Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]I.Br[C:4]1[CH:5]=[C:6]2[C:19]3[C:9]([CH2:10][C@@H:11]4[C@@H:16]([C:17]=3[CH:18]=1)[CH2:15][C@H:14]([NH:20][C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:13][N:12]4[CH3:28])=[CH:8][N:7]2[Si](C(C)(C)C)(C)C>>[CH2:23]([N:22]([CH2:25][CH3:26])[C:21]([NH:20][C@H:14]1[CH2:15][C@H:16]2[C@@H:11]([CH2:10][C:9]3[C:19]4[C:6](=[CH:5][CH:4]=[C:18]([I:1])[C:17]2=4)[NH:7][CH:8]=3)[N:12]([CH3:28])[CH2:13]1)=[O:27])[CH3:24]
Reactant: II
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(Br)cc4c3c(cn4[Si](C)(C)C(C)(C)C)C[C@H]2N(C)C1
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(I)ccc4[nH]cc(c34)C[C@H]2N(C)C1

Procedure:
With iodine and 3-(13-bromo-1-tert-butyldimethylsilyl-6-methyl-8α-ergolinyl)-1,1-diethylurea:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=O)[CH3:12])=[C:6](I)[CH:5]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1C#C>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.[Cu]I.O1CCOCC1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[NH:10][C:11]([C:18]1[C:17]([Cl:16])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:23])=[CH:12]2)=[O:15]
Reactant: COC(=O)c1ccc(NC(C)=O)c(I)c1
Reactant: C#Cc1c(Cl)cccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1COCCO1
Product: COC(=O)c1ccc2[nH]c(-c3c(Cl)cccc3Cl)cc2c1
Temperature: 100 °C

Procedure:
To a solution of 4-acetylamino-3-iodo-benzoic acid methyl ester (0.17 g) in TMG (1.5 mL) and dioxane (1.5 mL) were added 1,3-dichloro-2-ethynyl-benzene (0.1 g), 10 mol % of Pd(PPh3)2Cl2, and 10 mol % of CuI. The reaction mixture was heated to 100° C. overnight. The solvent were evaporated and the resulting mixture was purified by column chromatography (SiO2, 2:3, EtOAc/Hexane) to give 2-(2,6-dichloro-phenyl)-1H-indole-5-carboxylic acid methyl ester: MS (m/z) 320.0 (M+1).
Reaction SMILES: [C:1](OCC12CC3CC(CC(O)(C3)C1)C2)(=[O:4])[CH:2]=[CH2:3].[C:18]([C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][C:23]([OH:31])([CH2:24]3)[CH2:22]1)[CH2:28]2)(=[O:20])[CH3:19]>>[C:18]([C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][C:23]([O:31][C:1](=[O:4])[CH:2]=[CH2:3])([CH2:24]3)[CH2:22]1)[CH2:28]2)(=[O:20])[CH3:19]
Reactant: C=CC(=O)OCC12CC3CC(CC(O)(C3)C1)C2
Reactant: CC(=O)C12CC3CC(CC(O)(C3)C1)C2
Product: C=CC(=O)OC12CC3CC(C1)CC(C(C)=O)(C3)C2
Yield: 97 %

Procedure:
The reaction was conducted in the same manner as the step of Example 36 (2) except that 1-acetyl-3-hydroxyadamantane was used instead of the 1,3-dicarboxy-5-adamantanol, and, as a result, a 1-acety-3-acryloyloxyadamantane (yield: 97%, white solid) was obtained.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)#[N:9].C(O)(=O)C>C1COCC1.CO>[C:8]([C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:17][CH2:18][CH:19]([C:22]([O:24][CH3:1])=[O:23])[CH2:20][CH2:21]2)=[CH:14][CH:15]=1)#[N:9]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: N#Cc1ccc(N2CCC(C(=O)O)CC2)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C1CCN(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
(Trimethylsilyl)diazomethane (2.0 M solution in hexane, 2.7 mL, 5.40 mmol) was added to a mixed solution of 1-(4-cyanophenyl)piperidine-4-carboxylic acid (1.13 g, 4.91 mmol) in THF (13 mL) and methanol (6.5 mL) (2:1, v/v), and the mixture was stirred at room temperature for 1 hour. Acetic acid (appropriate amount) was added to the reaction solution to stop the reaction. Then, the solvent was distilled off under reduced pressure. A saturated sodium bicarbonate aqueous solution was added to the obtained residue, followed by extraction with ethyl acetate. The obtained organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elute: hexane/ethyl acetate=80/20] to obtain the title compound (1.06 g, yield: 88%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH2:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH3:15]>ClCCl>[N:8]1[CH:5]=[CH:4][C:14]([N:16]2[CH2:19][CH2:20][CH:6]([CH2:7][C:2]([O:1][C:2]3[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=3)=[O:1])[CH2:18][CH2:17]2)=[CH:15][CH:9]=1
Reactant: COC(=O)CNc1ccc(O)cc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CNc1ccc(OC(=O)CC2CCN(c3ccncc3)CC2)cc1
Reaction time: 16 h

Procedure:
A solution of the foam in dry dichloromethane (5 ml) was added dropwise to a stirred solution of methyl N-(4-hydroxyphenyl)glycinate (210 mg) and triethylamine (0.33 ml) in dry dichloromethane (10 ml) and the mixture stirred for 16 hours. The mixture was diluted with dichloromethane, washed with water, dried and evaporated. Purification by flash chromatography on silica, eluting with 0-10% v/v methanol/dichloromethane and trituration of the resulting gum with diethyl ether gave the title compound, 80 mg, as a white solid: m.p. 120°-122° C.; NMR(d6DMSO), δ 8.13(2H,d), 6.84(2H,d), 6.81(2H,d), 6.54(2H,d), 6.01(1H,t), 3.96(2H,bd), 3.90(2H,d), 3.66(3H,s), 2.90(2H,dt), 2.50(2H,d +DMSO), 2.07(1H,m), 1.81(2H,bd), 1.30(2H,dq); m/e 384(M+H)+ ; calculated for C21 H25N3O4. 0.5 H2O: C, 64.3; H, 6.6; N, 10.7. found: C, 64.2; H, 6.3; N, 10.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C1N=CN(C(N2C=NC=C2)=O)C=1.[C:27]([C:29]1[C:30]([C:43]([F:46])([F:45])[F:44])=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([CH2:38][C:39](=[NH:42])[NH:40]O)[CH:33]=[CH:32]2)#[N:28]>CC#N>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:8][N:42]=[C:39]([CH2:38][N:34]3[C:35]4[C:31](=[C:30]([C:43]([F:46])([F:44])[F:45])[C:29]([C:27]#[N:28])=[CH:37][CH:36]=4)[CH:32]=[CH:33]3)[N:40]=2)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3ccc(Cl)c(C(F)(F)F)c3)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 65.5 %

Procedure:
To 4-chloro-3-(trifluoromethyl)benzoic acid (0.0159 g, 0.071 mmol) in CH3CN (3 mL) was added CDI (0.0115 g, 0.071 mmol) and the resulting mixture was stirred for 5 min at rt. Next, 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 64) (0.02 g, 0.071 mmol) was added and the mixture was stirred for 1 h at rt. Heating at 150° C. in a microwave for 10 min was followed by direct purification (column chromatography, EtOAc/hexanes) to obtain the title compound (0.0219 g): MS (ES) m/z 471 (M+1).
Reaction SMILES: [CH:1]1([C@H:4]([OH:27])[CH2:5][O:6][C:7]2[C:22]([F:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[CH:19][C:8]=2[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12]C(C)(C)C)[CH2:3][CH2:2]1.Cl.O1CCOCC1.[CH2:35](OC(ON1C(=O)CCC1=O)=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)C(C)C)(C)C>CCOC(C)=O>[CH:1]1([C@H:4]([OH:27])[CH2:5][O:6][C:7]2[C:22]([F:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[CH:19][C:8]=2[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:3][CH2:2]1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CN(Cc1cc([N+](=O)[O-])cc(F)c1OC[C@@H](O)C1CC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN(Cc1cc([N+](=O)[O-])cc(F)c1OC[C@@H](O)C1CC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.3 %

Procedure:
To 21D (88 mg, 0.229 mmol) in EtOAc (2 mL) was added 4.0 M HCl in dioxane (1.5 mL, 6.00 mmol). The mixture was stirred rt for 1 h, concentrated. The residue was dissolved in DMF (10 ml). N-(benzyloxycarbonyloxy) succinimide (62.8 mg, 0.252 mmol) was added, followed by N,N-diisopropylethylamine (0.120 mL, 0.687 mmol). The mixture was stirred rt for 16 h, then was quenched with water, extracted with EtOAc (3×30 ml). The organic layer was washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0-60% EtOAc in hexane) to give 21E (99 mg, 103% yield). MS (ESI) m/z: 419.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(Cl)Cl>C1COCC1.CN(C=O)C>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:11](=[O:13])[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:21][CH2:20]1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN1CCN(C(=O)Cc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 8 h

Procedure:
4-Nitrophenylacetic acid (2.00 g, 0.011 mol) was dissolved in anhydrous THF (20 mL) with gradual addition of thionyl chloride (1.03 mL, 0.0143 mol) and a catalytic amount of DMF (2 drops) at RT and stirred for 24 h. On completion, the reaction was quenched in situ with N-methylpiperazine (3.85 g, 0.038 mol) added dropwise in a solution of DCM (20 mL) at RT and stirred overnight to give a beige suspension. The solvent was removed in vacuo and the residue partitioned between DCM (30 mL) and sodium hydroxide (1N, 30 mL). The organic layer was washed twice, dried over sodium sulphate and filtered. Removal of the solvent in vacuo yielded the title compound as an amber oil, 1.50 g (solidified on standing).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[N:26]1([CH2:32][CH2:33][OH:34])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[OH:34][CH2:33][CH2:32][N:26]1[CH2:31][CH2:30][N:29]([C:22]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:25])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:17])([CH3:16])[C:10]=3[CH:18]=2)=[O:24])[CH2:28][CH2:27]1
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: OCCN1CCNCC1
Product: CC1(C)c2cc(C(=O)N3CCN(CCO)CC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and 2-piperazin-1-yl ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=2[C:20]2[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=2[O:29][CH3:30])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:34][C:35]1[CH:36]=[C:37]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:38]#[N:39].N1CCOCC1>CN(C)C=O.O1CCCC1.O.C(OCC)(=O)C.C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=2)[C:38]#[N:39])[CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:13]=[CH:12][C:11]=2[C:20]2[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=2[O:29][CH3:30])=[N:6][CH:7]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNc1ccc(Br)cn1
Reactant: N#Cc1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: C1COCCN1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C#N)cc(C(F)(F)F)c1)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.5 %

Procedure:
(5-Bromo-pyridin-2-yl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amine (700 mg) is dissolved in N,N-dimethylformamide (5 ml), and thereto is added sodium hydride (60%) (88 mg) under nitrogen atmosphere at −10° C., and the mixture is stirred at the same temperature for 5 minutes, and thereto is added 3-bromomethyl-5-trifluoromethyl-benzonitrile (771 mg), and the mixture is stirred under ice-cooling for 1 hour and 40 minutes. To the reaction solution are added ethyl acetate and a saturated aqueous citric acid solution, and the mixture is separated, and the organic layer is washed twice with a saturated brine, and the mixture is dried over magnesium sulfate and is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→17:3) and (hexane:ethyl acetate=49:1→9:1). The residue is dissolved in diethyl ether, and filtered. The filtrate is concentrated under reduced pressure, and the residue obtained above (630 mg) is dissolved in tetrahydrofuran (3 ml), and thereto are added morpholine (119 μl) and triethylamine (190 μl), and the mixture is stirred at 50° C. for 4 hours, and the reaction solution is cooled to room temperature, and stirred at same temperature overnight. To the reaction solution are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with water and a saturated brine, and the mixture is dried over magnesium sulfate and is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→17:3) to give 3-{[(5-bromo-pyridin-2-yl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-methyl}-5-trifluoromethyl-benzonitrile (440 mg). MS (m/z): 662/664 [M+H]+
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[N:10]2)[N:3]=1.[NH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1>>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[N:10]2)[N:3]=[C:2]([NH:16][CH:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)[CH:7]=1
Reactant: NC1Cc2ccccc2C1
Reactant: Cc1cc(C)n(-c2nc(Cl)cc(Cl)n2)n1
Product: Cc1cc(C)n(-c2nc(Cl)cc(NC3Cc4ccccc4C3)n2)n1

Procedure:
Was prepared according to example 3 from 4,6-dichloro-2-(3,5-dimethyl-pyrazol-1-yl)-pyrimidine and 2-aminoindan.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18](OC(C)(C)C)=O)[CH2:13][C:12]=3[CH:25]=2)=[CH:4][C:3]=1[N+:26]([O-])=O.ClC1[C:39]2[C:34](=[CH:35][C:36]([O:40][CH3:41])=[CH:37][CH:38]=2)[N:33]=[C:32]([CH3:42])[N:31]=1>>[CH2:6]([NH:7][C:2]1[NH:26][C:3]2[C:2]([N:1]=1)=[N:7][CH:6]=[C:5]([C:8]1[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18]4[C:39]5[C:34](=[CH:35][C:36]([O:40][CH3:41])=[CH:37][CH:38]=5)[N:33]=[C:32]([CH3:42])[N:31]=4)[CH2:13][C:12]=3[CH:25]=1)[CH:4]=2)[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cnc(N)c([N+](=O)[O-])c3)cc2C1
Reactant: COc1ccc2c(Cl)nc(C)nc2c1
Product: CCNc1nc2ncc(-c3ccc4c(c3)CN(c3nc(C)nc5cc(OC)ccc35)CCO4)cc2[nH]1

Procedure:
Prepared according to the method of example 11 by using tert-butyl 7-(6-amino-5-nitropyridin-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Example 26) in step 1 and 4-chloro-7-methoxy-2-methylquinazoline in step 4. 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 0.5H), 8.07 (s, 0.5H), 7.90 (d, 1H), 7.68-7.42 (m, 3H), 7.17-6.84 (m, 4H), 5.00 (s, 2H), 4.47-4.39 (m, 2H), 4.18-4.10 (m, 2H), 3.88 (s, 3H), 3.40-3.30 (m, 2H), 2.43 (s, 3H), 1.26-1.13 (m, 3H); MS (EI) for C27H27N7O2: 482 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(N2CCNCC2)cc1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (3 mL) was added dropwise with stirring at 0° C. to a solution of t-butyl 4-(4-chlorophenyl)piperazine-1-carboxylate (360.6 mg, 1.21 mmol, 1.00 equiv) in dichloromethane (12 mL). The resulting solution was stirred for 3 h at 20° C. in an oil bath. The pH value of the solution was adjusted to 7-8 with a saturated solution of sodium bicarbonate. The resulting solution was extracted with 6×20 mL of dichloromethane, the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 264.5 mg (102%) of 1-(4-chlorophenyl)piperazine as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[CH:9].[CH3:10][O:11][C:12]([C:14]1[C:19](Br)=[CH:18][N:17]=[C:16]([S:21][CH3:22])[N:15]=1)=[O:13].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.[Cu]I.CN(C)C=O>[CH3:10][O:11][C:12]([C:14]1[C:19]([C:9]#[C:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:18][N:17]=[C:16]([S:21][CH3:22])[N:15]=1)=[O:13]
Reactant: COC(=O)c1nc(SC)ncc1Br
Reactant: C#Cc1ccccc1Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1nc(SC)ncc1C#Cc1ccccc1Cl
Temperature: 100 °C
Yield: 74.3 %

Procedure:
A mixture of 1-chloro-2-ethynylbenzene (0.63 g, 4.6 mmol), 5-bromo-2-methylsulfanylpyrimidine-4-carboxylic acid methyl ester (1.0 g, 3.8 mmol), triethylamine (2.5 ml), triphenylphosphine (0.125 g, 0.48 mmol), copper (I) iodide (0.025 g, 0.13 mmol), bistriphenyphosphinepalladium (II) dichloride (0.10 g, 0.14 mmol) and dimethylformamide (1 ml) was stirred in a heavy-walled Smith process vial and irradiated with microwaves to maintain 100° C. for 20 min. The mixture was diluted with dichloromethane (20 ml) and washed with 5% hydrochloric acid (20 ml), water (20 ml), saturated aqueous sodium hydrogencarbonate solution (20 ml) and water (20 ml) then dried (MgSO4) and evaporated in vacuo. The residual oil was purified by flash column chromatography over silica using a 1:4 mixture of hexane and dichloromethane as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 5-(2-chlorophenylethynyl)-2-methylsulfanylpyrimidine-4-carboxylic acid methyl ester (0.9 g) as a yellow oil. 250 MHz 1H-NMR (CDCl3) δ (ppm): 2.5 (s, 3H) (—SCH3), 3.9 (s, 3H) (—CO2CH3), 7.1-7.5 (m, 4H) (ArH), 8.65 (s, 1H) (ArH); m/z (M+H)+. 319, HPLC purity 91%, HPLC retention time 4.08 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:31]=[CH:32][N:33]=3)[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].C(O)(C(F)(F)F)=O>ClCCl>[NH2:23][CH:20]1[CH2:21][CH2:22][N:18]([C:16]2[CH:17]=[C:12]([NH:11][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[N:7]=3)[C:13]3[N:14]([CH:31]=[CH:32][N:33]=3)[N:15]=2)[CH2:19]1
Reactant: COc1ccc(Nc2cc(N3CCC(NC(=O)OC(C)(C)C)C3)nn3ccnc23)nc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Nc2cc(N3CCC(N)C3)nn3ccnc23)nc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 126.6 %

Procedure:
A suspension of tert-butyl 1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-ylcarbamate (180 mg, 0.40 mmol) and TFA (2 mL) in dichloromethane (5 mL) was stirred at 25° C. for 6 h. The residue was concentrated to give 6-(3-aminopyrrolidin-1-yl)-N-(5,6-dimethoxypyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (180 mg, crude) as a red liquid. This was used directly without purification. LC-MS: 356 [M+1]+, tR=1.187 min.
Reaction SMILES: [CH2:1]([C@H:9]1[CH2:14][NH:13][CH2:12][CH2:11][NH:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:15]1([C:20]2[S:29][C:28]3[NH:27][C:26]4[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=4[NH:24][C:23](=S)[C:22]=3[N:21]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1>N1C=CC=CC=1>[CH:15]1([C:20]2[S:29][C:28]3[NH:27][C:26]4[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=4[N:24]=[C:23]([N:13]4[CH2:12][CH2:11][NH:10][C@@H:9]([CH2:1][CH2:2][C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=5)[CH2:14]4)[C:22]=3[N:21]=2)[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: S=C1Nc2ccccc2Nc2sc(C3CCCC3)nc21
Reactant: c1ccc(CC[C@H]2CNCCN2)cc1
Solvent: c1ccncc1
Product: c1ccc(CC[C@H]2CN(C3=Nc4ccccc4Nc4sc(C5CCCC5)nc43)CCN2)cc1
Temperature: 25 °C
Yield: 38.6 %

Procedure:
Combine (S)-2-phenethyl-piperazine (0.537 g, 3.0 mmol) and 2-cyclopentyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo{f}azulene-10-thione (0.451 g, 1.5 mmol) in 10 ml of pyridine, and heat to 85° C. for 20 hour. Cool to room temperature, remove pyridine, the residue purify on silica gel using 2N ammonia in methanol/dichloromethane (1:10) as the eluent to give 265 mg of title compound as yellow solid. Mass spectrum (electrospray) (m/e): C27H31N5S, Cacl. Mass: 457.2; Found: 458.3 (M+1); 1H NMR (400 MHz, CDCl3) δ ppm: 7.31–7.27 (m, 2H), 7.24–7.16 (m, 3H), 7.05–6.97 (m, 2H), 6.86 (dt, 1H, J=7.8 Hz, J=1.9 Hz), 6.62 (dd, 1H, J=7.8 Hz, J=1.0 Hz), 5.00 (br, 1H), 4.25 (br, 1H), 3.25 (t, 1H, J=7.8 Hz), 3.02–2.88 (m, 4H), 2.73–2.63 (m, 3H), 2.07–2.03 (m, 2H), 1.77–1.61 (m, 10H).
Reaction SMILES: Br[C:2]1[C:28]([F:29])=[CH:27][C:5]([O:6][C@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:8]2=[O:26])=[C:4]([F:30])[CH:3]=1.[CH3:31][S:32]([O-:34])=[O:33].[Na+].[C@H]1(N)CCCC[C@@H]1N>CS(C)=O.CCOC(C)=O>[F:30][C:4]1[CH:3]=[C:2]([S:32]([CH3:31])(=[O:34])=[O:33])[C:28]([F:29])=[CH:27][C:5]=1[O:6][C@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:15][CH2:14]2)[C:8]1=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](Oc3cc(F)c(Br)cc3F)C2=O)CC1
Reactant: CS(=O)[O-]
Agent: N[C@H]1CCCC[C@@H]1N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](Oc3cc(F)c(S(C)(=O)=O)cc3F)C2=O)CC1
Temperature: 110 °C
Reaction time: 18 h
Yield: 43.6 %

Procedure:
A suspension of (S)-tert-butyl 3-(4-bromo-2,5-difluorophenoxy)-2-oxo-1,4′-bipiperidine-1′-carboxylate (700 mg, 1.39 mmol), and sodium methanesulfinate (219 mg, 2.08 mmol) in DMSO (5.55 mL), was deoxygenated and purged with nitrogen. Cu(I) triflate benzene complex (77.6 mg, 0.139 mmol) and (1S,2S)-cyclohexane-1,2-diamine (63.4 mg, 0.555 mmol) were introduced and the heterogeneous mixture was sealed and heated to 110° C. in an oil bath and stirred for 18 hours. The mixture was cooled to ambient temperature, diluted with EtOAc (75 mL), washed with water (30 mL) and brine (three 50 mL washes), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified over silica gel (EtOAc) to afford (S)-tert-butyl 3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-2-oxo-1,4′-bipiperidine-1′-carboxylate (305 mg, 0.606 mmol, 44% yield) as a light yellow oil that solidified. Mass spectrum (apci) m/z=389.1 (M+H-Boc).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:20][C:21]3[CH:22]=[C:23]([CH2:27][C:28](O)=[O:29])[CH:24]=[CH:25][CH:26]=3)=[C:7]([CH3:19])[N:8]2[C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][CH3:18])[CH:15]=2)=[CH:4][CH:3]=1.[C:31]1([S:37]([NH2:40])(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:20][C:21]3[CH:22]=[C:23]([CH2:27][C:28]([NH:40][S:37]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)(=[O:39])=[O:38])=[O:29])[CH:24]=[CH:25][CH:26]=3)=[C:7]([CH3:19])[N:8]2[C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][CH3:18])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: CCCn1cc(-n2c(C)c(Sc3cccc(CC(=O)O)c3)c3ccc(Cl)cc32)cn1
Reactant: NS(=O)(=O)c1ccccc1
Product: CCCn1cc(-n2c(C)c(Sc3cccc(CC(=O)NS(=O)(=O)c4ccccc4)c3)c3ccc(Cl)cc32)cn1

Procedure:
Prepared according to the procedure described in the synthesis of Example 117 using the following starting materials: {3-[6-Chloro-1-(1-propyl-1H-pyrazol-4-yl)-2-methyl-1H-indol-3-ylsulfanyl]-phenyl}-acetic acid and benzenesulfonamide.