Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([CH:7]=[C:8]([Br:12])[C:9]=1[O:10][CH3:11])[CH:5]=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C>[Br:12][C:8]1[C:9]([O:10][CH3:11])=[C:2]([Br:1])[C:3]2[O:13][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5][C:4]=2[CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: COc1c(Br)cc(C=O)c(O)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Br)c(OC)c(Br)c2o1
Temperature: 80 °C
Reaction time: 6 h
Yield: 79.3 %

Procedure:
16 g (51,6 mmol) of 3,5-dibromo-2-hydroxy-4-methoxybenzaldehyde (Biorg. Med. Chem. 1998, 6, 1153–1162) and 17.84 g (129 mmol) of potassium carbonate are initially introduced in DMF and 8.62 g (51.6 mmol) of ethyl bromoacetate are then added dropwise to the mixture. The latter is stirred at 80° C. for 6 hours and then poured onto ice water after having been cooled; the precipitate is filtered off with suction. The precipitate is washed with water and dried. 15.47 g (79%) of ethyl 5,7-dibromo-6-methoxy-1-benzofuran-2-carboxylate are obtained.
Reaction SMILES: [CH2:1]([Li])CCC.[CH:6]([C:8]1[N:12]([CH:13]([CH3:15])[CH3:14])[N:11]=[C:10]([C:16]([O:18][CH3:19])=[O:17])[CH:9]=1)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:13]([N:12]1[C:8]([CH:6]=[CH2:1])=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11]1)([CH3:15])[CH3:14]
Reactant: COC(=O)c1cc(C=O)n(C(C)C)n1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cc(C(=O)OC)nn1C(C)C
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 262.7 %

Procedure:
A suspension of methyltriphenylphosphonium bromide (2.69 g, 7.52 mmol) in dry THF (40 mL) was cooled to −78° C. and n-butyllithium (1.6 M solution in hexane, 3.7 mL, 5.91 mmol) was added dropwise. The yellow-orange suspension was stirred at −78° C. for 50 min and then a solution of methyl 5-formyl-1-isopropyl-1H-pyrazole-3-carboxylate (prepared as described in WO 2011/020615, 1.05 g, 5.37 mmol) in dry THF (10 mL) was added dropwise. The mixture was stirred at −78° C. for 1.75 h, the cooling bath was removed and the mixture (off-white suspension) was stirred at rt for 1 h. The mixture was then partitioned between diluted aq. NaHCO3 solution (150 mL) and EA (150 mL). The aq. layer was extracted twice with EA (50 mL each) and the combined organic layer was washed twice with water (50 mL each) and concentrated without drying to give 2.74 g of a yellow oil which slowly crystallized. The crude product was purified by CC (preadsorption with CH2Cl2, hexane/EA 4:1) to give alkene 7a (590 mg, 57%) as a colorless oil. 1H NMR (DMSO-d6) δ: 7.02 (s, 1H), 6.87 (dd, J=17.3, 11.2 Hz, 1H), 5.94 (dd, J=17.3, 1.3 Hz, 1H), 5.45 (dd, J=11.2, 1.3 Hz, 1H), 4.80 (sept, J=6.6 Hz, 1H), 3.79 (s, 3H), 1.38 (d, J=6.6 Hz, 6H). C10H14N2O2 (194.23). LC-MS (ESI): 195 [M+H]+.
Reaction SMILES: CO[C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([Cl:13])[C:6]=1[Cl:14].[CH3:16][N:17]1[C:22](=[O:23])[CH:21]=[CH:20][C:19]([C:24]([OH:26])=O)=[CH:18]1>>[Cl:14][C:6]1[C:7]([Cl:13])=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=1[CH:4]([CH3:3])[C:24]([C:19]1[CH:20]=[CH:21][C:22](=[O:23])[N:17]([CH3:16])[CH:18]=1)=[O:26]
Reactant: COC(=O)Cc1ccc(OC)c(Cl)c1Cl
Reactant: Cn1cc(C(=O)O)ccc1=O
Product: COc1ccc(C(C)C(=O)c2ccc(=O)n(C)c2)c(Cl)c1Cl

Procedure:
The title compound was prepared in analogy to Example 189, steps 1-3, from (2,3-dichloro-4-methoxyphenyl)acetic acid methyl ester and 1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid. Colorless solid. MS (m/e)=340.1 [M+H+].
Reaction SMILES: [C:1]([NH:4][C:5](=[N:8][N+:9]([O-:11])=[O:10])SC)(=[O:3])[CH3:2].[NH2:12][CH2:13][C:14]1[S:18][C:17]([Cl:19])=[N:16][CH:15]=1>C(#N)C>[C:1]([NH:4][C:5]([NH:12][CH2:13][C:14]1[S:18][C:17]([Cl:19])=[N:16][CH:15]=1)=[N:8][N+:9]([O-:11])=[O:10])(=[O:3])[CH3:2]
Reactant: NCc1cnc(Cl)s1
Reactant: CSC(=N[N+](=O)[O-])NC(C)=O
Solvent: CC#N
Product: CC(=O)NC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a mixture of 0.22 g of N-acetyl-S-methyl-N'-nitroisothiourea and 5 ml of acetonitrile was dropwise added 0.2 g of 5-(aminomethyl)-2-chlorothiazole at -2° C. Stirring was continued at the same temperature for additional 1 hour, and then the reaction mixture concentrated. The residue solidified was recrystallized from ethanol to give 0.31 g of N-actyl-N'-(2-chloro-5-thiazolylmethyl)-N"-nitroguanidine (reference compound No. 5), mp 132°-133° C. NMR (CDCl3): 2.33(3H, s), 4.68(2H, d, J=6 Hz), 7.50(1H, s), 9.60(1H, br), 11.85(1H, br).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:9]([N:14]([CH2:22][CH2:23][CH3:24])C(=O)OC(C)(C)C)=[C:10]([S:12][CH3:13])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl.C(OCC)(=O)C.[OH-].[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[C:3]2[N:4]([C:9]([NH:14][CH2:22][CH2:23][CH3:24])=[C:10]([S:12][CH3:13])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CCCN(C(=O)OC(C)(C)C)c1c(SC)nc2c(Br)cc(C)cn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCCNc1c(SC)nc2c(Br)cc(C)cn12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
tert-Butyl N-[8-bromo-6-methyl-2-(methysulfanyl)imidazo[1,2-a]pyridin-3-yl]-N-propylcarbamate was dissolved in ethyl acetate (5 mL), then a 4N hydrochloric acid-ethyl acetate solution (10 mL) was added thereto at room temperature, and the mixture was stirred at room temperature for 20 hours. Under ice-cooling, a 5N aqueous sodium hydroxide solution was added to neutralize the solution, which was extracted with ethyl acetate. The organic layers were combined, which was dried over anhydrous magnesium sulfate, and evaporated, to give the title compound (103 mg) as a yellow amorphous.
Reaction SMILES: OS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([CH3:42])([CH3:41])[C:28]([CH:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:31]([O:33]CC)=O)=[O:29]>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:22]=1[C:27]([CH3:42])([CH3:41])[C:28](=[O:29])[C:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:31]2[OH:33]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccccc1F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1=C(O)c2cccc(F)c2C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A flask containing H2SO4 (12 mL, 219 mmol) and P2O5 (12 g, 88 mmol) was cooled in an ice-water bath for 20 minutes. To this viscous mixture was slowly added diethyl 2-(2-(2-fluorophenyl)-2-methylpropanoyl)malonate (7.1 g, 22 mmol). The ice bath was removed, and the mixture was stirred at room temperature for 1 hour before being poured over crushed ice and diluted with IPAc (100 mL). Water (50 mL) was added, and the resulting mixture was extracted with EtOAc (2×100 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo to afford a yellow oil that was further purified using flash chromatography (10% EtOAc/hexane, 2.5 g). MS (m/z)=279 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:21]2[CH2:25][CH2:24][C@@H:23]([OH:26])[CH2:22]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[N:19]([CH3:20])[N:18]=[N:17][N:16]=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N1C2N=C(C(C)(C)C)N=C(N3CCC(O)C3)C=2N=N1)C1C=CC=CC=1.ClCC1N(C)N=NN=1>>[C:1]([C:5]1[N:6]=[C:7]([N:21]2[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[N:19]([CH3:20])[N:18]=[N:17][N:16]=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nnnc1Cn1nnc2c(N3CC[C@@H](O)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(O)C2)c2nnn(Cc3ccccc3)c2n1
Agent: Cn1nnnc1CCl
Product: Cn1nnnc1Cn1nnc2c(N3CCC(O)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of (R)-1-(5-tert-butyl-3-((1-methyl-1H-tetrazol-5-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)pyrrolidin-3-ol (example 219, step b) 1-(3-Benzyl-5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-ol was hydrogenated and subsequently reacted with 5-(chloromethyl)-1-methyl-1H-tetrazole and isolated as light yellow oil. MS(m/e): 358.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28](O)=[O:29])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:31][NH:32][C@@H:33]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([N:32]([CH3:31])[C@@H:33]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34]5)=[O:29])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)cc1Cl
Reactant: CN[C@@H]1CCN(C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC[C@@H](N(C)C(=O)c2ccc3c(n2)CCC2C3=NN(c3ccc(C#N)c(Cl)c3)C2C2CCCC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.5 %

Procedure:
In a dried reaction flask, 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (0.421 g, 1.0 mmol), (R)—N,1-dimethylpyrrolidine-3-amine (0.308 g, 2.697 mmol), DIEA (0.4 mL, 2.30 mmol), and HATU (0.836 g, 2.2 mmol) were added to a mixed solvent of DMF (3 mL) and dichloromethane (6 mL). The mixture was stirred at room temperature for 18 hr and was concentrated under reduced pressure. Water was added to the residue. The mixture was washed with water, and was purified by a preparative chromatography to produce a purified product as pale yellow solid (80 mg) in 15.5% yield.
Reaction SMILES: CO[C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[C:14]([F:17])([F:16])[F:15].[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][NH:19][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:5]=1[C:14]([F:15])([F:16])[F:17]
Reactant: NCc1ccccn1
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Product: O=C(NCc1ccccn1)c1ccc(C(F)(F)F)cc1C(F)(F)F
Yield: 60.8 %

Procedure:
5.4 g of 2,4-bis(trifluoromethyl)benzoic acid methyl ester and 2.5 g of 2-aminomethylpyridine were heated to 160°-180° C for 6 hours. After cooling, the product was recrystallized from toluene. 4.2 g (64% of theory) of N-(pyrid-2-ylmethyl)-2,4-bis(trifluoromethyl)benzoic acid amide of melting point 112°-113° C were thus obtained.
Reaction SMILES: Cl.Cl.[N:3]1([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[C:17]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:18][C:19]4[C:24]([C:25]=3[C:26](O)=[O:27])=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:35][C@H:36]([NH2:41])[C:37]([CH3:40])([CH3:39])[CH3:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[CH3:35][C@H:36]([NH:41][C:26]([C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:16]=1[CH2:15][N:12]1[CH2:11][CH2:10][CH:9]([N:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:14][CH2:13]1)=[O:27])[C:37]([CH3:40])([CH3:39])[CH3:38]
Reactant: O=C(O)c1c(CN2CCC(N3CCCCC3)CC2)c(-c2ccccc2)nc2ccccc12
Reactant: C[C@H](N)C(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)c1c(CN2CCC(N3CCCCC3)CC2)c(-c2ccccc2)nc2ccccc12)C(C)(C)C
Yield: 60.2 %

Procedure:
539 mg (0.94 mmol) of 3-[1,4′]bipiperidinyl-1′-ylmethyl-2-phenyl-quinoline-4-carboxylic acid dihydrochloride (compound of Description 6), 202 microliters (1.5 mmol) of (S)-1,2,2-trimethyl-propylamine (Lancaster), 570 mg (1.5 mmol) of HBTU, 610 microliters (4.4 mmol) of triethylamine were dissolved in 12 ml THF and 8.5 ml of CH2Cl2 and the mixture was refluxed for 18 h. The solvent was concentrated, the residue was dissolved in methylene chloride, washed with water, then with 0.5 N aqueous NaOH, again with water, and the organic phase was dried over MgSO4. After concentration of the solvent, the residue was purified by flash chromatography over 40 g of silicagel (eluent EtOAc/MeOH/NH4OH:90/10/0.1), affording 290 mg (yield 56%) of the title compound as a beige amorphous solid.
Reaction SMILES: Cl[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][OH:16])[CH:10]=1.[H-].[Na+]>CN1CCCC1=O>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=2)[CH:10]=1
Reactant: OCc1cccnc1
Reactant: Nc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Nc1nccnc1OCc1cccnc1
Yield: 79.7 %

Procedure:
Prepared as for Example 121a using 3-chloro-2-aminopyrazine (0.5 g), pyridine-3-methanol (0.42 g) and sodium hydride (0.31 g of a 60% dispersion in oil) in N-methylpyrrolidinone (5 mL) to afford the sub-titled compound as a solid (0.62 g).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].[Cl:12][C:13]1[CH:14]=[C:15]([C:19]#[C:20][C:21]2[CH:22]=[CH:23][C:24]([F:28])=[C:25]([NH2:27])[CH:26]=2)[CH:16]=[N:17][CH:18]=1>ClCCl>[Cl:12][C:13]1[CH:14]=[C:15]([C:19]#[C:20][C:21]2[CH:22]=[CH:23][C:24]([F:28])=[C:25]([NH:27][S:8]([CH3:7])(=[O:10])=[O:9])[CH:26]=2)[CH:16]=[N:17][CH:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(C#Cc2cncc(Cl)c2)ccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(C#Cc2cncc(Cl)c2)ccc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.5 %

Procedure:
Add pyridine (193 mg, 2.44 mmol) followed by methanesulfonyl chloride (127 mg, 1.11 mmol) to a solution of 5-(5-chloropyridin-3-ylethynyl)-2-fluorophenylamine, (prepared as described in EXAMPLE 190), (275 mg, 1.11 mmol) in dichloromethane (10 mL) at 0° C. under nitrogen. Warm to room temperature and stir 20 h. Add additional methanesulfonyl chloride (32 mg, 0.28 mmol). Stir at room temperature for 2 h. Concentrate and purify by silica gel chromatography, eluting with 3:1 ethyl acetate:hexanes, to give the title compound as a white solid (330 mg, 92%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[C:30]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][CH:31]=1>>[C:30]1([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:31]=[CH:32][C:33]([CH2:36][NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:17]4[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])[CH:5]=[CH:6][CH:7]=2)=[CH:34][CH:35]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(NCc2ccc(-c3ccccc3)cc2)c1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and biphenyl-4-carbaldehyde according to the procedure of Example 66. MS (ES) m/z 559.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[CH2:14][CH2:15][C:16](OC)=[O:17].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[CH2:14][CH2:15][CH2:16][OH:17]
Reactant: COC(=O)CCc1cnoc1-c1ccc(Cl)cc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1cnoc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
To a solution of methyl 3-[5-(2,4-dichlorophenyl)-4-isoxazolyl]propionate (2.00 g) in tetrahydrofuran (30 ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution, 15 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-[5-(2,4-dichlorophenyl)-4-isoxazolyl]propan-1-ol (1.67 g, yield 92%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). NMR (CDCl3) δ: 1.20–1.32 (1H, br t), 1.70–1.88 (2H, m), 2.44–2.60 (2H, m), 3.56–3.70 (2H, m), 7.35–7.39 (2H, m), 7.53–7.57 (1H, m), 8.27 (1H, s).
Reaction SMILES: C([O:8][C@@:9]1([C:36]([F:39])([F:38])[F:37])[CH2:33][C@H:13]2[CH2:14][CH2:15][CH2:16][C:17]3[C:18](=[CH:19][C:20]4[CH:21]=[N:22][N:23]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)[C:24]=4[CH:25]=3)[C@:12]2([C:34]#N)[CH2:11][CH2:10]1)C1C=CC=CC=1.CC(C[AlH]CC(C)C)C.[BH4-].[Na+].C1C[O:54]CC1>>[F:32][C:29]1[CH:28]=[CH:27][C:26]([N:23]2[C:24]3[CH:25]=[C:17]4[CH2:16][CH2:15][CH2:14][C@@H:13]5[CH2:33][C@:9]([C:36]([F:37])([F:38])[F:39])([OH:8])[CH2:10][CH2:11][C@@:12]5([CH2:34][OH:54])[C:18]4=[CH:19][C:20]=3[CH:21]=[N:22]2)=[CH:31][CH:30]=1
Reactant: N#C[C@@]12CC[C@](OCc3ccccc3)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Reactant: C1CCOC1
Agent: CC(C)C[AlH]CC(C)C
Agent: [BH4-]
Agent: [Na+]
Product: OC[C@@]12CC[C@](O)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of (3R,4aR,12bS)-3-(benzyloxy)-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carbonitrile (33, R1=4-Fluorophenyl, R3=Trifluoromethyl) (79 mg, 0.158 mmol) was dissolved in THF (2 mL) and cooled to about 0° C. under nitrogen. The mixture was treated dropwise with DIBAL-H (1M in cyclohexane, 0.90 mL, 0.90 mmol). The reaction was stirred at about 0° C. for about 2 h, then quenched by addition of 6% acetic acid in sat. aq. sodium acetate solution (3 mL). The reaction was concentrated to about 3 mL volume and extracted with DCM (2×20 mL). The organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Intermediate LC/MS, method 3, Rt=3.14 min, MS m/z 537 (M+H)+. The residue was dissolved in EtOH (3 mL) and treated with NaBH4 (18 mg, 0.47 mmol) at rt for about 1 h. The reaction was quenched with aq. NH4Cl solution (2 mL) and stirred about 15 min at rt. The mixture was further diluted with water (2 mL) and extracted with DCM (2×5 mL). The combined DCM layers were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure to yield (3R,4aR,12bS)-9-(4-fluorophenyl)-12b-(hydroxymethyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol), (37, R1=4-Fluorophenyl, R3=Trifluoromethyl) (85 mg, 100%) as a glass: LC/MS, method 3, Rt=3.02 min, MS m/z 539 (M+H)+. The residue was used in step #2 without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7](=O)[CH2:8][CH3:9])[O:4][N:3]=1.[CH3:11][C:12]([S@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:1][C:2]1[CH:6]=[C:5](/[C:7](=[N:17]/[S:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])/[CH2:8][CH3:9])[O:4][N:3]=1
Reactant: CCC(=O)c1cc(Br)no1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: ClCCl
Product: CC/C(=N\S(=O)C(C)(C)C)c1cc(Br)no1
Temperature: 45 °C
Reaction time: 24 h

Procedure:
To a solution of 1-(3-bromo-isoxazol-5-yl)-propan-1-one (452 mg, 2.22 mmol) and (R)-(+)-2-methyl-2-propanesulfinamide (342 mg, 2.82 mmol) in CH2Cl2 (5 mL) was added titanium (IV) isopropoxide (1.4 mL, 4.9 mmol) and the mixture was warmed at 45° C. After 24 hours, the reaction was monitored by LC-MS, and the solvent was concentrated in vacuo and the remaining residue was diluted with EtOAc (32 mL) and saturated aqueous NaCl (8 mL) was added. The heterogeneous mixture was filtered through a pad of diatomaceous earth. The EtOAc layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc in heptane to afford 2-methyl-propane-2-sulfinic acid [1-(3-bromo-isoxazol-5-yl)-prop-(E)-ylidene]-amide. MS m/z 307 (M), 309 (M+2).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:39][C:40]1[CH:41]=[CH:42][C:43]([CH3:62])=[C:44]([CH:61]=1)[O:45][C:46]1[N:51]=[C:50]2[S:52][C:53]([NH:55][C:56]([CH:58]3[CH2:60][CH2:59]3)=[O:57])=[N:54][C:49]2=[CH:48][CH:47]=1>N1C=CC=CC=1>[C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:39][C:40]1[CH:41]=[CH:42][C:43]([CH3:62])=[C:44]([O:45][C:46]2[N:51]=[C:50]3[S:52][C:53]([NH:55][C:56]([CH:58]4[CH2:60][CH2:59]4)=[O:57])=[N:54][C:49]3=[CH:48][CH:47]=2)[CH:61]=1)=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)Oc1cccc(C(=O)O)c1
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(OC(C)(C)C)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.8 %

Procedure:
To a solution of 3-tert-butoxybenzoic acid (64 mg, 0.330 mmol) in pyridine (3.0 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (125 mg, 0.330 mmol), and the mixture was stirred at room temperature for 10 min. N-[5-(5-Amino-2-methylphenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (102 mg, 0.30 mmol) was added to the obtained solution, and the mixture was stirred at 70° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate (100 mL)/tetrahydrofuran (10 mL), washed with 1% aqueous citric acid solution (100 mL), 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with diisopropyl ether to give the title compound (88 mg, 57%) as a colorless powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:10][N:9]=[C:8]([S:19][CH3:20])[N:7]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[C:6]([C:4]([OH:5])=[O:3])=[N:7][C:8]([S:19][CH3:20])=[N:9][CH:10]=1
Reactant: CCOC(=O)c1nc(SC)ncc1-c1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ncc(-c2ccccc2Cl)c(C(=O)O)n1
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of 3.00 g (9.72 mmol) 5-(2-chloro-phenyl)-2-methylsulfanyl-pyrimidine-4-carboxylic acid ethyl ester in 15 ml ethanol a solution of 0.58 g (14.5 mmol) NaOH in 15 ml was added at RT and the reaction solution was stirred for 1 hr. The pH of the solution was than adjusted to 1 by addition of 25% HCl. The resulting solution was extracted twice with 100 ml CH2Cl2/methanol (2:1). The combined organic phases were dried (MgSO4), filtered and evaporated. The residue was suspended in 20 ml diisopropylether, filtered and dried to give 2.40 g (88%) 5-(2-chloro-phenyl)-2-methylsulfanyl-pyrimidine-4-carboxylic acid as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[Br:23][C:24]1[CH:25]=[C:26]2[CH2:32][C:31](=[O:33])[NH:30][C:27]2=[N:28][CH:29]=1>>[Br:23][C:24]1[CH:25]=[C:26]2[C:27]([NH:30][C:31](=[O:33])/[C:32]/2=[CH:21]\[C:3]2[NH:4][C:5]3[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[C:7](=[O:20])[C:6]=3[C:2]=2[CH3:1])=[N:28][CH:29]=1
Reactant: O=C1Cc2cc(Br)cnc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Product: Cc1c(/C=C2\C(=O)Nc3ncc(Br)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Yield: 60 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 10 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 10c obtained from step 3 of Example 10 and 5-bromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one as starting materials to obtain (Z)-2-(5-bromo-2-oxo-1,2-dihydro-pyrrolo[2,3-b]pyrid in-3-ylidenemethyl)-3-methyl-5-(2-morpholin-4-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 22 (59 mg, yield 60%) as an orange solid.