Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.Br[C:24]1[C:25]([F:31])=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=1>>[F:31][C:25]1[C:24]([N:17]2[CH2:16][CH2:15][C:12]3([C:11](=[O:20])[N:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)[CH2:19][CH2:18]2)=[CH:29][C:28]([CH3:30])=[CH:27][N:26]=1
Reactant: Cc1cnc(F)c(Br)c1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Product: Cc1cnc(F)c(N2CCC3(CC2)CCN(c2ccc(OC(F)(F)F)cc2)C3=O)c1

Procedure:
The title compound was prepared in analogy to example 1 step D from a mixture of 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 1 step C) and 3-bromo-2-fluoro-5-methylpyridine. Light yellow solid. MS (ESI): 424.1 (MH+)
Reaction SMILES: [C:1]1([N:7]2[N:11]=[N:10][C:9]([C:12]([OH:14])=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:15]1[CH:16]=[CH:17][N:18]2[CH:23]=[CH:22][N:21]=[C:20]([N:24]3[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25]3)[C:19]=12.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O>[N:15]1[CH:16]=[CH:17][N:18]2[CH:23]=[CH:22][N:21]=[C:20]([N:24]3[CH2:28][CH2:27][C@H:26]([NH:29][C:12]([C:9]4[N:10]=[N:11][N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:8]=4)=[O:14])[CH2:25]3)[C:19]=12
Reactant: N[C@H]1CCN(c2nccn3ccnc23)C1
Reactant: O=C(O)c1nnn(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCN(c2nccn3ccnc23)C1)c1nnn(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
To a solution of 2-phenyl-2H-tetrazole-5-carboxylic acid (0.10 g, 0.53 mmol, 1 eq) and (S)-1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-amine (0.15 g, 0.53 mmol, 1 eq) in 1 mL of DMSO was added triethylamine (0.22 mL, 0.58 mmol, 1.1 eq) and HATU (0.22 g, 0.58 mmol, 3 eq). The mixture was stirred at room temperature for 1 h and was then concentrated and purified by HPLC to afford (S)—N-(1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)-2-phenyl-2H-tetrazole-5-carboxamide (0.10 g, 0.26 mmol, 49%). 1H NMR (400 MHz, CD3OD) δ 8.19 (d, J=7.0 Hz, 2 H), 8.06 (s, 1 H), 7.95 (d, J=5.5 Hz, 1H), 7.82 (s, 1H), 7.70-7.58 (m, 3 H), 7.19 (d, J=5.8 Hz, 1 H), 5.00-4.90 (m, 1H), 4.80-3.80 (br, 4 H), 2.62-2.38 (m, 2 H); MS: (ES) m/z calculated for C18H17N9O [M+H]+ 376.2, found 376.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([NH:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([N:34]2[CH2:33][CH2:32][N:31]([C:25]3[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=3)[CH2:36][CH2:35]2)=[O:20])[C:5]([NH:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: CNc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Product: CNc1nc(C)c(C)cc1NC(=O)N1CCN(c2cc(OC)cc(OC)c2)CC1
Yield: 53 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methylaminopyridin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[C:25]([CH3:31])[N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[C:6]([N:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C:9]2=[O:14])[CH:7]=1.[NH:32]1[CH2:36][CH2:35][CH2:34][C:33]1=[O:37]>>[CH3:13][N:10]1[CH2:11][CH2:12][N:8]([C:6]2[CH:7]=[C:2]([N:32]3[CH2:36][CH2:35][CH2:34][C:33]3=[O:37])[CH:3]=[CH:4][C:5]=2[C:15]([N:17]2[CH2:18][CH2:19][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[C:25]([CH3:31])[N:24]=3)[CH2:21][CH2:22]2)=[O:16])[C:9]1=[O:14]
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Cl)cc3N3CCN(C)C3=O)CC2)nc1C
Reactant: O=C1CCCN1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3N3CCN(C)C3=O)CC2)nc1C
Yield: 49.1 %

Procedure:
Using 1-{5-chloro-2-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-3-methylimidazolidin-2-one (55 mg) described in Preparation Example 259 and pyrrolidin-2-one (16 mg) and by the reaction and treatment in the same manner as in Example 666, the title compound (30 mg) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:11]([C:12]([O:14]CC)=[O:13])[C:10]=1[C:21]([O:23]CC)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O.C(O)C>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:11]([C:12]([OH:14])=[O:13])[C:10]=1[C:21]([OH:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(C)ccc(OCc2ccccc2)c1C(=O)OCC
Solvent: CCO
Solvent: O
Product: Cc1ccc(OCc2ccccc2)c(C(=O)O)c1C(=O)O

Procedure:
The crude ester is heated under reflux for 3 hours in 150 ml water and 100 ml 95% ethanol containing 20 g NaOH. The mixture is poured into water and the resulting solid removed by filtration, washed with water and air-dried to give 24.4 g crude 3-benzyloxy-6-methylphthalic acid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[C:33](B(O)O)[C:28]=2[O:27][CH2:26]1.O1CCOCC1>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[C:33]([C:2]3[N:7]4[N:8]=[CH:9][CH:10]=[C:6]4[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]4[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:21])[CH3:22])=[CH:16][CH:15]=4)[CH:3]=3)[C:28]=2[O:27][CH2:26]1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: OB(O)c1cccc2c1OCO2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(-c3cccc4c3OCO4)n3nccc3n2)cc1
Temperature: 110 °C
Yield: 4.5 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 0.151 mmol), benzo[d][1,3]dioxol-4-ylboronic acid (50 mg, 0.302 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9 mg, 12 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (330 microliters of 1,4-dioxane and 670 microliters of saturated aqueous NaHCO3) was prepared in a 2 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 20 minutes. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC, 5-95% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (2.8 mg, 4%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6 H) 5.20 (s, 1 H) 6.18 (s, 2 H) 6.57 (d, J=2.27 Hz, 1 H) 7.17 (d, J=8.34 Hz, 1 H) 7.56-7.69 (m, 3 H) 7.72 (d, J=1.77 Hz, 1 H) 7.98-8.10 (m, 3 H) 8.19 (d, J=2.27 Hz, 1 H) 11.23 (s, 1 H). ESI-MS: m/z 417.0 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][S:8]([NH2:11])(=[O:10])=[O:9].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[CH2:42]([C:46]1[O:47][C:48]2[CH:54]=[CH:53][C:52](Br)=[CH:51][C:49]=2[CH:50]=1)[CH2:43][CH2:44][CH3:45]>O1CCOCC1.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]>[CH2:42]([C:46]1[O:47][C:48]2[CH:54]=[CH:53][C:52]([NH:11][S:8]([CH3:7])(=[O:10])=[O:9])=[CH:51][C:49]=2[CH:50]=1)[CH2:43][CH2:44][CH3:45]
Reactant: CCCCc1cc2cc(Br)ccc2o1
Reactant: CS(N)(=O)=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1
Temperature: 100 °C

Procedure:
The following are placed in an equipped reactor under an argon atmosphere: 13 g of cesium carbonate (39.9 mmol), 3 g of methanesulfonamide (31.5 mmol), 250 mg of Pd(dba)2 (0.4 mmol) and 440 mg of 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl (ligand L1) (1.04 mmol). 5.5 g of 2-n-butyl-5-bromobenzofuran (compound IX or II) (21.7 mmol) dissolved in 55 ml of dioxane are then added by syringe. The reaction medium is then stirred and heated at 100° C. for 24 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C@H:14]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH:13][C@H:14]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NS(=O)(=O)c3cc(Cl)ccc3Cl)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using 2,5-dichlorobenzenesulfonyl chloride and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 588.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[C:11]([N+:12]([O-])=O)=[C:10]([NH:15][CH3:16])[N:9](C)[N:8]=1.O.NN>[Ni].C(O)C>[NH2:12][C:11]1[C:7]([CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:8][NH:9][C:10]=1[NH:15][CH3:16]
Reactant: CNc1c([N+](=O)[O-])c(COCCOC)nn1C
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CNc1[nH]nc(COCCOC)c1N
Yield: 106.5 %

Procedure:
3-(2-Methoxyethoxy)methyl-1-methyl-5-methylamino-4-nitropyrazole (0.73 g, 3 mmoles), hydrazine hydrate (0.5 ml) and Raney nickel (200 mg) were stirred in ethanol (12 ml) at 50° C. for 1.5 hours. The Raney Nickel was filtered off and the ethanol removed under reduced pressure yielding the title compound (0.64 g, 100%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[S:9]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)([OH:12])(=[O:11])=[O:10].[CH3:20][NH:21]CCCCC=C>>[S:9]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)([OH:12])(=[O:11])=[O:10].[CH3:20][NH:21][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH:7][CH3:8]
Reactant: C=CCCCCCBr
Reactant: C=CCCCCNC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC=CCCCCNC

Procedure:
N-Methylhept-5-en-1-amine tosylate salt 31b was synthesized from 7-bromo-heptene, according to the procedure as described for compound 31a, as a white solid in quantitative yield. 1H NMR (CDCl3, 400 MHz) δ 1.38 (q, J=7.76 Hz, 2H), 1.71 (q, J=7.76 Hz, 2H), 1.80 (q, J=6.98 Hz, 2H), 1.99 (q, J=6.98 Hz, 2H), 2.38 (s, 3H), 2.70 (t, J=5.17 Hz, 3H), 2.87-2.93 (m, 2H), 4.92-4.99 (m, 2H), 5.67-5.73 (m, 1H), 7.20 (d, J=7.76 Hz, 2H), 7.75 (d, J=7.76 Hz, 2H), 8.62 (br s, 2H).
Reaction SMILES: [NH:1]([C:3](=[NH:18])[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=2)[CH:9]=1)[NH2:2].[CH:19](O)=O>>[NH:2]1[CH:19]=[N:18][C:3]([C:4]2[CH:5]=[CH:6][C:7]3[N:8]([CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=3)[CH:9]=2)=[N:1]1
Reactant: O=CO
Reactant: CCOC(=O)c1cn2cc(C(=N)NN)ccc2n1
Product: CCOC(=O)c1cn2cc(-c3nc[nH]n3)ccc2n1
Temperature: 85 °C

Procedure:
A suspension of 580 mg of ethyl 6-[hydrazino(imino)methyl]imidazo[1,2-a]pyridine-2-carboxylate in 6 mL of formic acid is heated for 20 hours at 85° C. The reaction mixture is concentrated to less than 20% of its initial volume and diluted with 20 mL of water. Solid sodium carbonate is added at 0-5° C. to obtain a pH of 8-9. The precipitate is filtered off by suction, and then purified by chromatography on silica, eluting with a mixture of dichloromethane and methanol (98/2) to give 320 mg of ethyl 6-(1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine-2-carboxylate.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[F:20][CH2:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:26]4[CH2:25][CH2:24][NH:23][CH:22]([CH2:21][F:20])[CH2:27]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: FCC1CNCCN1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNC(CF)C3)c(F)cc2c1=O
Temperature: 115 °C
Yield: 93.9 %

Procedure:
A suspension of 530.4 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 90.7 mg of 2-(fluoromethyl)piperazine and 2 ml of pyridine was heated at 115° C. for 30 minutes, then filtered and the filtrate refrigerated overnight. The resulting crystals were collected, washed with water, ether and dried, giving 262 mg of the desired compound as light yellow crystals, mp 202°-203° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([NH:16]C(OCC2C=CC=CC=2)=O)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:16][C@H:13]1[CH2:14][CH2:15][C@H:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](N)CC1
Reaction time: 1 h

Procedure:
1.4 g of trans-4-(tert-butyloxycarbonylaminomethyl)-benzyloxycarbonylaminocyclohexane are dissolved in 30 ml of methanol and, after addition of 0.3 g of palladium/active carbon catalyst, hydrogenated at room temperature under 50 psi for one hour. After filtration, the solvent is distilled off in a rotary evaporator. The residue is employed without purification. P Yield: 1.02 g (100% of theory) of a colourless wax,; Rf : 0.28 (alumina; -methylene chloride/methanol=10:1)
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.COC1C=C2C(CCC(=O)C2(C)C)=CC=1.Cl.[Cl:40]C1C=C(NN)C=CC=1>>[Cl:40][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: NNc1cccc(Cl)c1
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(Br)ccc3c1C2=O
Agent: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Agent: Cl
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(Cl)ccc3c1C2=O

Procedure:
Under the same conditions as the method for synthesizing Compound A3-1 and Compound A4, the title compound was prepared as a crude product from Compound A2 and (3-chlorophenyl)-hydrazine hydrochloric acid salt.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1>C(O)CCC>[N:13]1([C:2]2[C:3]3[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: Cc1[nH]c2ncnc(Cl)c2c1C
Reactant: c1ccc2c(c1)CCN2
Solvent: CCCCO
Product: Cc1[nH]c2ncnc(N3CCc4ccccc43)c2c1C

Procedure:
Under an argon atmosphere, 0.2 g (1.1 mmol) of 4-chloro-5,6-dimethyl-7H-pyrrolo[2,3-d]-pyrimidine (see Liebigs Ann. Chem. 1986(9), 1485-1505; CAS-Reg. No. 82703-38-6) and 0.15 ml (1.32 mmol) of 2,3-dihydroindole (Fluka, Buchs, Switzerland) in 5 ml of abs. n-butanol are heated at reflux for 2 hours until the starting material is no longer present in TLC. The reaction mixture is concentrated by evaporation in vacuo at 50° C. The brown residue is dissolved in 30 ml of ethyl acetate, and 10 ml of 1 N NaOH solution are added. The organic phase is separated off and washed three times with a small amount of water, dried and concentrated by evaporation. The crude product is dissolved in 10 ml of THF, and n-hexane is added until crystallization begins. Stirring is carried out at 0° C. and the product is filtered off with suction and dried under a high vacuum. Pure 4-(2,3-dihydroindol-1-yl)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine is obtained in the form of colorless crystals having a melting point of 220-221° C. FAB-MS: (M+H)+ =265 (corresponds to C16H16N4); Rf value (toluene-acetone--4:6)=0.46.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>[Pd](Cl)Cl.C(N(CC)CC)C>[CH3:12][Si:13]([C:16]#[C:17][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1)([CH3:15])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 67.5 °C
Reaction time: 20 h

Procedure:
A stirred mixture of 3.05 g (14. 31 mmol) of 4-tert-butyl-bromobenzene (Compound 20), 1.41 g (14.39 mmol) of trimethylsilylacetylene (Compound 16), 139 mg (0.13 mmol) of cuprous iodide, 293 mg (0.42 mmol) of bis(triphenyophosphine) palladium (II) chloride and 3 ml of triethylamine was flushed with nitrogen and then heated under nitrogen at 65-70 degrees C. for 20 hours. The reaction mixture was stirred at room temperature for a further 4 hours and the triethylamine then removed under vacuum. The residue was purified by flash chromatography (silica; hexanes) to give the title compound as a colorless oil. PMR (CDCl3): & 0.26 (9H, s), 1.31 (9H, s), 7.32 (2H, d, J~8.2 Hz), 7.42 (2H, d, J~8.2 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][N:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([N-]C(C)C)(C)C.[Li+].O1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:1][O:2][C:3](=[O:13])[CH:4]([CH2:26][CH2:25][CH:24]=[CH2:23])[N:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)CN=Cc1ccccc1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: C=CCCC(N=Cc1ccccc1)C(=O)OC

Procedure:
In step a, the N-(phenylmethylene)glycine methyl ester of structure 55 can be treated with one equivalent of a non-nucleophilic base, such as lithiumdiisopropylamide, in a suitable aprotic solvent, such as tetrahydrofuran, followed by addition of a 4-halobutene of structure 56 to give 2-(3-butenyl)-N-(phenylmethylene)glycine methyl ester of structure 57.
Reaction SMILES: [H-].[Na+].C(S)C.[CH2:6]([C:8]1[O:19][C:11]2=[C:12]([O:17]C)[N:13]=[CH:14][C:15]([Br:16])=[C:10]2[CH:9]=1)[CH3:7].O>CN(C)C=O>[Br:16][C:15]1[C:10]2[CH:9]=[C:8]([CH2:6][CH3:7])[O:19][C:11]=2[C:12](=[O:17])[NH:13][CH:14]=1
Reactant: CCc1cc2c(Br)cnc(OC)c2o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCS
Product: CCc1cc2c(Br)c[nH]c(=O)c2o1
Temperature: 150 °C
Yield: 89.4 %

Procedure:
To a stirred solution of sodium hydride (50 mg) (60% suspension in mineral oil) in dry N,N-dimethylformamide (3 ml) under an atmosphere of dry nitrogen at room temperature was added dropwise a solution of ethanethiol (0.09 ml) in N,N-dimethylformamide (3 ml). After stirring for 10 mins a solution of 2-ethyl-4-bromo-7-methoxyfuro[2,3-c]pyridine (200 mg) in N,N-dimethylformamide (5 ml) was added dropwise and the reaction mixture heated at 150° C. for 60 mins. Water (5 ml) was added and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (100 ml), washed with ammonium chloride solution (25 ml), water (25 ml) and brine (25 ml), dried over magnesium sulphate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with ethyl actate afforded the title compound as a white solid (169 mg).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]([CH2:34][CH2:35][CH3:36])[C:14]3[CH:15]=[C:16]([CH:31]=[CH:32][CH:33]=3)[CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])=[CH:21][CH:20]=3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[OH-].[Na+].Cl>O.O1CCCC1>[C:1]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]([CH2:34][CH2:35][CH3:36])[C:14]3[CH:15]=[C:16]([CH:31]=[CH:32][CH:33]=3)[CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:23][CH:24]=3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCN(Cc1nc(-c2ccccc2)cs1)c1cccc(COc2ccc(CCC(=O)OC)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCCN(Cc1nc(-c2ccccc2)cs1)c1cccc(COc2ccc(CCC(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
To a mixture of methyl 3-[4-({3-[[(4-phenyl-1,3-thiazol-2-yl)methyl](propyl)amino]benzyl}oxy)phenyl]propanoate (360 mg, 0.72 mmol), ethanol (5 mL) and tetrahydrofuran (5 mL) was added 2N aqueous sodium hydroxide solution (2 mL) and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4-4:1 in volume ratio) to give the title compound (262 mg, yield 75%) as colorless prism crystals (recrystallized from acetone-heptane).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:5][CH:4]=1.[C:25]([O:29][C:30]([NH:32][C:33]([CH3:51])([CH3:50])[CH2:34][C:35]([NH:37][C@@H:38]1[CH2:44][CH2:43][C:42]2[CH:45]=[CH:46][CH:47]=[CH:48][C:41]=2[NH:40][C:39]1=[O:49])=[O:36])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([O:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:40]3[C:41]4[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=4[CH2:43][CH2:44][C@@H:38]([NH:37][C:35](=[O:36])[CH2:34][C:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:26])[CH3:28])([CH3:50])[CH3:51])[C:39]3=[O:49])=[CH:4][CH:5]=2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2-c2ccc(CBr)cc2)cc1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3Oc3ccc([N+](=O)[O-])cc3)cc2)C1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 4'-bromomethyl-2-(4-nitrophenoxy)-1,1'-biphenyl and 3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3-(R)-yl]-butanamide (Example 57, Step A) by the procedure described in Example 69, Step D. 1H NMR (200 MHz,CDCl3): 1.32 (s,6H), 1.38 (s,9H), 1.78 (m,1H), 2.3-2.7 (m,5H), 4.47 (m,1H), 4.75 (d,15 Hz,1H), 5.13 (d,15 Hz,1H), 6.63 (d,7 Hz,1H), 6.75 (d,8 Hz,2H), 7.05-7.50 (m,/11H), 7.97 (s,1H), 7.98 (d,8 Hz,2H).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:15])[CH2:14][CH2:13]1>CCO>[CH:12]1([NH:15][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N+:9]([O-:11])=[O:10])[CH2:14][CH2:13]1
Reactant: COc1ccncc1[N+](=O)[O-]
Reactant: NC1CC1
Solvent: CCO
Product: O=[N+]([O-])c1cnccc1NC1CC1

Procedure:
A solution of 4-methoxy-3-nitropyridine (7.71 g, 50 mmol) and cyclopropylamine (7.14 g, 125 mmol) in EtOH (20 mL) was heated at 80° C. in a sealed tube for 2 h. The solvent was evaporated to give cyclopropyl-(3-nitro-pyridin-4-yl)-amine as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:12]1[O:29][C@H:28]([CH2:30][O:31]C(=O)C)[C@@H:23]([O:24]C(=O)C)[C@H:18]([O:19]C(=O)C)[C@H:13]1[O:14]C(=O)C.[O:35]1[CH:39]=[CH:38][C:37]2[CH:40]=[C:41]([C:44](Cl)=O)[CH:42]=[CH:43][C:36]1=2>>[O:35]1[CH:39]=[CH:38][C:37]2[CH:40]=[C:41]([CH2:44][C:4]3[C:3]4[C:7](=[CH:8][CH:9]=[C:10]([F:11])[C:2]=4[Cl:1])[N:6]([C@@H:12]4[O:29][C@H:28]([CH2:30][OH:31])[C@@H:23]([OH:24])[C@H:18]([OH:19])[C@H:13]4[OH:14])[CH:5]=3)[CH:42]=[CH:43][C:36]1=2
Reactant: O=C(Cl)c1ccc2occc2c1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)c(F)ccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: OC[C@H]1O[C@@H](n2cc(Cc3ccc4occc4c3)c3c(Cl)c(F)ccc32)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The above 4-chloro-5-fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole and benzo[b]furan-5-carbonyl chloride were treated in a manner similar to Example 27 to give the titled compound, 3-(benzo[b]furan-5-yl-methyl)-4-chloro-5-fluoro-1-(β-D-glucopyranosyl)indole as a colorless powder. APCI-Mass m/Z 462/464 (M+H). 1H-NMR (DMSO-d6) δ 3.15-3.45 (m, 4H), 3.65 (m, 2H), 4.35 (s, 2H), 4.54 (t, J=5.5 Hz, 1H), 5.11 (d, J=5.3 Hz, 1H), 5.17 (d, J=5.0 Hz, 1H), 5.24 (d, J=5.8 Hz, 1H), 5.40 (d, J=9.0 Hz, 1H), 6.87 (d, J=1.4 Hz, 1H), 7.16 (t, J=9.2 Hz, 1H), 7.21 (dd, J=8.4, 1.0 Hz, 1H), 7.37 (s, 1H), 7.44 (s, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.57 (dd, J=9.0, 4.0 Hz, 1H), 7.93 (d, J=1.9 Hz, 1H).