Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:15][C:16]1[N:21]=[C:20]2[NH:22][N:23]=[CH:24][C:19]2=[C:18]([N:25]2[CH2:31][CH:30]3[O:32][CH:27]([CH2:28][CH2:29]3)[CH2:26]2)[N:17]=1.O[CH:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:27]12[O:32][CH:30]([CH2:29][CH2:28]1)[CH2:31][N:25]([C:18]1[N:17]=[C:16]([Cl:15])[N:21]=[C:20]3[N:22]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]4)[N:23]=[CH:24][C:19]=13)[CH2:26]2
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cn[nH]c2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(Cl)nc32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Diisopropyl azodicarboxylate (0.71 mL, 3.6 mmol) was added in drops to a suspension of 3-(6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (0.53 g, 2.0 mmol), tert-butyl 4-hydroxy-1-piperidinecarboxylate (0.48 g, 2.4 mmol), and triphenylphosphine (0.79 g, 3.0 mmol) in tetrahydrofuran (20 mL). After stirring at room temperature for 16 hours, the mixture was adsorbed onto flash silica gel and purified by automated flash chromatography (hexanes/ethyl acetate) to provide tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate as a white solid contaminated with a light yellow material (0.81 g, 90%). MS (ES+): 448.9, 450.2 (M+H)+
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Cl[C:13]1[N:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=1>C1(C)C=CC=CC=1.C(O)C>[Cl:19][C:16]1[CH:15]=[N:14][C:13]([C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)=[N:18][CH:17]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: O=Cc1ccc(B(O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1ccc(-c2ncc(Cl)cn2)cc1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
Palladium dichloro-bis(triphenylphosphine) (3.5 g) was added to a stirred solution of 4-formylbenzene boronic acid (32.5 g), 2,5-dichloro-pyrimidine (30 g) in toluene (1000 ml) and ethanol (100 ml) under an argon atmosphere. The solution was purged with argon and aqueous sodium carbonate (2N) (200 ml) was added. The reaction mixture was stirred at 60° C. for 90 minutes, cooled to ambient temperature, diluted with ethyl acetate, and washed successively with aqueous sodium hydrogen carbonate (saturated), water and brine. The combined organic extracts were treated with charcoal, dried over sodium sulfate, filtered through Hyflo® and concentrated in vacuo. The residue was triturated with diethyl ether (100 ml), the solid isolated by filtration and dried under high vacuum to give 4-(5-chloro-pyrimidin-2-yl)-benzaldehyde as a white solid. M.p. 186° C. 1H NMR (400 MHz, DMSO) 8.10 (d, 2H), 8.55 (d, 2H), 9.1 (s, 2H).
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[C:21]([O:25][C:26](=[O:39])[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][C@H:32]([NH2:38])[C:33]([N:35]([CH3:37])[CH3:36])=[O:34])([CH3:24])([CH3:23])[CH3:22]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:38][C@H:32]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][NH:27][C:26](=[O:39])[O:25][C:21]([CH3:22])([CH3:23])[CH3:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CN(C)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Product: COc1ccccc1C1(N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.73 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 78-2 (6.76 mmol, crude form) as starting materials respectively 0.90 g (Isomer A, colorless amorphous) and 1.69 g (Isomer B, colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)=[O:3].[CH3:20][N:21]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]1.C(OCC)(=O)C>ClC1C=CC=CC=1>[CH3:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]2=3)=[O:3])[CH2:23][CH2:22]1
Reactant: CN1CCC(O)CC1
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ccccc21
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: CN1CCC(OC(=O)N2c3ccccc3NC(=O)c3ccccc32)CC1

Procedure:
A quantity of 4.1 gm (0.015 mol) of 5-chlorocarbonyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one was refluxed with 3.45 gm (0.03 mol) of 1-methyl-4-piperidinol in 50 ml of chlorobenzene for two hours. After cooling, the reaction solution was diluted by the addition of 200 ml of ethyl acetate and then extracted exhaustively with 15% hydrochloric acid. The combined extracts were neutralized with potassium carbonate and extracted several times with chloroform, and the combined chloroform extracts were evaporated to dryness in vacuo. By recrystallization from ethyl acetate, colorless crystals were obtained, m.p.: 203°-204° C. Yield: 1.2 gm (23% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:12]=[C:13]([F:23])[C:14]3[O:19][CH2:18][C:17](=[O:20])[N:16]([CH3:21])[C:15]=3[CH:22]=2)=[O:10])=[C:4]([Cl:24])[CH:3]=1.[H-].[Na+].[CH3:27]I>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:11]2[CH:12]=[C:13]([F:23])[C:14]3[O:19][CH2:18][C:17](=[O:20])[N:16]([CH3:21])[C:15]=3[CH:22]=2)=[O:10])=[C:4]([Cl:24])[CH:3]=1
Reactant: CI
Reactant: CN1C(=O)COc2c(F)cc(C(=O)Cc3ccc(Br)cc3Cl)cc21
Agent: [H-]
Agent: [Na+]
Product: CC(C(=O)c1cc(F)c2c(c1)N(C)C(=O)CO2)c1ccc(Br)cc1Cl

Procedure:
In analogy to Example 1, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-acetyl]-8-fluoro-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with sodium hydride and methyl iodide to give the title compound as a light yellow foam. MS (m/e, ISP neg. ion)=423.9 [M−H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.F[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cccc(F)n1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1cccc(-n2cc(C#Cc3ccnc(Cl)c3)nc2C)n1

Procedure:
The title compound, MS: m/e=309.5 (M+H+), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-fluoro-6-methyl-pyridine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C1COCC1>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][NH:1][C:20](=[O:22])[CH3:21])=[CH:5]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tryptamine (192 mg/1.2 mmol) was initially introduced into abs. THF (5 ml), and triethylamine (179 μl/1.3 mmol) was added. Acetic anhydride (132 mg/1.3 mmol) was then added and the mixture was stirred at RT for 4 h. The mixture was concentrated to dryness i. vac. The residue was taken up in ethyl acetate and this solution was washed with saturated NaHCO3 solution (two times 20 ml) and with NaCl solution (two times 20 ml). The organic phase was dried over Na2SO4 and concentrated i. vac.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[OH-].[Na+].CN(C)[CH2:10][CH2:11][C:12]([C:14]1[O:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[CH:17][CH:18]=1)=O>CO>[NH2:5][C:3]([N:2]1[CH2:10][CH2:11][C:12]([C:14]2[O:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[CH:17][CH:18]=2)=[N:1]1)=[S:4]
Reactant: CN(C)CCC(=O)c1ccc(-c2cccc(Cl)c2)o1
Reactant: NNC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=S)N1CCC(c2ccc(-c3cccc(Cl)c3)o2)=N1

Procedure:
Thiosemicarbazide (1.0 equiv.) was dissolved in MeOH upon heating under nitrogen. Aqueous sodium hydroxide (6 M, 9.0 equiv.) was added to the reaction. A methanol solution of 3-(dimethylamino)-1-[5-(3-chlorophenyl)(2-furyl)]propan-1-one (1.0 equiv) was then added dropwise to the reaction mixture. The solvent was removed and the residue was dissolved in DCM and washed with water, brine, dried over MgSO4, and concentrated. The final compound was purified by preparative-HPLC to give amino{3-[5-(3-chlorophenyl)(2-furyl)](2-pyrazolinyl)}methane-1-thione; LC/MS m/z 306.2 (MH+); Rt=3.06 minutes.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:4][C:3]=1[C:17](=O)[CH2:18][C:19](=O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].O.[NH2:32][NH2:33]>C(O)C>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([C:17]2[CH:18]=[C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[NH:33][N:32]=2)[CH:4]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: NN
Reactant: CCCCCCCCCC(=O)CC(=O)c1cc(CCCCCCCCC)ccc1O
Solvent: O
Solvent: CCO
Product: CCCCCCCCCc1ccc(O)c(-c2cc(CCCCCCCCC)[nH]n2)c1

Procedure:
1-(2-hydroxy-5-nonyl-phenyl)dodecane-1,3-dione (0.1 M) dissolved in ethanol (50 ml), hydrazine hydrate (0.105M) added and the reaction solution heated to reflux. Held at reflux for 2 hours, cooled to ambient and organic phase washed with water (2×25 ml). Toluene removed by vacuum evaporation to produce a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([CH:8]([CH:14]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)C(OCC)=O)=[O:7])=[CH:4][CH:3]=1.CS(C)=O>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:7])[CH2:8][CH:14]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[O:21][C:22]3[C:27]2=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:28][CH:29]=1
Reactant: CCOC(=O)C(C(=O)c1ccc(Br)cc1)C1c2ccccc2Oc2ccccc21
Solvent: CS(C)=O
Solvent: O
Product: O=C(CC1c2ccccc2Oc2ccccc21)c1ccc(Br)cc1

Procedure:
Ethyl 2-(4-bromobenzoyl)-2-(9H-xanthen-9-yl)acetate (10.0 g, 0.02 mol) was heated in a solution of dimethylsulphoxide (100 ml) and water (0.72 ml) following the procedure described in Example (iv) to give 1-(4-bromophenyl)-2-(9H-xanthen-9-yl)ethanone as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:14]([C:15]=2[C:16]([CH3:18])=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:21](OCC)(=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1C=CC=CC=1>[C:1]1([C:7]2[CH:8]=[C:9]3[N:14]([C:15]=2[C:16](=[O:17])[CH2:18][C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)c1c(-c2ccccc2)cc2ccccn12
Reactant: CCOC(=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)C(=O)CC(=O)c1c(-c2ccccc2)cc2ccccn12
Temperature: 60 °C
Yield: 81.9 %

Procedure:
To a solution of 25.7 g of methyl 2-phenyl-3-indolizinyl ketone in 360 ml of benzene were added 8.3 g of 50% sodium hydride and 28.2 g of diethyl oxalate, and the mixture was heated at 60° C. for 30 minutes. After cooling, the benzene was distilled off. To the residue was added 200 ml of water and the aqueous solution was acidified with acetic acid. Crystals precipitated were filtered off and washed with water, and then recerystallized from ethanol to give 30 g of ethyl 4-(2-phenyl-3-indolizinyl)-2,4-dioxobutyrate, melting at 100°-102° C.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]2[CH2:15][O:14][CH2:13][CH2:12][C:10]=2[N:11]=1)[CH2:2][CH3:3].[F:17][C:18]1[CH:35]=[CH:34][C:21]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31](O)=[O:32])[CH2:26][CH2:25]2)=[O:23])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([CH:24]2[CH2:25][CH2:26][N:27]([CH2:30][C:31]([N:4]([CH2:5][C:6]3[NH:7][C:8](=[O:16])[C:9]4[CH2:15][O:14][CH2:13][CH2:12][C:10]=4[N:11]=3)[CH2:1][CH2:2][CH3:3])=[O:32])[CH2:28][CH2:29]2)=[O:23])=[CH:34][CH:35]=1
Reactant: CCCNCc1nc2c(c(=O)[nH]1)COCC2
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Product: CCCN(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
Following general procedure of Example 4, the title compound was prepared (37.3 mg) from 2-((propylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C25H31FN4O4 470.5. found 471.6 (ESI, M+H); 1H NMR (400 MHz, dichloromethane-d2) δ ppm 7.89-8.08 (m, 2H) 7.19 (t, J=8.34 Hz, 2H) 4.60 (s, 2H) 4.42-4.57 (m, 2H) 4.27 (br. s., 2H) 3.85-4.01 (m, 3H) 3.81 (br. s., 1H) 3.57 (br. s., 1H) 3.39 (br. s., 1H) 3.31 (br. s., 2H) 3.12-3.28 (m, 1H) 2.72 (br. s., 1H) 2.13 (s, 4H) 1.58-1.80 (m, 1H) 1.40-1.58 (m, 1H) 0.76-1.00 (m, 3H).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:3]=1[C:4]#[N:5].[CH3:17][C:18]1[C:23]([OH:24])=[C:22]([CH3:25])[CH:21]=[C:20]([CH3:26])[N:19]=1>CN1C(=O)CCC1>[CH2:13]([CH:12]([NH:11][C:6]1[C:3]([C:4]#[N:5])=[C:2]([O:24][C:23]2[C:18]([CH3:17])=[N:19][C:20]([CH3:26])=[CH:21][C:22]=2[CH3:25])[N:9]=[C:8]([CH3:10])[CH:7]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: Cc1cc(C)c(O)c(C)n1
Reactant: CCC(CC)Nc1cc(C)nc(Cl)c1C#N
Solvent: CN1CCCC1=O
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)nc2C)c1C#N

Procedure:
The title compound was prepared by heating 2-chloro-4-(1-ethyl-propylamino)-6-methyl-nicotinonitrile with 2,4,6-trimethyl-3-hydroxy-pyridine in NMP.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:20]#[C:21][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CCO.C1COCC1>[CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:20]#[C:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:31][CH:32]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(OC)cc2)=CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-methoxyphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 8) 80.0 mg (0.183 mmol) in 3 ml of EtOH and 2 ml of THF was added 40.0 mg (1.00 mmol, 1.0 ml) of NaOH (1.0 M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCI. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ 7.90 (2H, d, J=8.3 Hz), 7.60 (2H, d, J=8.3 Hz), 7.45 (2H, s), 7.24 (2H, d, J=8.6 Hz), 7.02-6.89 (3H, m), 5.98 (1H, t, J=4.4 Hz), 3.79 (3H, s), 2.31 (2H, d, J=4.7 Hz), 1.29 (6H, s).
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:21]([Cl:22])=[CH:20][C:17]([CH2:18]O)=[CH:16][C:15]=3[Cl:23])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:24]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CC=CC=1>C(#N)C>[CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:21]([Cl:22])=[CH:20][C:17]([CH2:18][Br:24])=[CH:16][C:15]=3[Cl:23])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)c1c[nH]c2ccc(Oc3c(Cl)cc(CO)cc3Cl)cc12
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)c1c[nH]c2ccc(Oc3c(Cl)cc(CBr)cc3Cl)cc12

Procedure:
Analogously to the procedure of Example VII, 4.8 g (12.66 mmol) of benzyl alcohol derivative from Example XVII are reacted with 6.95 g (16.46 mmol) of dibromotriphenylphosphorane and 1.6 g (20.26 mmol) of pyridine in 80 ml of acetonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7](Cl)[CH2:6][CH2:5]2.C(=O)([O-])[O-].[Na+].[Na+].[N:18]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([N:21]1[CH2:20][CH2:19][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22]1)[CH2:6][CH2:5]2
Reactant: ClC1CCc2cc(Br)ccc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(C2CCc3cc(Br)ccc32)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
5-Bromo-1-chloro-2,3-dihydro-1H-indene (10 g, 43 mmol) was dissolved in 80 mL of acetonitrile, and sodium carbonate (4.8 g, 45 mmol) was added followed by tert-butyl piperazin-1-carboxylate (9.7 g, 52 mmol). The mixture was stirred at 60° C. overnight. The insoluble substance was removed by filtration and the filtrate was concentrated. The residue was separated by silica gel column using ethyl acetate/hexanes (1:2 to 1:1) as the eluent to obtain 12 g (72% yield) of the subtitle compound. MS (M+1)=381.11, 383.11.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][C:12]1[CH:13]=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:16][C:17]=1[Cl:18]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:11][C:12]1[CH:13]=[C:14]([C:19]([F:20])([F:21])[F:22])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Product: FC(F)(F)c1ccc(Cl)c(Nc2nc3ccccc3[nH]2)c1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 3-amino-4-chlorobenzotrifluoride by Procedure A. The product was isolated upon basic work-up and purified by preparative LCMS to give the title compound as the free base. 1NMR (CDCl3) δ 6.40 (br s, 2H), 7.11-7.15 (d, 1H), 7.18-7.25 (m, 2H), 7.35-7.41 (d, 1H), 7.42-7.46 (m, 2H), 8.57 (s, 1H). MS(ES+) m/z 312 ([M+1]+, 100).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N: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]([O:27][CH3:28])[CH:20]=2)[C:10]2[CH:15]=[C:14]([Cl: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]([O:27][CH3:28])[CH:20]=3)[C:10]3[CH:15]=[C:14]([Cl:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(Cl)cc23)cc1OC
Reactant: c1nc[nH]n1
Product: COc1ccc(CNc2nc(-n3cncn3)nc3sc(Cl)cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2,6-dichloro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-chloro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.Cl[C:14]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1>COCCO.O>[CH3:11][CH:9]([CH3:10])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:14]2[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:7][CH:6]=1)=[O:12]
Reactant: CC(C)C(=O)c1ccc(N)cc1
Reactant: COC(=O)c1cccnc1Cl
Solvent: COCCO
Solvent: O
Product: COC(=O)c1cccnc1Nc1ccc(C(=O)C(C)C)cc1
Yield: 118.9 %

Procedure:
A mixture of 1-(4-aminophenyl)-2-methyl-1-propanone (0.0637 mol) and methyl 2-chloro-3-pyridinecarboxylate (0.0637 mol) in 2-methoxyethanol (200 ml) was stirred and refluxed for 90 hours. The mixture was taken up in water and EtOAc and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 22.6 g of methyl 2-[[4-(2-methyl-1-oxopropyl)phenyl]amino]-3-pyridinecarboxylate (interm. 20).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.P(Br)(Br)[Br:13].O>C(OCC)C>[Br:13][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: OCCCc1ccc(F)cc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: O
Product: Fc1ccc(CCCBr)cc1

Procedure:
Compound 20-1 (9.39 g) was dissolved in diethyl ether (100 ml), phosphorus tribromide (8.58 ml) was added under ice-cooling, and the mixture was stirred under ice-cooling for 3.5 hr. To the reaction mixture was slowly added water, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (4.93 g) as a pale-yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C([Li])CCC.[B:14]([O:23]C(C)C)([O:19]C(C)C)[O:15]C(C)C.Cl>CCCCCC.O1CCCC1>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([O:15][B:14]([OH:23])[OH:19])=[CH:3][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(OB(O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.4 %

Procedure:
To a mixture of 4-bromotoluene (743 mmol) and 500 ml of tetrahydrofuran (THF) was added dropwise 500 ml of a solution of n-butyl lithium (corresponding to 780 mmol) in hexane at −78° C. in 1.6 hours, and stirred at the same temperature for 1.5 hours. To this solution was added dropwise 200 ml of a solution of triisopropyl borate (1,486 mmol) in THF, the solution was gradually warmed up to room temperature, and then the solution was stirred overnight. After 750 ml of 7.3% hydrochloric acid was added and stirred for 30 min, the reaction solution was extracted twice with diethyl ether, washed thrice with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was recrystallized from about 1,000 ml of toluene to give a white solid of 4-methylphenyl boric acid (545 mmol).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[NH:2]2.[CH3:15][C:16]1[S:17][C:18]([C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[C:19]([C:21](O)=[O:22])[N:20]=1>>[F:11][C:10]([F:12])([F:13])[C:9]([NH:8][CH2:7][C@@H:3]1[CH2:4][C@H:5]2[C@H:1]([CH2:6]2)[N:2]1[C:21]([C:19]1[N:20]=[C:16]([CH3:15])[S:17][C:18]=1[C:24]1[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=1)=[O:22])=[O:14]
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)C(F)(F)F
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2[C@H](CNC(=O)C(F)(F)F)C[C@@H]3C[C@@H]32)c1

Procedure:
prepared by reaction of N-[(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-2,2,2-trifluoro-acetamide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS (acidic): tR=0.99 min; [M+H]+=424.1.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C[N:9]([CH2:11][C:12]1[CH:13]=[C:14]([C:20]2[CH:21]=[C:22]3[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=2)[NH:25][CH:24]=[C:23]3[CH:32]2[CH2:37][CH2:36][N:35]([S:38]([CH2:41][CH3:42])(=[O:40])=[O:39])[CH2:34][CH2:33]2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH3:10].[CH3:43][C:44](C)([CH3:47])[CH2:45]N.CNC>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:43][C:44]([CH3:47])([CH3:45])[CH2:10][NH:9][CH2:11][C:12]1[CH:13]=[C:14]([C:20]2[CH:21]=[C:22]3[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=2)[NH:25][CH:24]=[C:23]3[CH:32]2[CH2:37][CH2:36][N:35]([S:38]([CH2:41][CH3:42])(=[O:39])=[O:40])[CH2:34][CH2:33]2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(OC)c(CN(C)C)c4)cc23)CC1
Reactant: CC(C)(C)CN
Agent: CNC
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(OC)c(CNCC(C)(C)C)c4)cc23)CC1
Yield: 16 %

Procedure:
The title compound was prepared according to the general procedure of 5-[3-[(dimethylamino)methyl]-4-(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 2,2-dimethyl-1-propanamine (20 μL, 0.214 mmol) for the dimethylamine to afford 11 mg of the title compound (16%).