Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[CH3:9][N:10]([CH3:14])[C:11](Cl)=[O:12].C(=O)([O-])O.[Na+]>CC(C)=O>[OH:8][C:3]1[CH:4]=[CH:5][C:6]([NH:7][C:11]([N:10]([CH3:14])[CH3:9])=[O:12])=[CH:1][CH:2]=1
Reactant: CN(C)C(=O)Cl
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CN(C)C(=O)Nc1ccc(O)cc1

Procedure:
This is made as described in British Patent Spectification No. 999 862. Thus, p-aminophenol (30 g), dimethylcarbamoyl chloride (30 g), sodium hydrogen carbonate (28 g), and dry acetone (600 ml) are stirred and heated under reflux for 3 hours. The mixture is filtered hot and the filtrate is allowed to cool overnight. The crystals which form are filtered off to give the desired urea, m.pt. 205° C. (decomp.). as measured on a Kofler bench (British Patent Specification No. 999 862 reports m.pt. 205°-206° C.).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[C:22]([NH:32][CH2:33][C:34](=[O:40])[CH2:35][CH2:36][C:37]([O-:39])=[O:38])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].[Cs+]>>[C:22]([NH:32][CH2:33][C:34](=[O:40])[CH2:35][CH2:36][C:37]([O:39][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:38])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]
Reactant: O=C(CCCCCCCCCCBr)OCc1ccccc1
Reactant: O=C([O-])CCC(=O)CNC(=O)OCc1ccccc1
Agent: [Cs+]
Product: O=C(CCC(=O)OCCCCCCCCCCC(=O)OCc1ccccc1)CNC(=O)OCc1ccccc1
Yield: 51.1 %

Procedure:
This compound was prepared from the product of 13a (0.96 g; 2.7 mmol) and 8b (1.0 g; 2.5 mmol) according to Procedure C. The crude product was purified on a 70×45 mm silica gel 60 column eluted with ethyl acetate-hexane (1:1) (1000 mL) collecting 13×50 mL fractions. The fraction containing the product (3) was evaporated and 0.69 g (47%) product was obtained (pinkish solid, mp 70-72° C.).
Reaction SMILES: C(OC1C=C(C(O)=O)C=CN=1)C.Cl.[Cl:14][C:15]1[CH:16]=[C:17]([NH:27][C:28](=[O:38])[C:29]2[CH:34]=[CH:33][N:32]=[C:31]([O:35][CH2:36][CH3:37])[CH:30]=2)[CH:18]=[CH:19][C:20]=1[C@H:21]1[O:26][CH2:25][CH2:24][NH:23][CH2:22]1>>[ClH:14].[Cl:14][C:15]1[CH:16]=[C:17]([NH:27][C:28](=[O:38])[C:29]2[CH:34]=[CH:33][N:32]=[C:31]([O:35][CH2:36][CH3:37])[CH:30]=2)[CH:18]=[CH:19][C:20]=1[C@@H:21]1[O:26][CH2:25][CH2:24][NH:23][CH2:22]1
Reactant: CCOc1cc(C(=O)Nc2ccc([C@@H]3CNCCO3)c(Cl)c2)ccn1
Agent: CCOc1cc(C(=O)O)ccn1
Agent: Cl
Product: CCOc1cc(C(=O)Nc2ccc([C@H]3CNCCO3)c(Cl)c2)ccn1

Procedure:
In analogy to Example 83, step a) using 2-ethoxy-4-pyridinecarboxylic acid (CAS 91940-86-2) instead of 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) and (−)-(S)-2-(4-Amino-2-chloro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (preparation described in example 91) instead of (+)-(R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester. Light yellow foam. MS (ISP): 362.0 ([M+H]+)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13](OC)=[O:14].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[F:18][C:2]([F:1])([F:17])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[CH2:13][OH:14]
Reactant: COC(=O)c1n[nH]c2ccc(OC(F)(F)F)cc12
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCc1n[nH]c2ccc(OC(F)(F)F)cc12
Temperature: -10 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
A solution of methyl 5-(trifluoromethoxy)-1H-indazole-3-carboxylate (0.370 g, 1.42 mmol) in THF (10 mL) was cooled to −10° C., and added dropwise with a 1 M solution of diisobutylaluminum hydride in toluene (5.11 mL, 5.11 mmol) over 5 minutes. The reaction mixture was stirred at −10° C. for 1 hour, and then stirred overnight at room temperature. The reaction mixture was added dropwise with saturated aqueous sodium sulfate under ice cooling to terminate the reaction, and then filtered through Celite. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain the objective [5-(trifluoromethoxy)-1H-indazol-3-yl]methanol (0.133 g, 40%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([NH:10][CH:11]([C:13]1[S:14][C:15]2[CH:21]=[C:20]([C:22](OC)=[O:23])[CH:19]=[CH:18][C:16]=2[N:17]=1)[CH3:12])(=[O:9])[CH3:8].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[OH:23][CH2:22][C:20]1[CH:19]=[CH:18][C:16]2[N:17]=[C:13]([CH:11]([NH:10][C:7](=[O:9])[CH3:8])[CH3:12])[S:14][C:15]=2[CH:21]=1
Reactant: COC(=O)c1ccc2nc(C(C)NC(C)=O)sc2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NC(C)c1nc2ccc(CO)cc2s1
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
To a suspension of lithium aluminum hydride (59.6 mg, 1.57 mmol) in THF (7 mL) was added dropwise a solution of methyl 2-[1-(acetylamino)ethyl]-1,3-benzothiazole-6-carboxylate (220 mg, 0.785 mmol) obtained in Reference Example 84 in THF (5 mL) under ice-cooling, and the mixture was stirred for 30 min. After completion of the reaction, sodium sulfate decahydrate (760 mg) was slowly added thereto, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the obtained residue was triturated with diisopropyl ether to give the title compound (142 mg, yield 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1)=[O:10].[N:19]1([CH2:25][CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.Cl>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[C:16]([NH:35][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH2:27][CH2:26][CH2:25][N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[CH:30][CH:31]=2)[N:15]=[CH:14][N:13]=1)=[O:10]
Reactant: O=C(Nc1cc(Cl)ncn1)Nc1ccccc1Cl
Reactant: Nc1ccc(OCCCN2CCOCC2)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(Nc1cc(Nc2ccc(OCCCN3CCOCC3)cc2)ncn1)Nc1ccccc1Cl
Temperature: 25 °C

Procedure:
A solution of 1-(2-chloro-phenyl)-3-(6-chloro-pyrimidin-4-yl)-urea (99 mg, 0.35 mmol), 4-(3-morpholin-4-yl-propoxy)-phenylamine [Chabrier et al. Bull. Soc. Chim. Fr. 1955; 1353] (83 mg, 0.35 mmol), and concentrated HCl (0.1 ml, 1.4 mmol) in ethanol (5 ml) was refluxed for 32 h. The reaction mixture is cooled to RT, and diluted with water. The acidic solution is washed with ethyl acetate, basified with aqueous ammoniac, and extracted with DCM. The combined organic phases are dried over sodium sulfate, evaporated in vacuo, the residue is crystallized from water/methanol/1 N HCl to afford the title compound.
Reaction SMILES: C=CC1C=CC=CC=1.C(C1C=CC=CC=1C=C)=C.[C:19]1([C:25]2[NH:26][C:27]3[C:32]([C:33]=2[CH2:34][CH2:35]OC2CCCCO2)=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC1C=CC(S([O-])(=O)=[O:51])=CC=1.C1C=C[NH+]=CC=1>ClCCCl.C(O)C>[C:19]1([C:25]2[NH:26][C:27]3[C:32]([C:33]=2[CH:34]([OH:51])[CH3:35])=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(-c2[nH]c3ccccc3c2CCOC2CCCCO2)cc1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: C=Cc1ccccc1C=C
Agent: c1cc[nH+]cc1
Solvent: ClCCCl
Solvent: C=Cc1ccccc1
Solvent: CCO
Product: CC(O)c1c(-c2ccccc2)[nH]c2ccccc12
Temperature: 70 °C

Procedure:
1-[4-Benzyloxycarbamoyl]phenoxymethyl-copoly(styrene- 1%-divinylbenzene)-2-phenyl-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole (7.87 g) was suspended in a mixture of DCE (125 ml) and ethanol (12.5 ml) containing PPTS (5.83 g) and warmed to 70° C. for 18 h. The resin was then filtered off and washed with DMF (4×25 ml), DCM (4×25 ml), MeOH (4×25 ml) and ether (25 ml). A portion of the recovered resin (100 mg) was then suspended in dry DMF (3.0 ml) containing 5% pyrrolidine and heated to 110° C. for 4 h. The resin was filtered off and the solvent removed from the filtrate under reduced pressure to afford 2-phenyl-1H-indol-3-ylethanol. 1H (360 MHz, CDCl3) δ3.21 (2H, t, J=7.0 Hz), 3.97 (2H, t, J=7.0 Hz), 7.13-7.22 (2H, m), 7.38 (2H, m), 7.45 (2H, m), 7.62 (3H, m) and 8.12 (1H, br s).
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[C:7]([CH3:15])=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10].[CH3:16]O>>[OH:5][C:6]1[C:7]([CH3:15])=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([O:11][CH3:16])=[O:10]
Reactant: CO
Reactant: Cc1c(O)cccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(O)c1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a methanol solution (25 mL) at 0° C. was dropwise added thionyl chloride (9.6 mL, 0.13 mol). After 15 minutes, 3-hydroxy-2-methylbenzoic acid (4 g, 0.033 mol) was added and the resulting mixture was stirred at room temperature for 24 hours. Volatile was removed under vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with water and saturated sodium chloride solution, and was dried over sodium sulfate. After concentration, the crude product was recrystallized from dichloromethane and hexane to gave 3.48 g of methyl 3-hydroxy-2-methylbenzoate.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:21]=[CH:20][C:16]3[O:17][CH2:18][O:19][C:15]=3[CH:14]=2)=[C:11]([NH2:22])[N:10]([CH3:23])[N:9]=1)(=O)C.[Na].[Cl-].[NH4+]>C(O)C.O>[NH2:22][C:11]1[N:10]([CH3:23])[N:9]=[C:8]([O:7][CH2:6][CH2:5][OH:4])[C:12]=1[C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[CH:14]=1
Reactant: CC(=O)OCCOc1nn(C)c(N)c1-c1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: Cn1nc(OCCO)c(-c2ccc3c(c2)OCO3)c1N
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To a solution of 2-{[5-amino-4-(1,3-benzodioxol-5-yl)-1-methyl-1H-pyrazol-3-yl]oxy}ethyl acetate (100 mg) (Preparation 33) in ethanol (6 ml) at room temperature, was added sodium hydroxyde (10 mg). After one hour, the reaction was diluted with water (5 ml ) and an aqueous saturated solution of ammonium chloride (10 ml ). The mixture was extracted with ethyl acetate (3×6 ml). The organic fraction was dried over sodium sulfate and concentrated under reduced pressure to yield the title compound as a white solid (85 mg).
Reaction SMILES: C(OC(N)=O)C1C=CC=CC=1.C(OC([NH:22][C:23]1([C:29](O)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=O)C1C=CC=CC=1.C(OC(NC1(CO)CCCCC1)=O)C1C=CC=CC=1.C(=O)([O-])N>>[NH2:22][C:23]1([CH2:29][OH:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(NC1(C(=O)O)CCCCC1)OCc1ccccc1
Agent: NC(=O)OCc1ccccc1
Agent: NC(=O)[O-]
Agent: O=C(NC1(CO)CCCCC1)OCc1ccccc1
Product: NC1(CO)CCCCC1

Procedure:
1-Amninocyclohexane-1-carboxylic acid was protected as the benzyloxycarbonylamine according to Method B1a, Step 1. 1-(Benzyloxycarbonylamino)cyclohexane-1-carboxylic acid was reduced to 1-(benzyloxycarbonylamino)-1-(hydroxymethyl)cyclohexane according to Method B1a, Step 2. The carbamate was deprotected according to Method B1a, Step 3 to give 1-amino-1-(hydroxymethyl)cyclohexane. The 2-hydroxyethylamine was sequentially treated with SOCl2 and 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.5]decane. The thiazolidine was alkylated with isobutyl bromide according to Method D2b to afford 2-(2-methyl-4-nitrophenylimino)-1-isobutyl-3-thia-1-azaspiro[4.5]decane.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N+:8]([O-])[CH:7]=[CH:6]2>P(Cl)(Cl)(Cl)=O>[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([Cl:1])=[N:8][CH:7]=[CH:6]2
Reactant: [O-][n+]1ccc2cc(Br)ccc2c1
Reactant: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1nccc2cc(Br)ccc12
Temperature: 90 °C
Yield: 72.8 %

Procedure:
70 mL of phosphorylchloride were added to 14.9 g of 1a and the mixture was heated at 90° C. for 2 hours. Excess of phosphorylchloride was evaporated, water was added, followed by aqueous 2N NaOH until pH 9 and the mixture was extracted with dichloromethane. The dichloromethane extract was washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel (toluene/ethyl acetate=4/1) giving 10.1 g of 1b. M.p.=102.7-103.7° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:23][C:24]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>C1COCC1>[F:23][C:24]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:25]=1[C:26](=[O:27])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)Cc1ccccc1
Reactant: Cc1ccc(C(=O)Cl)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)c1ccc(C)cc1F)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The solution of ethyl 2-phenylacetate (5 g, 30.5 mmol) in THF (20 mL) was cooled to −78° C. and LiHMDS (30.5 mL, 30.5 mmol) was added, followed by prior made solution of 2-fluoro-4-methylbenzoyl chloride in THF (10 mL). The reaction was allowed to warm to room temperature slowly and stirred for 4 h. Quenched with AcOH (2 mL), extracted with EtOAc, washed with brine, dried over MgSO4, and purified by column chromatography to give the title compound as clear liquid (7.10 g). LCMS m/z=301.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (t, J=7.07 Hz, 3H), 2.32 (s, 3H), 4.22 (q, J=7.07 Hz, 2H), 5.77 (s, 1H), 7.03-7.17 (m, 3H), 7.24-7.40 (m, 4H), 7.82 (t, J=8.21 Hz, 1H).
Reaction SMILES: Br[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[CH:10]=2)[C:5]([CH3:17])([CH3:16])[O:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:24][CH2:25][C@@H:26]([OH:45])[C@@H:27]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1>CN(C)C=O.C(OCC)(=O)C>[F:35][C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([F:36])[CH:32]=1)[CH2:28][C@H:27]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[C@H:26]([OH:45])[CH2:25][NH:24][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[CH:10]=2)[C:5]([CH3:17])([CH3:16])[O:4][CH2:3]1
Reactant: CC(C)Oc1ccc2c(c1)C(Br)COC2(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc2c(c1)C(NC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C)COC2(C)C
Yield: 46.8 %

Procedure:
A solution of 4-bromo-6-isopropoxy-1,1-dimethyl-3,4-dihydro-1H-isochromene (0.61 g, 2.04 mmol), cesium carbonate (1.33 g, 4.08 mmol), and tert-butyl (1S,2R)-3-amino-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate (0.64 g, 2.04 mmol) in N,N-dimethylformamide (10 mL) was stirred at 60° C., under nitrogen, for 24 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with 5% lithium chloride (3×40 mL), water (2×30 mL), saturated sodium chloride (30 mL), dried (sodium sulfate), and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica, 95:5 methylene chloride/methanol) to afford the desired product (0.51 g, 47%) as a pale-yellow foam: ESI MS m/z 535 [C29H40F2N2O5+H]+.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.C[N:16]1[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:22])[C:18]([C:30]([F:33])([F:32])[F:31])=[N:17]1.[C:34]1(=[O:38])[CH2:37][CH2:36][CH2:35]1.B(F)(F)F.[NH4+].[Cl-]>C1COCC1.CCCCCC>[CH2:28]([O:27][C:25](=[O:26])[CH:24]([C:34]1([OH:38])[CH2:37][CH2:36][CH2:35]1)[NH:23][C:21]([C:19]1[C:18]([C:30]([F:33])([F:32])[F:31])=[N:17][NH:16][CH:20]=1)=[O:22])[CH3:29]
Reactant: O=C1CCC1
Reactant: CCOC(=O)CNC(=O)c1cn(C)nc1C(F)(F)F
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: FB(F)F
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(NC(=O)c1c[nH]nc1C(F)(F)F)C1(O)CCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
23.0 ml of hexamethyldisilazane (mmol) were dissolved in 200 ml of THF, and 46 ml of 2.5M (115 mmol) of butyllithium solution in hexane were added dropwise at −78° C. After 30 min, 7.90 g (22.3 mmol) of ethyl [(1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)amino]acetate, dissolved in 50 ml of THF, were added dropwise, and the mixture was stirred at −78° C. for 1.5 h. 3.0 g (42.8 mmol) of cyclobutanone and 4.14 g (29.2 mmol) of BF3-etherate, dissolved in 50 ml of THF, were added dropwise, and the mixture was stirred at −78° C. for 2 h, at −50° C. for 1 h and at 0° C. for 1 h. 100 ml of saturated NH4Cl solution were added dropwise, and the mixture was stirred for 30 min. The organic phase was separated off and the solvents were removed under reduced pressure. This gave 9.88 g (100%) of colorless crystals which were reacted without further purification.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)\[C:11]2[N:12]([CH3:17])[O:13][C:14](=[O:16])[N:15]=2)[N:6]=1.[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28]C=CC=1>C1COCC1.[Cu](I)I>[CH:24]1([C:29]#[C:28][C:2]2[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)\[C:11]3[N:12]([CH3:17])[O:13][C:14](=[O:16])[N:15]=3)[N:6]=2)[CH2:30][CH2:31]1
Reactant: Cn1oc(=O)nc1/C(=N\OCc1csc(Br)n1)c1ccccc1
Reactant: C#Cc1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Product: Cn1oc(=O)nc1/C(=N\OCc1csc(C#CC2CC2)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.7 %

Procedure:
To a solution of 3-[(Z)-{[(2-bromo-1,3-thiazol-4-yl)methoxy]imino}(phenyl)methyl]-2-methyl-1,2,4-oxadiazol-5(2H)-one (210 mg, 0.514 mmol, 1 eq) in degased THF (2 mL) was added in a microwave tube under argon tetrakis(triphenylphosphine)palladium (0) (59.4 mg, 0.051 mmol, 0.1 eq), copper iodide (14.6 mg, 0.077 mmol, 0.15 eq) N,N-diisopropylethylamine (0.358 ml, 2.06 mmol, 4 eq) and phenylacetylene (157 mg, 1.54 mmol, 3 eq). The mixture was stirred at room temperature for 2 days. The mixture was concentrated, diluted with ethyl acetate and filtered over a celite cartridge. The solvent was evaporated and the residue was purified by chromatography on silica gel to afford 3-[(Z)-({[2-(cyclopropylethynyl)-1,3-thiazol-4-yl]methoxy}imino)(phenyl)methyl]-2-methyl-1,2,4-oxadiazol-5(2H)-one (148 mg, 73% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=3)=[CH:21][C:20]=2[C:33]2[C:34]([N+:38]([O-])=O)=[N:35][NH:36][CH:37]=2)=[CH:4][C:5]([F:17])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].S(S([O-])=O)([O-])=O.[Na+].[Na+].O>C(#N)C>[NH2:38][C:34]1[NH:35][N:36]=[CH:37][C:33]=1[C:20]1[CH:21]=[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=2)[CH:23]=[CH:24][C:19]=1[O:18][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:9])=[O:10])=[C:5]([F:17])[CH:4]=1
Reactant: N#Cc1cccc(-c2ccc(Oc3cc(F)c(S(=O)(=O)Nc4nncs4)cc3Cl)c(-c3c[nH]nc3[N+](=O)[O-])c2)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1cccc(-c2ccc(Oc3cc(F)c(S(=O)(=O)Nc4nncs4)cc3Cl)c(-c3cn[nH]c3N)c2)c1
Temperature: 50 °C

Procedure:
5-Chloro-4-(3′-cyano-3-(3-nitro-1H-pyrazol-4-yl)biphenyl-4-yloxy)-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 62, 51 mg, 0.0853 mmol) was dissolved in acetonitrile (1 mL) and heated at 50° C. Potassium carbonate (58.8 mg, 0.426 mmol) followed by sodium dithionite (59.4 mg, 0.341 mmol) and water (1 mL) were added. The reaction mixture was heated at 50° C. for 2 hours, cooled to room temperature and partitioned between EtOAc (10 mL) and water (5 mL). The aqueous phase was separated and extracted with EtOAc (2×3 mL) and the combined organic phases were washed with a saturated solution of brine (3 mL), dried over MgSO4 and concentrated in vacuo. The crude residue was purified by reverse phase HPLC.
Reaction SMILES: [I-].[Na+].[C:3](OC(=O)C)(=[O:5])[CH3:4].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][C:18]2[C:26]3[C:25](=[N:27]O)[CH2:24][CH2:23][CH2:22][C:21]=3[N:20]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:19]=2[CH3:35])=[CH:13][CH:12]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1(C)C(C)=CC=CC=1.C(O)(=O)C.O>[C:3]([NH:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:18]([S:17][C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=1)=[C:19]([CH3:35])[N:20]2[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])(=[O:5])[CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c1CCCC2=NO
Agent: O=S([O-])([O-])=S
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c(NC(C)=O)cccc21
Temperature: 102.5 °C
Reaction time: 2.5 h
Yield: 81 %

Procedure:
A mixture of sodium iodide (0.0625 mol equiv) in xylene (1.99 rel vol), acetic acid (0.27 rel vol) and acetic anhydride (1.27 mole equiv) was heated to 102.5° C. in vessel 1 with stirring. In vessel 2, acetic anhydride (1.27 mole equiv) was added to a stirred slurry of ethyl [3-(4-chlorophenylsulfanyl)-4-(hydroxyimino)-2-methyl-4,5,6,7-tetrahydro-1H-indol-1-yl]acetate (1 mole equiv, limiting reagent) in xylene (2.24 rel vol) and acetic acid (0.27 rel vol) at 22° C. After stirring at this temperature for 30 mins, this mixture was added to the contents of reaction vessel 1 over 50 mins maintaining the temperature at 102.5° C. The reaction was held at this temperature for a further 2.5 h. The reaction was cooled to 60° C. and sodium thiosulfate (0.05 mole equiv) and water (0.5 rel vol) were added. After mixing, and allowing the layers to separate, the lower aqueous layer was discarded then the organic layer was distilled under vacuum, removing 1.8 rel vol distillate. The temperature was adjusted to 95° C. and the product precipitated by the addition of heptanes (3 rel vol). The suspension was cooled to 20° C. over 1 h then the solid product was collected by filtration, washed with ethanol (2 rel vol) and dried in vacuo at 40° C. to afford crude ethyl [4-acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-1H-indol-1-yl]acetate as a solid; 81% yield; purity by UHPLC 98.3 area %.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][NH:6][CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]([OH:10])=[O:9].[CH3:17]O>>[CH3:5][NH:6][CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]([O:10][CH3:17])=[O:9]
Reactant: CNC(C(=O)O)c1ccccc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CNC(C(=O)OC)c1ccccc1
Reaction time: 2 h

Procedure:
6.63 mL of thionyl chloride are slowly added to a solution of 1.5 g of 2-methylamino-2-phenylacetic acid in 100 mL of methanol. The mixture is heterogenous and becomes limpid after two hours stirring. The mixture is stirred for 48 h at rt then the solvent is evaporated to dryness. The crude product is diluted with an aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phases are washed with water then brine, and dried over magnesium sulfate, filtered and evaporated to provide the desired product, which is used as such for the next step.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH2:16])[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH:4]=[N:3]1.Br[C:18]1[CH:26]=[C:25]2[C:21]([C:22]([C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][NH:24]2)=[CH:20][CH:19]=1.BrC1C=C2C(C=CN2)=CC=1.C(O)(C(F)(F)F)=O>CN(C=O)C>[F:31][C:28]([F:29])([F:30])[C:27]([C:22]1[C:21]2[C:25](=[CH:26][C:18]([NH:16][C:14]3[N:15]=[C:8]4[C:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)=[N:12][CH:11]=[CH:10][N:9]4[N:13]=3)=[CH:19][CH:20]=2)[NH:24][CH:23]=1)=[O:32]
Reactant: O=C(c1c[nH]c2cc(Br)ccc12)C(F)(F)F
Reactant: Cn1cc(-c2nccn3nc(N)nc23)cn1
Agent: Brc1ccc2cc[nH]c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cn1cc(-c2nccn3nc(Nc4ccc5c(C(=O)C(F)(F)F)c[nH]c5c4)nc23)cn1

Procedure:
8-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine is reacted with 1-(6-bromo-1H-indol-3-yl)-2,2,2-trifluoro-ethanone, available by reaction of 6-bromo-1H-indole (1 eq.) with TFA (1.6 eq) in DMF at 120° C. for 1 h, under conditions described in general procedure 2.