Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:7]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[N:18]=3)[C:6]=2[CH:24]=1.[CH3:25][C:26]1[O:30][N:29]=[C:28]([C:31]([OH:35])([C:33]#[CH:34])[CH3:32])[CH:27]=1.C(N(CC)CC)C>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:23][C:19]1[N:18]=[C:17]([N:7]2[C:6]3[CH:24]=[C:2]([C:34]#[C:33][C:31]([C:28]4[CH:27]=[C:26]([CH3:25])[O:30][N:29]=4)([OH:35])[CH3:32])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[O:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:22]=[CH:21][N:20]=1
Reactant: C#CC(C)(O)c1cc(C)on1
Reactant: Nc1nccc(-n2c(OC3CCOCC3)nc3ccc(Br)cc32)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc(C(C)(O)C#Cc2ccc3nc(OC4CCOCC4)n(-c4ccnc(N)n4)c3c2)no1
Temperature: 70 °C
Reaction time: 5 h
Yield: 24.1 %

Procedure:
A mixture of 4-[6-bromo-2-(oxan-4-yloxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (150 mg, 0.27 mmol, 70%), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (200 mg, 1.32 mmol), bis(triphenylphosphine)palladium(II) dichloride (220 mg, 0.31 mmol) and triethylamine (1 mL) in dimethylsulfoxide (2 mL) was stirred under nitrogen atmosphere for 5 hr at 70° C. The reaction mixture was cooled to room temperature then filtered through a frit filter to remove the catalyst. The filtrate was purified by preparative HPLC to give 30 mg (24%) of 4-[1-(2-aminopyrimidin-4-yl)-2-(oxan-4-yloxy)-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol as a white solid. 1H NMR (400 MHz, DMSO) delta 8.41 (d, J=5.6 Hz, 1H), 8.15 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.28-7.07 (m, 1H), 7.08 (s, 2H), 6.99 (d, J=5.6 Hz, 1H), 6.46 (s, 1H), 6.37 (s, 1H), 5.39-5.35 (m, 1H), 3.88-3.82 (m, 2H), 3.06-3.55 (m, 2H), 2.51 (s, 3H), 2.24-2.16 (m, 2H), 1.88-1.82 (m, 5H); LC-MS: m/z=+461 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27]>>[NH2:27][C:26]1[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=1[C:6]1[CH:5]=[CH:4][C:3]([C:17]2[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=2)=[C:2]([F:1])[CH:7]=1
Reactant: Nc1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3N)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 2-bromoaniline. MS (ESI): mass calcd. for C16H13FN4, 280.11; m/z found, 281.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.02 (s, 1H), 7.91 (m, 1H), 7.31 (d, J=12.7, 2H), 7.04 (d, J=7.3, 2H), 6.82-6.58 (m, 4H), 4.94 (s, 2H).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:8]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])N>C(O)(=O)C>[CH2:5]1[C:6]2[NH:8][C:10]3[C:18](=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=[O:14])[CH:11]=3)[C:1]=2[CH2:2][CH2:3][CH2:4]1
Reactant: NNc1cccc(C(=O)O)c1
Reactant: O=C1CCCCC1
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c3c([nH]c2c1)CCCC3

Procedure:
A mixture of 2,3,4,9-tetrahydro-1H-carbazole-7-carboxylic acid and 2,3,4,9-tetrahydro-1H-carbazole-5-carboxylic acid was obtained by allowing cyclohexanone and 3-hydrazinobenzoic acid to undergo the reaction under heating in acetic acid. By separating and purifying this mixture by a silica gel column chromatography, 2,3,4,9-tetrahydro-1H-carbazole-5-carboxylic acid [Reference Example 16a: FAB: 216 (M+H)+] and 2,3,4,9-tetrahydro-1H-carbazole-7-carboxylic acid [Reference Example 16b: FAB: 216 (M+H)+] were obtained.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[C:7]([C:9]2[S:19][C:12]3=[N:13][CH:14]=[C:15]([CH:17]=O)[CH:16]=[C:11]3[CH:10]=2)[CH:6]=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.[NH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33].C(N(CC)CC)C.[BH4-].[Na+]>CO>[F:26][C:2]([F:1])([F:27])[C:3]1[CH:8]=[C:7]([C:9]2[S:19][C:12]3=[N:13][CH:14]=[C:15]([CH2:17][NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:16]=[C:11]3[CH:10]=2)[CH:6]=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1cnc2sc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)cc2c1
Reactant: NCCC(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)CCNCc1cnc2sc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)cc2c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 58.1 %

Procedure:
To a solution of 2-(2-trifluoromethyl-biphenyl-4-yl)-thieno[2,3-b]pyridine-5-carbaldehyde (32 mg, 0.083 mmol) in MeOH (2 mL) is added β-alanine HCl salt (37 mg, 0.42 mmol) and triethylamine (23 uL, 0.16 mmol). The mixture is stirred at 50° C. for 20 minutes. Sodium borohydride (30 mg, 0.8 mmol) is added at room temperature and it is stirred for 10 minutes. The mixture is purified with preparative LCMS to give 22 mg of 3-{[2-(2-trifluoromethyl-biphenyl-4-yl)-thieno[2,3-b]pyridin-5-ylmethyl]-amino}-propionic acid, which is converted to HCl salt: 1H NMR (400 MHz, CD3OD) δ 8.56 (d, 1 H), 8.30 (d, 1 H), 8.08 (d, 1 H), 7.98 (dd, 1 H), 7.84 (s, 1 H), 7.42 (d, 1 H), 7.40-7.34 (m, 3 H), 7.30-7.24 (m, 2 H); MS (ES) 457.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C@@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[CH:16]=1)[CH3:14])[CH:6]=[N:5]2.[C:28]([N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>O1CCOCC1.C(OCC)(=O)C>[C:31]([O:30][C:28]([N:35]1[CH:39]=[C:38]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([NH:12][C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]4[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]4)[CH:16]=2)[CH3:14])[CH:6]=[N:5]3)[CH:37]=[N:36]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[C@@H](Nc1cnc2cc(Br)ccc2n1)c1cccc(N2CCN(C)CC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H](Nc1cnc2cc(-c3cnn(C(=O)OC(C)(C)C)c3)ccc2n1)c1cccc(N2CCN(C)CC2)c1
Temperature: 105 °C

Procedure:
A mixture of (6-Bromo-quinoxalin-2-yl)-{(R)-1-[3-(4-methyl-piperazin-1-yl)-phenyl]ethyl}-amine (0.250 g, 1 eq., 0.588 mmol), 1-Boc-4-pyrazole boronic acid pinacol ester (0.190 g, 1.1 eq., 0.647 mmol), caesium carbonate (0.764 g, 4.0 eq., 2.35 mmol) and potassium iodide (0.010 g, 0.1 eq., 0.00588 mmol) in 1,4-dioxane (15 mL) was degassed at RT under vacuum and placed under an atmosphere of nitrogen. The process was repeated twice and Fu's catalyst (Bis(tri-tert-butylphosphine)palladium(0)) (0.015 g, 0.05 eq., 0.029 mmol) was added at room temperature. The reaction mixture was heated at 105° C. in a microwave reactor for 180 minutes. After completion of the reaction (confirmed by TLC), the organic mixture was diluted with ethyl acetate (325 mL) and washed with water (100 mL×3) and brine (100 mL). The organic layer was dried and concentrated under vacuum to give a crude residue.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[NH:19]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@H:20]([C:27](O)=[O:28])[CH2:21][O:22][C:23]([CH3:26])([CH3:25])[CH3:24].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[NH:19]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@H:20]([C:27]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:28])[CH2:21][O:22][C:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(N)=O
Reactant: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](COC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
8.90 g of H-Asn-Leu-OMe and 11.0 g of Z-Ser(tBu)-OH are dissolved in 100 ml of freshly distilled dimethylformamide. The solution is cooled to 0°C and 3.90 g of N-hydroxysuccinimide followed by 8.70 g of dicyclohexylcarbodiimide are added. After 30 minutes standing at 0°C and 18 hours at 25°C the precipitated dicyclohexylurea is filtered off and the filtrate is poured into 800 ml of ice water. The crystalline precipitate which hereupon separates out is dried in vacuo at 40°C and then recrystallised from methanol-water. The Z-Ser(tBu)-Asn-Leu-OMe which is hereupon obtained in an analytically pure form melts at melting point 202° - 205°C; [α]D20 =-18° (c = 1.05 in glacial acetic acid).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[Cl:9].[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: Fc1ccc(Br)c(Cl)c1
Reactant: C1CNCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Fc1ccc(N2CCNCC2)c(Cl)c1
Temperature: 120 °C

Procedure:
A suspension of 1-bromo-2-chloro-4-fluorobenzene (4.19 g, 20 mmoles), piperazine (10.32 g, 120 mmoles), sodium tert-butoxide (2.3 g, 1.5 mmoles), tris(dibenzylideneacetone)dipalladium (366 mg, 0.4 mmoles) and racemic (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (747 mg, 1.2 mmoles) in toluene (2 mL) was heated to 120° C. overnight. The mixture was cooled, filtered and the filtrate concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0-5% 2N methanolic ammonia in DCM) to provide the title compound.
Reaction SMILES: [CH3:1][Li].[F:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]([OH:16])=O.[OH-].[Na+]>C1COCC1>[F:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14](=[O:16])[CH3:1]
Reactant: O=C(O)c1cccc2c(F)cccc12
Reactant: [Li]C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)c1cccc2c(F)cccc12
Temperature: 25 °C

Procedure:
Methyl lithium (1.4M solution in ether; 6.6 ml) was added dropwise to a stirred solution of 5-fluoro-1-naphthalene carboxylic acid (870 mg) in dry THF (15 ml) at -78° under nitrogen. The reaction mixture was allowed to warm to room temperature over 2 h and was treated with 2N sodium hydroxide (60 ml). The mixture was extracted with ether (2×30 ml), and the combined, dried organic extracts were evaporated to give the title compound (865 mg) as an oil, t.l.c. (System B, 1:6) Rf 0.3.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[C:25](Cl)=[N:24][S:23][N:22]=1>CC#N.CCOC(C)=O.O>[Cl:20][C:21]1[C:25]([N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)=[N:24][S:23][N:22]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nsnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2nsnc2Cl)CC1
Temperature: 100 °C
Reaction time: 96 h

Procedure:
A mixture of N-Boc-piperazine (2.97 g, 15.9 mmol), K2CO3 (2.20 g, 15.9 mmol) and 3,4-dichloro-1,2,5-thiadiazole (1.5 mL, 15.9 mmol) in CH3CN (30 mL) was stirred at 100° C. for 19 h and at room temperature for 4 days. The reaction mixture was then diluted with EtOAc and water. The organic phase was dried (K2CO3) and the solvent was removed under reduced pressure. The residue was purified by chromatography on two successive silica gel columns eluting with hexane/EtOAc (1:1) and (7:3), respectively. This gave 1.54 g (31%) of the title product as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=O)=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39]([O:43][C:44](=[O:52])[NH:45][CH:46]1[CH2:51][CH2:50][CH2:49][NH:48][CH2:47]1)([CH3:42])([CH3:41])[CH3:40].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[C:39]([O:43][C:44](=[O:52])[NH:45][C@@H:46]1[CH2:51][CH2:50][CH2:49][N:48]([C:22]([C:21]2[N:20]=[C:19]([C:25]([F:28])([F:27])[F:26])[N:16]3[CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:29][C:30]4[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=4[F:38])[CH2:14][C:15]=23)=[O:24])[CH2:47]1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 62.6 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.12 g, 0.218 mmol), piperidin-3-yl-carbamic acid tert-butyl ester 11b (0.173 g, 0.545 mmol) and triethylamine (0.275 g, 2.18 mmol) were dissolved in 12 mL of dichloromethane under stirring, and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.138 g, 0.545 mmol) was then added to the mixture. The reaction mixture was reacted at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-(1-{7-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carbonyl}-piperidin-3-yl)-carbamic acid tert-butyl ester 11c (0.1 g, yield 63%) as an oil.
Reaction SMILES: C#C.[CH:3](NC(C)C)(C)[CH3:4].C#C.C1COCC1.C([Li])CCC.[CH3:22][C@H:23]1[CH2:28][C@H:27]2[C@H:29]3[C:39](=[CH:40][CH2:41][C@:25]2([CH3:26])[C:24]1=[O:43])[C@:37]1([CH3:38])[C:32](=[CH:33][C:34](=[O:42])[CH:35]=[CH:36]1)[CH2:31][CH2:30]3>C1COCC1>[C:3]([C@:24]1([OH:43])[C@@H:23]([CH3:22])[CH2:28][C@H:27]2[C@H:29]3[C:39](=[CH:40][CH2:41][C@:25]12[CH3:26])[C@:37]1([CH3:38])[C:32](=[CH:33][C:34](=[O:42])[CH:35]=[CH:36]1)[CH2:31][CH2:30]3)#[CH:4]
Reactant: CC(C)NC(C)C
Reactant: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)C1=O
Agent: C#C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#C[C@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@@]21C
Reaction time: 0.5 h

Procedure:
Dry THF (5 l) is cooled to -20° and acetylene (0.27 kg) is dissolved in the THF at -20°. Diisopropylamine (880 ml) is added to the acetylene/THF solution. n-Butyllithium (1.6M, 3.88 l) is added to the mixture maintaining the temperature at -20° and stirred for 30 min. 16β-Methylandrosta-1,4,9(11)-triene-3,17-dione (IB) in (THF) is added to the reaction mixture at or below -20° and stirred for 20 min to give the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:32]=[CH:31][C:20]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([OH:27])=O)=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:33]([F:36])([F:35])[F:34])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:50][O:51][NH:52][CH3:53].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:8]1[C:16]([C:17]2[CH:32]=[CH:31][C:20]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([N:52]([O:51][CH3:50])[CH3:53])=[O:27])=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:33]([F:35])([F:34])[F:36])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: O=C(O)c1cccc(Oc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(Oc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 3-{4-[2-benzyl-7-(trifluoromethyl)-2H-indazol-3-yl]phenoxy}benzoic acid (115.8 mg, 0.237 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (86 mg, 0.356 mmol), O,N-dimethyl-hydroxylamine hydrochloride (69 mg, 0.711 mmol) and 0.3 mL of triethylamine dissolved in 2 mL CH2Cl2 was stirred at room temperature overnight. The reaction mixture was quenched with 1M HCl(aq) and the crude material was extracted with CH2Cl2. The crude material was purified with flash chromatography using EtOAc/heptane, 3:7, as eluent to afford 17 mg of analytically pure product.
Reaction SMILES: [CH3:1][Mg]I.[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[N:13][C:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:27])[CH:24]=3)[C:19]([CH:34]=[O:35])=[CH:18]2)=[N:15][CH:16]=1>C1COCC1>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[N:15][C:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:27])[CH:24]=3)[C:19]([CH:34]([OH:35])[CH3:1])=[CH:18]2)=[N:13][CH:12]=1
Reactant: C[Mg]I
Reactant: O=Cc1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Solvent: C1CCOC1
Product: CC(O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Reaction time: 2 h

Procedure:
Methyl magnesium iodide (3M solution in diethyl ether, 0.17 mL, 0.522 mmol, 1.5 eq) was added at −70° C. to a stirred solution of 28a) (150 mg, 0.348 mmol, 1.0 eq) in dry THF (10 mL) and stirring was continued for 2 h at −50° C. The reaction mixture was quenched with ammonium chloride solution, diluted with water (20 mL), and extracted with ethyl acetate (2×20 mL). The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by preparative TLC using 70% ethyl acetate in petrolether as eluent. White solid. Yield: 70 mg (45% of theory). Melting range: 209-213° C. HPLC (method 1): Rt=10.09 min. Mass spectroscopy: m/z: [M+H]+=447.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]([O:18]CC)=[O:17])=[N:4][C:5]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:7]=1.[OH-].[Na+]>C1COCC1.CO.O>[Cl:1][C:2]1[C:3]([C:16]([OH:18])=[O:17])=[N:4][C:5]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(CNC(=O)C(C)(C)C)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)n1
Yield: 82.7 %

Procedure:
The title compound was prepared following the procedure described in Step 3 of Intermediate-2 using ethyl 3-chloro-6-(pivalamidomethyl)picolinate (1.00 g, 3.35 mmol) in THF:MeOH:H2O (3:2:1; 6 mL) and NaOH (268 mg, 6.71 mmol) to afford 750 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 13.85 (br s, 1H), 8.25 (br t, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 4.32 (d, J=6.0 Hz, 2H), 1.19 (s, 9H).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[OH:32]>>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[O:32][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: Oc1cc(F)ccc1Br
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: Fc1ccc(Br)c(OC2CCCCO2)c1

Procedure:
Procedure analogous to Example 5. Use of 478.0 ml (5.24 mol) of 3,4-dihydropyran, 65.4 g (260 mmol) of pyridinium p-toluenesulfonate and 500.0 g (2.62 mmol) of 2-bromo-5-fluorophenol. The yield was 562.2 g (78.0%) at a purity of greater than 98.0% by 1H NMR.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([NH2:13])=[O:12])=[CH:4][CH:3]=1.O[CH2:15][NH:16][C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].O1CCCC1>Cl.O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([NH:13][CH2:15][NH:16][C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:12])=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCCCCCCC(=O)NCO
Reactant: NC(=O)CCSc1ccc(O)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC(=O)NCNC(=O)CCSc1ccc(O)cc1
Temperature: 60 °C
Yield: 72 %

Procedure:
Into a 200-ml flask equipped with a stirrer and a condenser were charged 8.0 g of 3-(p-hydroxyphenylthio)propanamide, 10.6 g of N-hydroxymethyl-n-octadecanamide, 5 drops of concentrated hydrochloric acid and 120 ml of tetrahydrofuran, and stirred with heating at 60° C. for 5 hours. The reaction mixture was cooled to room temperature and then poured into 300 ml of distilled water. The white crystals precipitated were collected by filtration and recrystallized from isopropanol to obtain 12.0 g of the desired compound. Melting point: 172° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([CH3:8])=[N:6][CH:7]=1.[CH2:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:13]#[CH:14]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:18]([O:17][C:16](=[O:22])[NH:15][CH2:12][C:13]#[C:14][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1ncc(C#CCNC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 79.3 %

Procedure:
To a solution of 5-bromo-2-methyl-3-nitropyridine (2.81 g, 12.9 mmol) in TEA (25 mL) was added tert-butyl prop-2-yn-1-ylcarbamate (2.58 g, 16.6 mmol). The solution was degassed with argon. To the reaction mixture were added bis(triphenylphosphine)palladium(II)chloride (0.18 g, 0.26 mmol) and copper(I)iodide (0.098 g, 0.52 mmol). The reaction mixture was allowed to stir at 70° C. for 2.5 h and was then concentrated and diluted with EtOAc (100 mL). The mixture was filtered over a pad of Celite® and the resulting filtrate was washed with sat. aq. NaHCO3 (100 mL). The organic solution was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give tert-butyl[3-(6-methyl-5-nitropyridin-3-yl)prop-2-yn-1-yl]carbamate (2.98 g, 79%) as a yellow solid. LCMS (FA): Rt=1.81 min, m/z=292.0 (M+H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]1([CH2:11][NH:12][C:13]([C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[CH:20][NH:21]3)=[CH:17][CH:16]=2)=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+].CN(C)[CH:28]=[O:29]>>[CH:6]1([CH2:11][NH:12][C:13]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([CH:28]=[O:29])=[CH:20][NH:21]3)=[CH:17][CH:16]=2)=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C(NCC1CCCC1)c1ccc2cc[nH]c2c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2cc(C(=O)NCC3CCCC3)ccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
N,N-Dimethylformamide (DMF)(20 ml) was cooled to 0° under an atmosphere of nitrogen and treated cautiously with phosphorus oxychloride (6.6 ml). This solution was stirred at 0° for 15 minutes, warmed to room temperature, and treated with a solution of 6-(N-cyclopentylmethylcarbamoyl)indole (14.3 g) in DMF (100 ml). The yellow mixture was stirred for 2 hours and then brought to pH 14 by the addition of ice and 20% (w/v) aqueous sodium hydroxide. The mixture was heated to reflux for 5 minutes and allowed to cool. The precipitate which formed was collected by filtration and triturated with ether to give 6-(N-cyclopentylmethylcarbamoyl)-3-formylindole (9.6 g, 60%) as a tan powder; mp 224°-225°.