N-(amino-imino-methyl)-benzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ11.2 (d, 1H), 10.9 (s, 1H), 9.3 (s, 1H), 8.1 (d, 1H), 7.85 (d, 1H), 7.8 (d, 2H), 7.5 (d, 2H), 7.4 (d, 1H), 7.3 (d, 1H), 6.5 (d, 1H), 5.7 (s, 1H); C17H14N6O3S2: APCI−MS m/z 415 (M+H)+.
Reaction SMILES: [N:1]([C@H:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:17][C:18](=[O:34])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[N:20]=2)[CH2:6][C@H:5]1[NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[N+:2]=[N-:3].C.[C:44]([C:46]1[CH:50]=[CH:49][S:48][CH:47]=1)#[CH:45].C(N(CC)CC)C>O1CCOCC1.[Cu]>[F:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([F:33])[C:26]=1[C:21]1[N:20]=[C:19]([C:18]([NH:17][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:11]=2[N:7]2[CH2:8][C@H:9]([CH3:10])[C@H:4]([N:1]3[CH:45]=[C:44]([C:46]4[CH:50]=[CH:49][S:48][CH:47]=4)[N:3]=[N:2]3)[C@H:5]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:6]2)=[O:34])[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Reactant: C#Cc1ccsc1
Agent: [Cu]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[C@H]1CN(c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1cc(-c2ccsc2)nn1
Temperature: 100 °C
Yield: 48 %

Procedure:
In a high pressure vial was added tert-butyl (3R,4S,5S)-4-azido-1-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-5-methylpiperidin-3-ylcarbamate (1.0 equiv.), copper in charcoal (0.4 equiv.), 3-ethynyl thiophene (5.0 equiv.) and triethylamine (1.0 equiv.), in dioxane (0.09 M) to give a black suspension. The pressure tube was sealed and the mixture was stirred with heating to 100° C. overnight. The reaction was cooled to RT, filtered through celite, concentrated to yield tert-butyl (3R,4S,5S)-1-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-5-methyl-4-(4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl)piperidin-3-ylcarbamate in 48% yield. LC/MS (m/z)=691.2 (MH+), Rt=0.98 min.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:22])([F:21])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C@@H:15]2[CH3:20])=[CH:10][CH:9]=1)([OH:7])[CH3:6].C(N(CC)CC)C.[O:30]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31]1>C(Cl)Cl>[F:22][C:4]([F:3])([F:21])[C:5]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([S:35]([C:32]3[CH:33]=[CH:34][O:30][CH:31]=3)(=[O:37])=[O:36])[CH2:16][C@@H:15]2[CH3:20])=[CH:12][CH:13]=1)([OH:7])[CH3:6]
Reactant: C[C@H]1CNCCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Reactant: O=S(=O)(Cl)c1ccoc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CN(S(=O)(=O)c2ccoc2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 21.6 %

Procedure:
To a solution of 1,1,1-trifluoro-2-(4-((2S)-2-methyl-1-piperazinyl)phenyl)-2-propanol dihydrochloride (100 mg, 0.277 mmol) and triethylamine (0.115 mL, 0.830 mmol) in CH2Cl2 (4.0 mL) was added 3-furansulfonyl chloride (55.3 mg, 0.332 mmol, Ryan Scientific, Inc., Mt. Pleasant, S.C.). After 30 min at room temperature, the reaction was concentrated and purified via column chromatography (12 g of silica, 0 to 70% EtOAc in hexanes) to yield 1,1,1-trifluoro-2-(4-((2S)-4-(3-furanylsulfonyl)-2-methyl-1-piperazinyl)phenyl)-2-propanol (25 mg) as a mixture of two isomers.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][C:25]4=[C:26]([CH:49]=3)[N:27]=[C:28]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:29][C:30]([C:32](=[O:40])[N:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36])=[CH:31]4)=[CH:18][CH:17]=2)=[O:15])[CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[CH2:37]([N:33]([CH2:34][CH2:35][CH3:36])[C:32]([C:30]1=[CH:31][C:25]2[CH:24]=[CH:23][C:22]([C:19]3[CH:20]=[CH:21][C:16]([C:14]([N:11]4[CH2:12][CH2:13][C@@H:9]([OH:8])[CH2:10]4)=[O:15])=[CH:17][CH:18]=3)=[CH:49][C:26]=2[N:27]=[C:28]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:29]1)=[O:40])[CH2:38][CH3:39]
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CC[C@@H](O[Si](C)(C)C(C)(C)C)C4)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CC[C@@H](O)C4)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl (1E,4E)-8-(4-((R)-3-(tert-butyldimethylsilyloxy)pyrrolidine-1-carbonyl)phenyl)-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate (225 mg, 0.327 mmol) in THF (4 mL) at 0° C. was added a solution of TBAF (0.34 mL, 0.34 mmol, 1 M solution in THF). The resulting mixture was warmed to room temperature and stirred for 1.5 hr. The reaction mixture was diluted with EtOAc and washed with brine (2×). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude tert-butyl (1E,4E)-4-(dipropylcarbamoyl)-8-(4-((R)-3-hydroxypyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepin-2-ylcarbamate that was used directly without further purification. MS APCI (+) m/z 575 (M+1) detected.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14](=[O:21])[CH2:15][S:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:4][CH:3]=1.B.CSC>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:21])[CH2:15][S:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CSC(C)(C)C
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)CSC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-tert-butylsulfanyl-ethanone (1 eq.) was dissolved in THF and cooled to 0° C. Borane-dimethylsulfide (2 eq.) was added and the reaction was allowed to slowly warm to room temperature. After stirring for 2 hours the reaction mixture was concentrated then purified on silica gel to afford the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23](OC)=[O:24])=[N:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]([NH:34][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:24])=[N:20][CH:21]=3)=[CH:14][CH:15]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Reactant: NCc1ccccc1
Product: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1

Procedure:
reacting methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate with benzylamine to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[N+:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][S:35](Cl)(=[O:37])=[O:36])([O-:27])=[O:26]>>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:35]([CH2:34][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N+:25]([O-:27])=[O:26])(=[O:36])=[O:37])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: O=[N+]([O-])c1ccccc1CS(=O)(=O)Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)Cc3ccccc3[N+](=O)[O-])cc2)c2ccc3ccccc3c2N1
Yield: 41 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and (2-nitrophenyl)methanesulfonyl chloride, the title compound (yield 41%) was obtained in the same manner as that of Example 145.
Reaction SMILES: B(Cl)(Cl)Cl.C([O:12][N:13]1[C:19](=[O:20])[N:18]2[CH2:21][C@H:14]1[CH2:15][CH2:16][C@H:17]2[C:22]1[S:23][CH:24]=[N:25][N:26]=1)C1C=CC=CC=1.CO>C(Cl)Cl>[OH:12][N:13]1[C:19](=[O:20])[N:18]2[CH2:21][C@H:14]1[CH2:15][CH2:16][C@H:17]2[C:22]1[S:23][CH:24]=[N:25][N:26]=1
Reactant: O=C1N2C[C@@H](CC[C@H]2c2nncs2)N1OCc1ccccc1
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: O=C1N(O)[C@@H]2CC[C@@H](c3nncs3)N1C2
Temperature: 0 °C
Reaction time: 6 h
Yield: 80.8 %

Procedure:
BCl3 (1 M in CH2Cl2, 9.0 mL, 9.0 mmol) was added dropwise to a solution of (2S,5R)-6-(benzyloxy)-2-(1,3,4-thiadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (560 mg, 1.8 mmol) in dry CH2Cl2 (20 mL) at −78° C. The mixture was stirred under a N2 atmosphere at 0° C. for 6 hrs., then, MeOH (9 mL) was slowly added dropwise at −78° C. The solvents were evaporated under vacuum at 0° C. to give (2S,5R)-6-hydroxy-2-(1,3,4-thiadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (329 mg, 81%) as a yellow solid, which was used directly in the next step. ESI-MS (EI−, m/z): 227.1 [M+H]−.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15]Br)[CH:7]=1.[C:20]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[C:20]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:15][CH2:14][CH2:13][O:12][C:8]2[CH:7]=[C:6]([CH2:5][CH:4]([O:17][CH3:18])[C:3]([OH:2])=[O:19])[CH:11]=[CH:10][CH:9]=2)[CH:21]=1
Reactant: Oc1cccc(-c2ccccc2)c1
Reactant: COC(=O)C(Cc1cccc(OCCCBr)c1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COC(Cc1cccc(OCCCOc2cccc(-c3ccccc3)c2)c1)C(=O)O

Procedure:
The title compound was prepared from 3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester (Example 323, Step 1) and biphenyl-3-ol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) for C25H26O5 [M+Na]+: 429.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:21]=[C:20]2[C:11]([N:12]3[C:17]([CH2:18][O:19]2)=[N:16][NH:15][C:14](=[O:22])[C@H:13]3[CH3:23])=[CH:10][C:9]=1[C@H:24]([C:26]1([CH3:30])[CH2:29][NH:28][CH2:27]1)[CH3:25].C=O.[BH3-][C:34]#N.[Na+].C([O-])(O)=O.[Na+]>CC(O)=O.CO>[CH3:34][N:28]1[CH2:29][C:26]([C@@H:24]([C:9]2[CH:10]=[C:11]3[C:20](=[CH:21][C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[O:19][CH2:18][C:17]2[N:12]3[C@H:13]([CH3:23])[C:14](=[O:22])[NH:15][N:16]=2)[CH3:25])([CH3:30])[CH2:27]1
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c([C@@H](C)C4(C)CNC4)cc3N21
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c([C@@H](C)C4(C)CN(C)C4)cc3N21
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
To a solution of (R)-7-(2-fluoro-phenyl)-4-methyl-6-[(R)-1-(3-methyl-azetidin-3-yl)-ethyl]-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.04 g, 0.098 mmol) in AcOH (0.5 mL) and MeOH (5 mL) was added paraformaldehyde (0.029 g, 0.979 mmol) and the resulting mixture was stirred at ambient temperature for 1 h. NaBH3CN (0.015 g, 0.245 mmol) was added and the reaction mixture was stirred at ambient temperature overnight. Aqueous NaHCO3 (10 mL) was added and the aqueous solution was extracted with EtOAc (3×30 mL). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo and the residue was purified by prep-HPLC (Table 3, Method 25) to give (R)-6-[(R)-1-(1,3-dimethyl-azetidin-3-yl)-ethyl]-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.017 g, 40%). 1H NMR (CD3OD, 400 MHz): δ 7.40-7.48 (m, 1H), 7.15-7.32 (m, 3H), 6.91 (s, 1H), 6.84 (s, 1H), 4.83 (m, 1H), 4.58-4.69 (m, 2H), 2.87-3.19 (m, 3H), 2.73-2.87 (m, 2H), 2.10-2.22 (m, 3H), 1.50 (m, 3H), 1.25-1.35 (m, 3H), 1.13-1.23 (m, 3H). LC/MS (Table 1, Method 4) Rt=1.858 min; MS m/z: 423 [M+H]+. SFC (Table 1, Method 15) Rt=1.592 min.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[F:12].[CH:13]1(B(O)O)[CH2:15][CH2:14]1>>[CH:13]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[F:12])[CH2:15][CH2:14]1
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1ccc(Br)c(F)c1
Product: COC(=O)c1ccc(C2CC2)c(F)c1

Procedure:
The title compound was prepared from methyl 4-bromo-3-fluorobenzoate and cyclopropylboronic acid according to the procedure for the preparation of EXAMPLE 152, part A. 1H NMR (400 MHz, CDCl3): δ 0.77-0.81 (2H, m), 1.04-1.09 (2H, m), 2.12-2.16 (1H, m), 3.89 (3H, s), 6.88-6.92 (1H, m), 7.63-7.66 (1H, m), 7.69-7.72 (1H, m).
Reaction SMILES: [F:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([NH2:6])=[C:4]([O:12][CH3:13])[CH:3]=1.N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].Cl>O1CCCC1>[F:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([NH:6][S:21]([CH3:20])(=[O:23])=[O:22])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(F)c([N+](=O)[O-])cc1N
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cc(F)c([N+](=O)[O-])cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-fluoro-2-methoxy-5-nitroaniline (0.16 g) and pyridine (0.21 mL) in tetrahydrofuran (3 mL) was added methanesulfonyl chloride (0.074 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 hours, and then stirred at 50° C. overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/3) to give 5-fluoro-2-methanesulfonylamino-4-nitroanisole (0.1 g). This material was dissolved in N,N-dimethylformamide (3 mL). To the solution were added potassium carbonate (68 mg) and 2,3-difluoro-6-methoxybenzyl bromide (99 mg), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=½) to give 5-fluoro-2-[N-(2,3-difluoro-6-methoxybenzyl)-N-methanesulfonylamino]-4-nitroanisole (0.14 g). This material was dissolved in tetrahydrofuran (2 mL). To the solution was added 10% palladium-carbon powder (13 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=½) to give the title compound (80 mg).
Reaction SMILES: [N+]([N:4]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:10]2)=[N:5]1)([O-])=O.[N:16]1([CH2:22][CH2:23][NH2:24])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C1COCC1.C(OCC)(=O)C>[N:16]1([CH2:22][CH2:23][NH:24][C:12]2[C:11]3[C:6](=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[CH:9][CH:10]=3)[NH:5][N:4]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: NCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc2cn([N+](=O)[O-])nc2c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(NCCN3CCOCC3)n[nH]c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2,6-dinitro-2H-indazole (1 mmol) (prepared by nitration of 6-nitroindazole; Wrzeciono, et al., E. Pharmazie, 1980, 35, 593-596) in dry THF (4 mL) at 0° C., 2-morpholin-4-yl-ethylamine (2 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The contents were diluted with ethyl acetate (20 mL), washed with water (2×10 mL), and brine (10 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to yield 3-(2-morpholin-4-yl-ethylamino)-6-nitro-1H-indazole as a brown solid, which was reduced to 3-(2-morpholin-4-yl-ethylamino)-1H-indazol-6-ylamine by hydrogenation following general procedure F.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[N:4][C:3]=1[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([N:7]2[C:8]([CH3:12])([CH3:11])[CH2:9][O:10][C:29]2=[O:31])=[N:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([C:17]#[N:18])=[CH:19][CH:20]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(CO)Nc1nc(-c2ccc(C#N)cc2)c(Cl)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)COC(=O)N1c1nc(-c2ccc(C#N)cc2)c(Cl)s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
4-{5-Chloro-2-[(2-hydroxy-1,1-dimethylethyl)amino]-1,3-thiazol-4-yl}benzonitrile (0.93 g, 3.0 mmol), prepared in the previous step, was dissolved in methylene chloride (25 mL), triethylamine (4.15 mL, 30 mmol) was added and the mixture was cooled to 0° C. Triphosgene (1.79 g, 6.0 mmol) was added and the mixture was stirred for 2 h. The mixture was then diluted with methylene chloride, washed with 2N HCl, saturated NaHCO3, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (10% acetone/hexane) afforded the title compound (220 mg, 22%) as a pale yellow solid. HRMS: calcd for C15H12ClN3O2S+H+, 334.04115; found (ESI, [M+H]+), 334.04; HPLC purity 100% at 210-370 nm, 10.6 min; 100% at 244 nm, 10.6 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 mm.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:20][C:21]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:22]=1[C:23]([NH:25][NH2:26])=[O:24].C(O)(=O)C>CCO>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12](=[N:26][NH:25][C:23](=[O:24])[C:22]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:21]=1[F:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCC(=O)c1ccccc1
Reactant: NNC(=O)c1cc(F)ccc1F
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OCCCC(=NNC(=O)c1cc(F)ccc1F)c1ccccc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of 4-(tert-butyldimethylsilanyloxy)-1-phenylbutan-1-one (420 mg, 1.5 mmol) in EtOH (4 mL) was added 2,5-difluorobenzoic acid hydrazide (260 mg, 1.5 mmol) and acetic acid (0.07 mL, 1.2 mmol). After stirring the reaction mixture at 90° C. for 5 hours, more acetic acid (0.1 mL) was added. The mixture was stirred at 90° C. for 40 hours and then concentrated under reduced pressure. The mixture of starting material and product was carried forward without further purification.