Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:16])[CH3:15])[CH:4]([CH3:6])[CH3:5].[CH3:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH:27]=O)[CH:25]=2)[NH:20][N:19]=1>C(O)C>[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:16])/[CH:15]=[CH:27]/[C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[C:18]2[CH3:17])[CH:4]([CH3:6])[CH3:5]
Reactant: CC(=O)c1ccccc1OCC(C)C
Reactant: Cc1n[nH]c2ccc(C=O)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1n[nH]c2ccc(/C=C/C(=O)c3ccccc3OCC(C)C)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.8 %

Procedure:
To a solution of NaOH (0.2 g, 5 mmol) in 3 mL ethanol were added commercially available 1-(2-isobutoxyphenyl)ethanone (100 mg, 0.52 mmol) and commercially available 3-methyl-1H-indazole-5-carbaldehyde (200 mg, 1.25 mmol). The reaction mixture was stirred at room temperature for 24 h, concentrated under reduced pressure and the product was purified by SiO2 flash chromatography (60:40 hexanes/ethyl acetate) to afford (E)-1-(2-isobutoxyphenyl)-3-(3-methyl-1H-indazol-5-yl)prop-2-en-1-one (50 mg, 28.6%). C21H22N2O2: 335 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:32][S:33]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:32][S:33]([C:36]1[CH:41]=[C:40]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)[CH:5]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:3]=2)[CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)Oc1ccc(Nc2cc(N3CCOCC3)cc(Cl)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cccc(-c2cc(N3CCOCC3)cc(Nc3ccc(OC(F)(F)F)cc3)n2)c1
Yield: 30 %

Procedure:
To a solution of (6-chloro-4-morpholin-4-yl-pyridin-2-yl)-(4-trifluoromethoxy-phenyl)-amine (75 mg, 0.20 mmol) in 1,4-dioxane (8 mL) were added 2N sodium carbonate solution (0.5 mL) and tetrakis(triphenylphosphine)palladium(0) (11.6 mg, 0.010 mmol), followed by 3-methanesulfonyl phenyl boronic acid (48 mg, 0.24 mmol). The resulting reaction mixture was refluxed for 8 hours, after which time water was added (100 mL) to the reaction mixture, and the product was extracted with ethyl acetate (100 mL×3). The organic layer was dried over sodium sulphate, filtered, and the filtrate was concentrated under vacuum. The resulting product was purified by column chromatography using 230-400 mesh silica gel (elution 2:98 methanol:DCM) to afford the desired compound pale yellow solid (30 mg, yield 30%.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:21][N:22]([CH3:33])[S:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Cl)(=[O:25])=[O:24]>C(N(C(C)C)C(C)C)C>[CH3:21][N:22]([CH3:33])[S:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:14][CH2:13]1)(=[O:24])=[O:25]
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CN(C)S(=O)(=O)CCCCCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)CCCCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Yield: 92 %

Procedure:
1-[(4-Chlorophenyl)phenylmethyl]piperazine (573.6 mg, 2.00 mmol) and N,N-dimethyl-6-chlorohexanesulfonamide (455.5 mg, 2.00 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (50:1), to give N,N-dimethyl-6-[4-[(4-chlorophenyl)phenylmethyl]1-piperazinyl]hexanesulfonamide (880.0 mg) as a pale brown oil (yield: 92.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.CS([C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: CS(=O)(=O)c1ncccn1
Reactant: NC1CCCc2c1[nH]c1ccc(Cl)cc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1ccc2[nH]c3c(c2c1)CCCC3Nc1ncccn1
Yield: 11.6 %

Procedure:
A solution of 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine (50 mg, 0.23 mmol) and 2-methylsulfonylpyrimidine (69 mg, 0.44 mmol) in N,N-dimethylformamide (0.50 mL) was heated at 150° C. for 900 seconds in a Smith Synthesizer microwave. The mixture was diluted with ethyl acetate and extracted with 5% aqueous lithium chloride. The organic layer was isolated and concentrated onto silica. Purification by flash chromatography (0-30% ethyl acetate-hexanes) yielded 6-chloro-N-pyrimidin-2-yl-2,3,4,9-tetrahydro-1H-carbazol-1-amine (8 mg, 12% yield) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].Br[CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:15]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCBr
Reactant: COC(=O)c1ccc(O)c(OC)c1
Product: CCCCOc1ccc(C(=O)O)cc1OC

Procedure:
Methyl 4-hydroxy-3-methoxybenzoate was alkylated with bromobutane by method H and hydrolyzed by method P-a. This resulted in the product with the molecular weight of 224.26 (C12H16O4); MS (ESI): 225 (M+H+).
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:8][C:9](C)(C)[CH3:10])(=[O:7])[CH3:6].C(O[C:16]([C:18]1[CH:19]=[C:20]2[CH:26]=[CH:25][O:24][C:21]2=[CH:22][N:23]=1)=[O:17])C.C(O)(=O)C>C1(C)C=CC=CC=1.O>[O:17]=[C:16]([C:18]1[CH:19]=[C:20]2[CH:26]=[CH:25][O:24][C:21]2=[CH:22][N:23]=1)[CH2:6][C:5]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1cc2ccoc2cn1
Reactant: CC(=O)OC(C)(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)CC(=O)c1cc2ccoc2cn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
As 510 mg (7.5 mmol) of sodium ethoxide was stirred in 5 mL toluene, 1.16 g (10.0 mmol) of t-butyl acetate was added dropwise at room temperature to the solution. Then, 956 mg (5.0 mmol) of 5-ethoxycarbonylfuro[2,3-c]pyridine dissolved in 5 mL of toluene was added dropwise at room temperature to the above solution. After all the solution had been added, the reaction mixture was heated to 60° C., and a reaction was carried out for 3 hours. The reaction solution was then cooled to 5° C. and was neutralized with 450 mg (7.5 mmol) of acetic acid as the temperature was held 5-10° C., the solution was stirred for 30 minutes as the temperature was maintained, 1 mL water was then added, and the solution was returned to room temperature. The organic layer was separated, the aqueous layer was extracted twice with 5 mL of methylene chloride, and the combined organic layer was dried with anhydrous magnesium sulfate and then concentrated in a rotary evaporator. The resulting solids were recrystallized from a mixed solvent of toluene-hexane mixture, giving 933 mg (80% yield) of ethyl β-oxo-5-furo[2,3-c]pyridinepropionate in a purity of 99% by HPLC.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)cc23)cc1Cl
Product: COc1ccc(CNc2nc(-n3ccnc3)nc3sc(C)cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][N:31]=2)[CH2:6][C@@H:5]1[CH3:37])(=[O:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH2:20][OH:21])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][N:31]=2)[CH2:6][C@@H:5]1[CH3:37])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3cn(CCO[Si](C)(C)C(C)(C)C)nn3)cc2[C@H](Nc2ccc(C)cn2)C[C@@H]1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(-c3cn(CCO)nn3)cc2[C@H](Nc2ccc(C)cn2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of (2S,4R)-1-acetyl-6-[1-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-1H-1,2,3-triazol-4-yl]-2-methyl-N-(5-methyl-2-pyridinyl)-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see intermediate 43) (34 mg, 0.065 mmol) in tetrahydrofuran (THF) (3 mL) was added TBAF (1M in THF, 0.085 mL, 0.085 mmol). The resulting mixture was stirred at room temperature for 30 min, and then was concentrated in vacuo. The residue was dissolved in a 1:1 (MeOH/DMSO) mixture (1 mL) and purified via MDAP (modifier: formic acid). The appropriate fractions were combined and concentrated under reduced pressure to give 2-(4-{(2S,4R)-1-acetyl-2-methyl-4-[(5-methyl-2-pyridinyl)amino]-1,2,3,4-tetrahydro-6-quinolinyl}-1H-1,2,3-triazol-1-yl)ethanol (19 mg, 0.045 mmol, 69%) as a colourless oil
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]3[N:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)[N:19]=[N:20][C:15]3=[CH:14][CH:13]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+].C1COCC1.Cl>CO.O>[F:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]3[N:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)[N:19]=[N:20][C:15]3=[CH:14][CH:13]=2)=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)ccc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.8 %

Procedure:
To a solution of Example 204 (0.080 g, 0.193 mmol) in methanol (1 ml), lithium hydroxide (0.075 g, 1.80 mmol) in water (1 ml) and THF (2 ml) were added and stirred at RT. After 12 h, pH was adjusted to ca. 7 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as an off-white solid (0.060 g, 78%). The acid was used without further purification in the next step.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](O)=[O:38].C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:37](=[O:38])[C:36]1[CH:40]=[CH:41][CH:42]=[C:34]([O:33][CH3:32])[CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: COc1cccc(C(=O)O)c1
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)N2CC[C@H](N(Cc3ccnc4ccccc34)C(=O)C(F)(F)F)C[C@H]2Cc2ccccc2)c1

Procedure:
200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4 with 85 mg (0.561 mmol) of 3-methoxybenzoic acid, 143 mg (0.561 mmol) of bis-(2-oxo-3-oxazalidinyl)phosphinic chloride and 144 μl (1.03 mmol) of triethylamine. The title compound is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.45, FD-MS: M+ =561.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:37][CH2:36][N:35]4[CH2:38][CH2:39][NH:40][CH2:41][CH:34]4[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>ClCCl>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:37][CH2:36][N:35]4[CH2:38][CH2:39][N:40]([S:54]([CH3:53])(=[O:56])=[O:55])[CH2:41][CH:34]4[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:44])([F:1])[F:45])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(F)ccc1-c1cc(N2CCN3CCNCC3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1cc(N2CCN3CCN(S(C)(=O)=O)CC3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 8 h
Yield: 52.4 %

Procedure:
To a solution of crude 2-[3,5-bis(trifluoromethyl)phenyl]-N-4-[4-(4-fluoro-2-methylphenyl)-6-(octahydro-2H-pyrazino[1,2-a]pyrazin-2-yl)-3-pyridinyl]-N,2-dimethylpropanamide (D80, 100 mg, 0.16 mmol) in 5 mL of dichloromethane were added triethylamine (44 μL, 0.32 mmol, 2 eq.) and, at 0° C., methanesulfonyl chloride (18 μL, 0.24 mmol, 1.5 eq.). The reaction was left at room temperature overnight. Additional 3 eq. of methanesulfonyl chloride were added. It was then diluted with dichloromethane, extracted with sat. NaHCO3, the organics dried (Na2SO4), and the solvent was removed. The product was purified by flash chromatography (silica, EtOAc). Obtained 60 mg of the title compound.
Reaction SMILES: CO[C:3](=[O:30])[CH:4]=[CH:5][C:6]1[CH:29]=[CH:28][C:9]2[N:10]([CH2:21][CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:11]([CH2:13][NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:12][C:8]=2[CH:7]=1.Cl.[NH2:32][OH:33].C[O-].[Na+].Cl>CO>[CH2:26]([N:23]([CH2:24][CH3:25])[CH2:22][CH2:21][N:10]1[C:9]2[CH:28]=[CH:29][C:6]([CH:5]=[CH:4][C:3]([NH:32][OH:33])=[O:30])=[CH:7][C:8]=2[N:12]=[C:11]1[CH2:13][NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:17])[CH3:18])[CH3:27]
Reactant: CCN(CC)CCn1c(CNC(=O)C(C)(C)C)nc2cc(C=CC(=O)OC)ccc21
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCN(CC)CCn1c(CNC(=O)C(C)(C)C)nc2cc(C=CC(=O)NO)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29.7 %

Procedure:
To a stirred solution of 3-{1-(2-diethylamino-ethyl)-2-[(2,2-dimethyl-propionylamino)-methyl]-1H-benzoimidazol-5-yl}-acrylic acid methyl ester (61-7, 73.8 mg, 0.18 mmol) and hydroxylamine hydrochloride (124 mg, 1.78 mmol) in MeOH (0.3 mL) was added sodium methoxide (30% in methanol) (0.8 mL, 3.6 mmol) at −78° C. The reaction mixture was then allowed to warm up slowly to room temperature. The reaction was monitored by LC/MS and was completed in around 15 min. 1N HCl was then added slowly into the reaction mixture at 0° C. The desired product was separated by reverse phase preparative HPLC. After lyopholyzation, 22.2 mg (24.3%) of 3-{1-(2-diethylamino-ethyl)-2-[(2,2-dimethyl-propionylamino)-methyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide was obtained as powder. HPLC purity: 99.5%, tR=0.94 min. LCMS m/z: 416 ([M+H]+). 1H NMR (CD3OD) δ 7.89 (s, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.55 (d, J=15.8 Hz, 1H), 6.53 (d, J=15.8 Hz, 1H), 4.98 (t, J=7.3 Hz, 2H), 4.73 (s, 2H), 3.75 (t, J=7.5 Hz, 2H), 3.42 (q, J=7.2 Hz, 4H), 1.37 (t, J=7.3 Hz, 6H), 1.22 (s, 9H); 13C NMR (CD3OD) δ 182.5, 168.9, 162.2, 161.9, 154.8, 140.8, 137.9, 135.0, 133.9, 126.0, 119.3, 117.1, 112.9, 50.9, 40.5, 39.7, 36.7, 27.6, 9.1.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[C:10]([CH3:16])=[CH:9][CH:8]=[C:7]([CH3:17])[C:6]2=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[C:10]([CH3:16])=[CH:9][CH:8]=[C:7]([CH3:17])[C:6]2=1
Reactant: COc1ccc2[nH]c3c(C)ccc(C)c3c2c1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(C)c2c1[nH]c1ccc(O)cc12

Procedure:
A solution of 30 g of 6-methoxy-1,4-dimethyl-carbazole in 300 g of absolutely anhydrous (water-free) pyridine hydrochloride was heated with gentle reflux on 180°-190° C. for 5 hours.
Reaction SMILES: FC1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=3)[CH:9]=[N:8]2)=CC=1.C1(C[N:28]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)CC1>>[CH:5]1([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:14][C:15]([C:19]([NH2:28])=[O:21])=[C:16]([CH3:18])[N:17]=3)[CH:9]=[N:8]2)[CH2:22][CH2:23]1
Reactant: Cc1nc(-n2cnn(CC3CC3)c2=O)sc1C(=O)O
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(-n2cnn(CC3CC3)c2=O)sc1C(N)=O
Yield: 43 %

Procedure:
Following the procedure as described in EXAMPLE 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid with 2-(1-(cyclopropylmethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as an off-white solid in 43% yield: mp 180-181° C. (ethanol/water); 1H NMR (300 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.63 (br, 2H), 3.66 (d, J=7.0 Hz, 2H), 2.55 (s, 3H), 1.21-1.11 (m, 1H), 0.54-0.48 (m, 2H), 0.38-0.32 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 162.6, 151.3, 150.9, 149.5, 131.4, 122.9, 49.4, 16.8, 10.0, 3.3; MS (ES+) m/z 280.3 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:34][C:35](=[O:47])[C:36]([NH:39]C(=O)OC(C)(C)C)([CH3:38])[CH3:37])[C:12]([N:14]2[CH2:33][CH2:32][CH2:31][C:16]3([C:20](=[O:21])[N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH:17]3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:15]2)=[O:13])=[CH:2]1.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:34][C:35](=[O:47])[C:36]([NH2:39])([CH3:38])[CH3:37])[C:12]([N:14]2[CH2:33][CH2:32][CH2:31][C:16]3([C:20](=[O:21])[N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH:17]3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:15]2)=[O:13])=[CH:2]1
Reactant: CC(C)N1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](Cc3c[nH]c4ccccc34)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](Cc3c[nH]c4ccccc34)NC(=O)C(C)(C)N)C2)C1=O

Procedure:
A mixture comprising tert-butyl 1-((2R)-3-(1H-indol-3-yl)-1-(2-isopropyl-1-oxo-4-phenyl-2,7-diazaspiro[4.5]decan-7-yl)-1-oxopropan-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (450.21 mg, 0.699 mmol) (step 1) and TFA (0.539 ml, 6.99 mmol) in DCM (5 ml) was stirred at room temperature for 17 hours. The solvent was removed in vacuo to afford a purple oil. The oil was dissolved with methanol (3 ml) and passed through a 10 g SCX-2 cartridge eluting with 2M NH3 in methanol (70 ml). The solvent was removed in vacuo to yield the title compound as diastereomeric mixture.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:18]3[CH:19]=[C:20]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)[S:31][CH:32]=4)[N:21]4[C:26]=3[C:25]([NH2:27])=[N:24][CH:23]=[N:22]4)[CH:14]=[CH:15]2)=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:2]([N:9]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:18]3[CH:19]=[C:20]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:38][CH2:37][N:36]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:35][CH2:34]5)[S:31][CH:32]=4)[N:21]4[C:26]=3[C:25]([NH2:27])=[N:24][CH:23]=[N:22]4)[CH:14]=[CH:15]2)=[N:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ncnn2c(-c3csc(C4CCNCC4)n3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCC(c2nc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)cs2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 28.2 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(2-piperidin-4-yl-1,3-thiazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine hydrochloride (100 mg, 0.17 mmol) in DMF (1.5 mL) was added methanesulfonyl chloride (15 μL, 0.19 mmol) and N,N-diisopropylethylamine (120 μL, 0.69 mmol). The reaction was stirred at rt for 17 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile to provide 28 mg (28%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1 H), 8.38 (s, 1 H), 8.10 (s, 1 H), 7.83 (d, 1 H), 7.67 (s, 1 H), 7.27-7.40 (m, 5H), 7.17-7.24 (m, 2 H), 5.66 (s, 2 H), 3.59-3.69 (m, 2 H), 3.16-3.28 (m, 1 H), 2.85-2.95 (m, 5H), 2.20 (d, 2 H), 1.78 (q, 2 H); ES-MS m/z 585.21 [M+H]+, HPLC RT (min) 2.97.
Reaction SMILES: Cl[Si](C)(C)C.[O:6]1[CH2:10][CH2:9][O:8][CH:7]1[CH2:11][CH2:12][CH2:13][C@H:14]([NH2:18])[C:15]([OH:17])=[O:16].S(OC)(O[CH3:22])=O.C[O-].[K+]>CO.C(OCC)(=O)C>[NH2:18][C@@H:14]([CH2:13][CH2:12][CH2:11][CH:7]([O:8][CH3:9])[O:6][CH3:10])[C:15]([O:17][CH3:22])=[O:16]
Reactant: COS(=O)OC
Reactant: N[C@@H](CCCC1OCCO1)C(=O)O
Agent: C[O-]
Agent: C[Si](C)(C)Cl
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](N)CCCC(OC)OC
Temperature: 42.5 °C
Reaction time: 72 h
Yield: 80.2 %

Procedure:
Under nitrogen, chlorotrimethyl silane (28.0 g) was added to a slurry of 5-(1,3-dioxolan-2-yl)-(S)-2-amino-pentanoic acid (20.0 g) and dimethyl sulfite (12.0 g) in methanol (240 mL) to afford a homogeneous solution. Following the observation of an exotherm to 29° C., the solution was heated to 40-45° C., stirred at that temperature for 8 h and at ˜22° C. for up to 72 hours. In-process HPLC analysis showed that the reaction was complete (˜93 M % conversion to product) and the resulting solution was cooled to −5 to −10° C. With stirring, the apparent pH of the mixture was adjusted to 11.7 to 11.9 by the slow careful addition of 32% (or 4.45 M) methanolic potassium methoxide solution (70 mL) maintaining the temperature in the range −5 to 0° C. Analysis of the product slurry (NMR) indicated that the neutralization was complete (chemical shift of the alpha proton of BMS-205787 was <3.36 ppm). The solvent of the product slurry was exchanged with ethyl acetate by first concentrating the thin slurry under vacuum at <30° C. to 300 mL volume followed by the addition of ethyl acetate until the removal of methanol was completed as judged by in-process GC analysis (<1 AP). Upon completion of the solvent exchange, the batch volume was adjusted to ˜400 mL with ethyl acetate and the resulting slurry was filtered. Poly(acrylic acid co-acrylamide), potassium salt (3.0 to 3.2 g) and water (30-32 mL) were added to the filtrate. The mixture was stirred for ˜35 minutes and filtered. Optionally, the Poly(acrylic acid co-acrylamide), potassium salt treatment can be repeated on the filtrate if the quantity of ethylene glycol exceeds 0.15 equivalents, as judged by in-process GC analysis. Following in-process HPLC analysis, (S)-2-Amino-6,6-dimethoxyhexanoic acid, methyl ester (17.4 g) was obtained as an ethyl acetate solution in 80.8 M % yield.