Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:17]([NH:19][C:20]3[S:21][CH:22]=[C:23]([C:25](OCC)=[O:26])[N:24]=3)=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.C(O)(=O)C(C(C(O)=O)O)O.[Na]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:17]([NH:19][C:20]3[S:21][CH:22]=[C:23]([CH2:25][OH:26])[N:24]=3)=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1csc(NC(=O)N2CCC(N3CCc4ccc(F)cc43)CC2)n1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [Na]
Solvent: ClCCl
Product: O=C(Nc1nc(CO)cs1)N1CCC(N2CCc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of ethyl 2-(4-(6-fluoroindolin-1-yl)piperidine-1-carboxamido)thiazole-4-carboxylate (83.6 mg, 0.2 mmol, 1 equiv) in dried CH2Cl2 (3 mL) under N2 at room temperature was then slowly added DIBAL-H (1M in CH2Cl2, 1 mL, 1 mmol, 5 equiv). The resulting mixture became a clear solution and was stirred at room temperature for 1 h. The resulting mixture was slowly poured into a vigorously stirred mixture of CH2Cl2/10 wt % sodium tartaric acid (aq.) (10 mL/10 mL). The resulting mixture was stirred for 1 h and the layers were separated. The aqueous layer was extracted with CH2Cl2 (30 mL). The combined organic layer was dried (Na2SO4) and filtered. The solvent was removed by roto-evaporator and the resulting residue purified by column using 80-90% EtOAc/hexane as the eluent to yield 4-(6-fluoroindolin-1-yl)-N-(4-(hydroxymethyl)thiazol-2-yl)piperidine-1-carboxamide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH3:15])[CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.CCN=C=NCCCN(C)C>CC#N.CCOC(C)=O>[CH3:15][N:4]([CH2:3][CH2:2][NH:1][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1)[CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13]
Reactant: CN(CCN)CCNC(=O)OC(C)(C)C
Reactant: O=C(O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN(CCNC(=O)OC(C)(C)C)CCNC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.3 %

Procedure:
tert-Butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate (400 mg, 1.84 mmol) was taken up in CH3CN (10 mL) along with nicotinic acid (227 mg, 1.84 mmol) and EDCI (353 mg, 2.02 mmol). The resulting reaction mixture was stirred at room temperature for 18 h and then diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (5% MeOH—CH2Cl2) to afford tert-butyl 2-(methyl(2-(nicotinamido)ethyl)amino)ethylcarbamate (180 mg, 30%). MS calculated for C16H26N4O3: 322.2. found: [M+H]+ 323.
Reaction SMILES: C(SCC(O)=O)(=[O:3])C.ON1C(=O)CCC1=O.[CH:17]1([N:23]=[C:24]=[N:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCOCC1>[CH:26]1([NH:25][C:24]([NH:23][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[O:3])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC(=O)SCC(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1COCCO1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 16 h
Yield: 66 %

Procedure:
S-Acetyl-2-mercaptoacetic acid (75 mmoles) and N-hydroxysuccinimide (75 mmoles), were dissolved in 150 ml dioxane and reacted with cooling in ice with N,N'-dicyclohexylcarbodiimide (75 mmoles) and the mixture was kept at 4° C. for 16 h. The N,N'-dicyclohexylurea formed was removed by filtration and the solvent evaporated in vacuo. The residue was twice recrystallized from 2-propanol.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:19][C:20](=[O:52])[C@H:21]([CH2:46][C:47]2[N:51]=[CH:50][NH:49][CH:48]=2)[NH:22][C:23](=[O:45])[CH:24]([CH2:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=[CH:37][CH:36]=2)[CH2:25][C:26](=[O:33])[N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:9]([OH:18])[CH2:10][S:11][C:12]2[S:13][C:14]([CH3:17])=N[N:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C[C@H](NC(=O)[C@H](CC2N=CNC=2)NC(=O)C(CC2C3C(=CC=CC=3)C=CC=2)CC(=O)N2CCOCC2)C(O)CSC2SN=NC=2)CCCCC1.C(N1C(SCC(O)CC)=NN=N1)C.CN1C(S(CC(O)CC)(=O)=O)=NN=N1.[N+](CC(O)CC)([O-])=O>>[CH:1]1([CH2:7][C@H:8]([NH:19][C:20](=[O:52])[C@H:21]([CH2:46][C:47]2[N:51]=[CH:50][NH:49][CH:48]=2)[NH:22][C:23](=[O:45])[CH:24]([CH2:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=[CH:37][CH:36]=2)[CH2:25][C:26](=[O:33])[N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[CH:9]([OH:18])[CH2:10][S:11][C:12]2[S:13][CH:14]=[CH:17][N:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nnc(SCC(O)[C@H](CC2CCCCC2)NC(=O)[C@H](Cc2c[nH]cn2)NC(=O)C(CC(=O)N2CCOCC2)Cc2cccc3ccccc23)s1
Agent: CCC(O)CS(=O)(=O)c1nnnn1C
Agent: CCC(O)CSc1nnnn1CC
Agent: CCC(O)C[N+](=O)[O-]
Product: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)C(O)CSc1nccs1)C(CC(=O)N1CCOCC1)Cc1cccc2ccccc12

Procedure:
(3S)-4-cyclohexyl-3-[(N-[1,4-dioxo-4-morpholino-2-(1-naphthylmethyl)butyl]-L-histidyl]amino]-1-[(5-methyl-1,3,4-thiadiazol-2-yl)thio]-2-butanol; (3S0-4-cyclohexyl-3-[(N-[1,4-dioxo-4-morpholino-2-(1-naphthylmethyl)butyl]-L-histidinyl]amino]-1-(2-pyrimidinylthio)-2-butanol; (3S)-4-cyclohexyl-3-[(N-[1,4-dioxo-4-morpholino-2-(1-naphthylmethyl)butyl]-L-histidyl]amino]-1-(1,2,3-thiadiazol-5-ylthio]-2-butanol; (3S)-cyclohexyl-3-[(N-[1,4-dioxy-2-(1-naphthylmethyl)-4-(3-thienyl)butyl]-L-histidyl]amino]-1-(1-methyl-5-tetrazolyl)-2-butanol; (3S)-4-cyclohexyl-3-[(N-[1,4-dioxo-4-morpholino)-2-(1-naphthyl)butyl]-L-histidyl]amino]-1-[(1-ethyl-5-tetrazolyl)thio]-2-butanol; (3S)-4-cyclohexyl-3-[(N-1,4-dioxo-4-morpholino)-2-(1-naphthylmethyl)butyl]-L-histidyl]amino]-1-[(1-methyl-5-tetrazolylsulfonyl] -2-butanol; and (3S)-4-cyclohexyl-3-[(N-[1,4-dioxo-4-morpholino)-2-(1-naphthylmethyl)butyl]-L-histidyl]amino]-1-nitro-2-butanol.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([NH:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:24]1([CH3:33])[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:24]1([CH3:33])[CH:29]=[CH:28][CH:27]=[C:26]([C:2]2[C:10]3[O:9][C:8]([NH:11][C:12]4[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=4)=[N:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:25]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: COc1cc(Nc2nc3cccc(Br)c3o2)cc(OC)c1OC
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(Nc2nc3cccc(-c4cccc(C)c4)c3o2)cc(OC)c1OC
Temperature: 100 °C
Reaction time: 3 h

Procedure:
0.12 g (0.316 mmol) (7-bromo-benzooxazol-2-yl)-(3,4,5-trimethoxy-phenyl)-amine and 0.048 g (0.353 mmol) 3-tolyl boronic acid are dissolved in 4 ml 1,2-dimethoxy-ethane, a solution of 0.1 g (0.95 mmol) Na2CO3 (in 0.5 ml water) is added and a stream of argon is bubbled through the mixture in order to exclude oxygen from the reaction mixture. Tetrakis (triphenylphosphine) palladium (76 mg, 0.064 mmol) is added and the reaction mixture is stirred at 100° C. or 3 h. After that the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with water, dried over MgSO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography (silicagel, hexane:EtOAc=3:1=>1:1) to afford the title compound as an off-white solid, m.p. 153-155° C. Rt=2.54 min (Waters Symmetry C8, 2.1×50 mm, detection 210-250 nM, 5% to 100% CH3CN in H2O in 2 min+0.05% TFA, flow rate 1.0 ml/min). MS: 391 (M+1)+; m.p. 155-158° C.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]([CH3:5])([CH3:4])[CH3:3].Br[C:9]1[CH:10]=[CH:11][C:12]([F:15])=[N:13][CH:14]=1.[OH-].[Na+].Cl>C1COCC1.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>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:14][N:13]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CC(C)(C)C[Mg]Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(C)(C)Cc1ccc(F)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred, cooled (−78° C.) solution of (1s,5s)-9-methoxy-9-bora-bicyclo[3.3.1]nonane (260 ml, 260 mmol) in THF (200 ml) was added neopentylmagnesium chloride (260 ml, 260 mmol) drop-wise. The mixture slowly warmed to RT and stirred for 3 h. The white solid was filtered off and washed thoroughly with pentane. The filtrate was concentrated to give the light yellow oil. This residue was diluted with p-dioxane (300 ml) and to this was added 5-bromo-2-fluoropyridine (35.20 g, 200 mmol), (Ph3P)4Pd (9.7 g, 8.4 mmol), and 5 N NaOH (168 ml, 838 mmol). The resulting reaction mixture was heated at 95° C. in 16 h. The mixture was cooled and added 5 N HCl (168 ml) and the reaction was stirred for 1 h and extracted with ether (3×). The organic layers were washed with brine, dried over MgSO4, concentrated and purified by ISCO (5% EtOAc/Hexanes) to give the light yellow oil. MS (m+1): 168.2.
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C)C=O>[Si:19]([O:3][C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([O:11][CH2:12][CH3:13])=[O:10])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)[C@@H](O)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](O[Si](C)(C)C(C)(C)C)c1ccccc1

Procedure:
Following a procedure similar to that described in Preparation 23, but using 23.8 g of ethyl (S)-(+)-mandelate, 26.6 g of imidazole, 400 ml of dimethylformamide, 30.1 g of t-butyldimethylsilyl chloride and 100 ml of dimethylformamide, the title compound was obtained as a liquid, boiling at 125.5°/3.0 mmHg (400 Pa). [α]D23 +40.9° (c=1.02, chloroform).
Reaction SMILES: [ClH:1].CC(C1C=C(C=C(C(C)(C)C)C=1O)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[NH:25])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])(C)C.[C:39]([C:43]1[CH:44]=[C:45]([CH2:54]C(O)=O)[CH:46]=[C:47]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:48]=1[OH:49])([CH3:42])([CH3:41])[CH3:40].C(C1C=C(C=C(C(C)(C)C)C=1O)C(O)=O)(C)(C)C>>[ClH:1].[CH3:42][C:39]([C:43]1[CH:44]=[C:45]([CH2:54][C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)=[NH:25])=[CH:19][CH:18]=3)[CH2:15][CH2:16]2)=[O:10])[CH:46]=[C:47]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:48]=1[OH:49])([CH3:40])[CH3:41]
Reactant: CC(C)(C)c1cc(C(=O)N2CCN(c3ccc(NC(=N)c4cccs4)cc3)CC2)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)c1cc(CC(=O)O)cc(C(C)(C)C)c1O
Agent: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: Cl
Product: CC(C)(C)c1cc(CC(=O)N2CCN(c3ccc(NC(=N)c4cccs4)cc3)CC2)cc(C(C)(C)C)c1O

Procedure:
The experimental protocol used is the same as that described for the compound 9, with 3,5-di-tert-butyl-4-hydroxyphenylacetic acid replacing the 3,5-di-tert-butyl-4-hydroxybenzoic acid in the first stage of synthesis. Yellow powder. Melting point: 176-180° C.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:20][C:21]1[N:22](COCC[Si](C)(C)C)[CH:23]=[C:24]([C:26]([OH:30])([C:28]#[CH:29])[CH3:27])[N:25]=1>>[F:19][C:3]1[C:2]([C:29]#[C:28][C:26]([OH:30])([C:24]2[N:25]=[C:21]([CH3:20])[NH:22][CH:23]=2)[CH3:27])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC(C)(O)c1cn(COCC[Si](C)(C)C)c(C)n1
Product: Cc1nc(C(C)(O)C#Cc2cc3c(cc2F)OCCn2cc(C(N)=O)nc2-3)c[nH]1

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)but-3-yn-2-ol to give the titled compound after removal of the SEM protecting group (n-Bu4NF, THF). White solid (9 mg, 6%).
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[O:7][CH:8]1[CH2:11][N:10]([C:12](=[O:18])[CH2:13][CH2:14][C:15](O)=[O:16])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:23][S:24]([NH2:27])(=[O:26])=[O:25].C(N(CC)CC)C.CC1C=CC=C([N+]([O-])=O)C=1C(OC(=O)C1C([N+]([O-])=O)=CC=CC=1C)=O>C(#N)C.CN(C)C1C=CN=CC=1>[C:1]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[O:7][CH:8]1[CH2:11][N:10]([C:12](=[O:18])[CH2:13][CH2:14][C:15]([NH:27][S:24]([CH3:23])(=[O:26])=[O:25])=[O:16])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(N)(=O)=O
Reactant: CC(C)(C)c1ccccc1OC1CN(C(=O)CCC(=O)O)C1
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)c1ccccc1OC1CN(C(=O)CCC(=O)NS(C)(=O)=O)C1
Reaction time: 16 h
Yield: 82.1 %

Procedure:
To a stirred solution of 4-[3-(2-tert-butylphenoxy)azetidin-1-yl]-4-oxobutanoic acid (610 mg, 2.00 mmol), methanesulfonamide (200 mg, 2.10 mmol) and triethylamine (0.84 ml, 6.00 mmol) in acetonitrile (5.0 mL) was added 2-methyl-6-nitrobenzoic anhydride (883 mg, 2.56 mmol) and N,N-dimethylpyridin-4-amine (244 mg, 2.00 mmol) at room temperature. After 16 h, the reaction mixture was partitioned between ethyl acetate and water and separated. The organic layer was washed with saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 10:90 hexane/ethyl acetate) to provide 4-[3-(2-tert-butylphenoxy)azetidin-1-yl]-N-(methylsulfonyl)-4-oxobutanamide (628 mg, 82%) as a colorless solid.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[C:27]([CH:31]1[CH2:36][CH2:35][CH:34]([C:37](O)=[O:38])[CH2:33][CH2:32]1)([CH3:30])([CH3:29])[CH3:28]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:37]([CH:34]3[CH2:35][CH2:36][CH:31]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:32][CH2:33]3)=[O:38])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: CC(C)(C)C1CCC(C(=O)O)CC1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: CC(C)(C)C1CCC(C(=O)N[C@H]2CC[C@H](CCN3CCCCC3c3coc4cccc-4c3)CC2)CC1

Procedure:
The title compound, off-white solid (77 mg, 63%), MS (ISP) m/z=493.4 [(M+H)+], mp 199° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-tert-butyl-cyclohexanecarboxylic acid.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[N:11])([O-])=O.[CH2:12]([SH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+]>CN(C)C=O>[CH2:12]([S:19][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[N:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1ccccc1[N+](=O)[O-]
Reactant: SCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1SCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A mixture consisting 2-nitrobenzenenitrile (5.0 g, 33.75 mmol) in 30 mL of anhydrous dimethylformamide (DMF) was cooled in an ice water bath (0° C.) and placed under N2 atmosphere. Benzylmercaptan (4.0 mL, 33.75 mmol) was added followed by the dropwise addition of an aqueous potassium hydroxide solution (3.40 g, 60.75 mmol in 10 mL of water). The reaction mixture was stirred at 0° C. for thirty minutes then allowed to warm to room temperature. After four hours the reaction appeared complete by thin layer chromatography (TLC). To the reaction mixture ice water (100 mL) was added. The solution was extracted with dichloromethane (200 mL) and washed with brine (100 mL). The organic layer was dried over sodium sulfate (Na2SO4) and then concentrated under reduced pressure to afford a red oil. The product was purified by flash silica column chromatography. Elution through an 80-g Silicycle® flash silica cartridge with 5% ethyl acetate in heptanes afforded the title compound as a bright yellow solid (6.08 g, 80%) Rf of 0.24″ with 95:5 v/v heptanes: ethyl acetate; 1H-NMR (400 MHz; CDCl3) δ 7.62 (dd, 1H), 7.47-7.42 (dt, 1H), 7.38 (dd, 1H), 7.32-7.25 (m, 6H); MS (ESI−) m/z 224.1 (Mz−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]([CH:18]([CH3:22])[C:19](O)=[O:20])[C:10](=[O:23])[CH:9]=2)[CH:7]=1.[NH2:26][C:27]1[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([C:14]([F:15])([F:17])[F:16])=[CH:12][N:11]([CH:18]([CH3:22])[C:19]([NH:26][C:27]3[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[CH:29][CH:28]=3)=[O:20])[C:10](=[O:23])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)O)n1cc(C(F)(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(C(F)(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
515 mg (purity 51%, 0.71 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl]propanoic acid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 251 mg (purity 79%, 51% of theory)
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11](O)=O)[CH:9]=2)[NH:4][N:3]=1.[NH2:14][NH:15][C:16]([NH2:18])=[S:17].[OH-].[K+]>>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:17][C:16]([NH2:18])=[N:15][N:14]=3)[CH:9]=2)[NH:4][N:3]=1
Reactant: NNC(N)=S
Reactant: Cc1n[nH]c2ccc(C(=O)O)cc12
Agent: [K+]
Agent: [OH-]
Product: Cc1n[nH]c2ccc(-c3nnc(N)s3)cc12
Temperature: 90 °C
Yield: 53 %

Procedure:
To a round bottom flash equipped with an overhead stir motor was added 80 g of polyphosphoric acid. The flask was heated to 90° C. and a finely ground mixture of 3-methyl-1H-indazole-5-carboxylic acid 4e (8.0 g, 45.5 mmol) and thiosemicarbazide (4.1 g (45.4 mmol) was slowly added over a period of 30 min. The resulting mixture was stirred for 24 hr. At this point 200 ml of ice water was added to the solution, and the pH of the resulting mixture was adjusted to 7.0 using solid KOH. A precipitate was formed in the process. The precipitate was isolated by filtration, washed sequentially with water and ether, and dried at reduced pressure, affording 5-(3-Methyl-1H-indazol-5-yl)-[1,3,4]thiadiazol-2-ylamine (4f) (5.50 g, 53% yield) as a tan colored solid. 1H 400 MHz NMR (d6 DMSO), 2.54 (3H, s), 3.17 (1H, s), 7.54 (1H, d, J=8.0 Hz), 7.83 (1H, t, J=8.0 Hz), 8.06 (1H, s). MS (API-ES) m/z (%): 232 (100%, M++H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:6][C:5]=1[F:19].[AlH4-].[Li+]>O1CCCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][NH:10][C:7]2[N:6]=[C:5]([F:19])[C:4]([CH2:3][OH:2])=[CH:9][CH:8]=2)=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(NCc2ccc(Cl)cc2)nc1F
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(NCc2ccc(Cl)cc2)nc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 6-(4-Chloro-benzylamino)-2-fluoro-nicotinic acid methyl ester (62, 2.00 g, 6.79 mmol) in tetrahydrofuran (100.0 mL) was added lithium tetrahydroaluminate (13.6 mL, 1.00 M in Tetrahydrofuran) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. To the reaction was added an excessive amount of NaSO4.10H2O, and then stirred for 1 hour. Filtration, concentration and purification with silica gel column chromatography eluting with 30% ethyl acetate in hexane provided compound 63 (1.0 g, 55.0%).
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[C:3](=[O:14])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].NCCC(O)=O.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CCCCCC.C(O)(=O)C.O>[CH3:1][CH:2]([CH3:15])[C:3](=[O:14])[C:4](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: O=Cc1ccccc1
Reactant: CC(C)C(=O)CC(=O)Nc1ccccc1
Agent: NCCC(=O)O
Solvent: CC(=O)O
Solvent: O
Solvent: CCCCCC
Product: CC(C)C(=O)C(=Cc1ccccc1)C(=O)Nc1ccccc1
Yield: 84.7 %

Procedure:
A suspension of 100 kg of 4-methyl-3-oxo-N-phenyl-pentanamide (Example A) in 660 kg of hexane was treated with agitation under nitrogen with 8 kg of β-alanine, 47 kg of benzaldehyde, and 13 kg of glacial acetic acid. The resulting suspension was heated to reflux with removal of water for 20 hours. An additional 396 kg of hexane and 3 kg of glacial acetic acid was added and reflux continued with water removal for 1 hour. The reaction mixture was cooled to 20° C. to 25° C., and the product was isolated by filtration. The product was purified by slurring in hexane at 50° C. to 60° C., cooling, and filtrating. The product was slurred twice with water at 20° C. to 25° C., filtered, and dried in vacuo to yield 110 kg of 4-methyl-3-oxo-N-phenyl-2-(phenylmethylene)pentanamide, mp 143.7-154.4° C. VPC: 30 meter DB-5 capillary column 50° C. to 270° C. at 15° C./min; 19.33 minutes, 99.7% (area). GC/MS: M/Z 293 [M]+.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH2:9]([C:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20](=[O:22])[CH3:21])=[CH:17][CH:18]=2)[N:13]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:12]=1)[CH3:10].O.C(OCC)(=O)C>CN(C)C=O>[CH3:3][N:4]([CH3:6])/[CH:5]=[CH:21]/[C:20]([C:16]1[CH:15]=[C:14]2[C:19]([C:11]([CH2:9][CH3:10])=[N:12][N:13]2[CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:18][CH:17]=1)=[O:22]
Reactant: CCc1nn(COCC[Si](C)(C)C)c2cc(C(C)=O)ccc12
Reactant: COC(OC)N(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nn(COCC[Si](C)(C)C)c2cc(C(=O)/C=C/N(C)C)ccc12
Temperature: 140 °C
Yield: 99.8 %

Procedure:
Under an atmosphere of argon, 1,1-Dimethoxy-N,N-dimethylmethanamine (4.4 mL, 0.033 mol) and 1-(3-Ethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-6-yl)ethanone (3.5 g, 0.011 mol) were mixed in N,N-dimethylformamide (110 mL) and the resulting mixture was heated at 140° C. for 16 hours. After cooling to room temperature, water (250 mL) and ethyl acetate (250 mL) were added, the layers were separated, and the product was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water and brine, dried (sodium sulfate), and the volatiles were removed in vacuo to afford 4.1 g (quantitative yield) of (2E)-3-(dimethylamino)-1-(3-Ethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-6-yl)prop-2-en-1-one, which was used without further purification.