Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH3:11])=[CH:7][CH:8]=2)[CH:3]1O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH2:10][C:9]2[C:4]([CH:3]=1)=[CH:5][C:6]([CH3:11])=[CH:7][CH:8]=2
Reactant: Cc1ccc2c(c1)C(O)C(Br)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)C=C(Br)C2
Reaction time: 0.33 h

Procedure:
Water (0.6 ml) and N-bromosuccinimide (6.1 g) was added to a solution of 5-methyl-1H-indene (4.4 g) in dimethylsulfoxide (50 ml), and the mixture was stirred for 40 minutes at room temperature. The reaction mixture was poured into ice-cooled water, and extracted with ether. The organic layer was washed with water, 5% sodium hydrogencarbonate aqueous solution, and saturated saline solution in order and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting crystals were washed with hexane to obtain, by filtration, 2-bromo-6-methylindane-1-ol (4.4 g). To a solution of 2-bromo-6-methylindane-1-ol in toluene (50 ml) was added p-toluene sulfonic acid monohydrate (0.1 g), and the mixture was stirred for 20 minutes. The temperature of the reaction mixture was returned to room temperature, and the reaction mixture was washed with water, 5% sodium hydrogencarbonate aqueous solution, and saturated saline solution in order and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain 2-bromo-5-methyl-1H-indene (1.7 g).
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3(SC3C=CC=CC=3)[S:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:36])[CH:4]=[CH:5][C:6](=[O:35])[CH:7]=1>C(C1C=CC=CC=1CC)C>[F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH:14]=[C:15]3[S:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:36])[CH:4]=[CH:5][C:6](=[O:35])[CH:7]=1
Reactant: C[C@]12C[C@H](O)[C@@]3(F)[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CCC2(Sc1ccccc1)Sc1ccccc1
Agent: CCc1ccccc1CC
Product: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CC=C(Sc4ccccc4)[C@@]3(C)C[C@H](O)[C@@]12F
Temperature: 190 °C
Reaction time: 0.75 h
Yield: 116.3 %

Procedure:
A suspension of 6.0 g of 9-fluoro-11β-hydroxy-17,17-bis(phenylthio)androsta-1,4-dien-3-one in 120 ml of diethylbenzene is stirred at 190° C. for 45 minutes. The solution is cooled at 0° C. and a solid crystallizes. This is filtered and dried in vacuo to give 5.5 g of material. Recrystallization from chloroform-methanol gives 4.21 g of the title compound, melting point 253°-255° C. (dec.).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C@H:13](O)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.P(Br)(Br)[Br:19].Br>>[Br:19][C@H:13]([C:5]1[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1)[CH3:14]
Reactant: C[C@@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: BrP(Br)Br
Agent: Br
Product: C[C@H](Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 20.5 °C
Reaction time: 0.5 h
Yield: 181.4 %

Procedure:
Under an argon atmosphere, (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (1.0 g, 3.87 mmol, >99.5% ee) was added dropwise with phosphorus tribromide (0.52 g, 1.94 mmol) on a water bath at a temperature lower than 20° C., and the mixture was stirred at 19 to 22° C. for 30 minutes. The reaction mixture was cooled, and added dropwise with hydrogen bromide (30% solution in acetic acid, 0.76 mL, 3.87 mmol) at a temperature lower than 0° C., and the mixture was stirred at 13 to 15° C. for 18 hours. The reaction mixture was poured into ice water, and the mixture was extracted with n-hexane (15 mL×2). The organic layers were combined, washed with saturated aqueous sodium hydrogencarbonate (15 mL×1) and then with saturated brine (15 mL×1), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, 8 g; developing solvent, n-hexane) to obtain 1.13 g of (S)-1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[F:20][C:21]([F:34])([F:33])[O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:29]([C:26]2[CH:25]=[CH:24][C:23]([O:22][C:21]([F:20])([F:33])[F:34])=[CH:28][CH:27]=2)(=[O:31])=[O:30])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Product: O=S(=O)(Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1)c1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 4-(trifluoromethoxy)benzene-1-sulfonyl chloride.
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[Cl:19])C.[OH-].[Na+].CO.Cl>O>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:20])=[O:3])=[C:6]([Cl:19])[CH:7]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1ccc(OCc2ccccc2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(OCc2ccccc2)cc1Cl
Yield: 53.1 %

Procedure:
17.7 g (60.9 mmol) of 4-benzyloxy-2-chloro-benzoic acid ethyl ester and 4.87 g (122 mmol) of sodium hydroxide were added to a mixed solvent consisting of 180 mL of methanol and 18 mL of water followed by refluxing for 6 hours. After cooling, concentrated hydrochloric acid was added to bring to a pH of 5 followed by filtering out the precipitate. The precipitate was washed with water and dried to obtain 8.5 g of a white solid.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][N:11]([CH2:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[C:8]([Cl:27])[N:7]=[C:6]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])[CH2:2][CH2:3][CH3:4].C1C(=O)N([Cl:42])C(=O)C1>C(#N)C>[CH2:1]([N:5]1[C:9]([CH2:10][N:11]([CH2:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[C:21]3[Cl:42])[CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])=[C:8]([Cl:27])[N:7]=[C:6]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCn1c(-c2ccccc2C)nc(Cl)c1CN(CCC(C)C)Cc1ccc2[nH]ccc2c1
Solvent: CC#N
Product: CCCCn1c(-c2ccccc2C)nc(Cl)c1CN(CCC(C)C)Cc1ccc2[nH]cc(Cl)c2c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
To a solution of (3-Butyl-5-chloro-2-o-tolyl-3H-imidazol-4-ylmethyl)-(1H-indol-5-ylmethyl)-(3-methyl-butyl)-amine (150 mg, 0.31 mmol) in 5 ml of anhydrous acetonitrile cooled to 0° C. is added NCS (44 mg, 0.33 mmol, 1.05 eq.), the resulting mixture is stirred at 40° C. overnight. The solvent is evaporated; the residue is purified through flash chromatography to give 112 mg of (3-butyl-5-chloro-2-o-tolyl-3H-imidazol-4-ylmethyl)-(3-chloro-1H-indol-5-ylmethyl)-(3-methyl-butyl)-amine as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.39 (1H, s), 7.52 (1H, S), 7.11˜7.36 (6H, m), 6.98 (1H, d, J=2.4 Hz), 3.67 (2H, m), 3.65 (2H, s), 3.54 (2H, s), 2.52 (2H, t, J=7.2 Hz), 2.11 (3H, s), 1.62 (1H, m), 1.45 (2H, q, J=6.9 Hz), 1.10 (2H, m), 0.84 (6H, d, J=6.6 Hz), 0.73 (2H, m), 0.47 (3H, t, J=6.9 Hz); MS (+VE) m/z 511 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:15]=[C:5]2[CH2:6][CH2:7][NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]2=[N:3]1.[C:16]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([NH:24][C:25]1[N:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1)=[O:23]>>[CH3:1][N:2]1[CH:15]=[C:5]2[CH2:6][CH2:7][N:8]([C:31]([C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:22]([C:17]4[C:16]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:23])=[N:30][CH:29]=3)=[O:32])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]2=[N:3]1
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Reactant: Cn1cc2c(n1)-c1ccccc1NCC2
Product: Cn1cc2c(n1)-c1ccccc1N(C(=O)c1ccc(NC(=O)c3ccccc3-c3ccccc3)nc1)CC2

Procedure:
As described for Example 12, 2,4,5,6-tetrahydro-2-methylpyrazolo[4,3-d][1]benzazepine is reacted with 6-[([1,1'biphenyl]-2-ylcarbonyl)amino]-3-pyridinecarbonyl chloride to give the product as a solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2([OH:17])[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)=[N:4][CH:3]=1.Cl.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[S:6][C:5]([C:7]2([OH:17])[CH2:8][CH2:9][C:10](=[O:11])[CH2:15][CH2:16]2)=[N:4][CH:3]=1
Reactant: OC1(c2ncc(Br)s2)CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1CCC(O)(c2ncc(Br)s2)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
The product of Step 2 (15 g, 46.8 mmol) was diluted with THF (10 mL). HCl (6 N, 78 mL) was added and stirred at 60° C. for 3 h. The reaction was cooled to RT and NaOH (6 N, 78 mL) was added. The reaction was diluted with EtOAc. The layers were separated and the aqueous layer back extracted with EtOAc (2×). The combined organic layers were dried (MgSO4) and evaporated. The residue was diluted with EtOAc to transfer and concentrated to ˜20 mL where hexanes (60 mL) was added drop wise. The slurry was cooled to room temperature, stirred for 1 h then filtered, washed with hexanes (2×15 mL) and dried to afford 4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxycyclohexanone (11.25 g, 40.8 mmol, 87% yield).
Reaction SMILES: Br[C:2]1C=C(N[C@@H]2CCCN(C(OC(C)(C)C)=O)C2)C(OC)=N[CH:7]=1.ClC[C:26]([N:28]1[CH2:33]CC[C@@H:30]([NH:34][C:35]2[C:40](=[O:41])[NH:39][CH:38]=[C:37]([C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)[CH:36]=2)[CH2:29]1)=[O:27]>>[C:26]([N:28]1[CH2:33][CH:30]([NH:34][C:35]2[C:40](=[O:41])[NH:39][CH:38]=[C:37]([C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)[CH:36]=2)[CH2:29]1)(=[O:27])[CH:2]=[CH2:7]
Reactant: O=C(CCl)N1CCC[C@@H](Nc2cc(-c3ccncc3)c[nH]c2=O)C1
Reactant: COc1ncc(Br)cc1N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Product: C=CC(=O)N1CC(Nc2cc(-c3ccncc3)c[nH]c2=O)C1

Procedure:
Following Example 1, but using tert-butyl 3-aminoazetidine-1-carboxylate (Example 1 Step 3) and reaction with acroyl chloride (Example 1 Step 6) provided the desired compound after purification: 1H NMR (300 MHz, DMSO-d6) 11.86 (br s, 1H), 8.52 (d, J=6.3 Hz, 2H), 7.62 (dd, J=4.2, 1.5 Hz, 2H), 7.25-7.35 (m, 1H), 6.61 (d, J=2.1 Hz, 1H), 6.20-6.40 (m, 2H), 6.10 (dd, J=17.1, 2.4 Hz, 1H), 5.67 (dd, J=10.2, 2.1 Hz, 1H), 4.61 (apparent t, J=7.8 Hz, 1H), 4.25-4.45 (m, 2H), 4.05-4.15 (m, 1H), 3.80-3.95 (m, 1H); MS (ES) m/z 297 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc(CN2CCOCC2)cc1

Procedure:
4-Bromobenzyl bromide (Aldrich Co., 2.0 g) and morpholine (0.73 ml) were dissolved in acetonitrile (15 ml), potassium carbonate (1.3 g) was added, and the mixture was heated under reflux for 4 hr. The insoluble material was filtered off, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate (5:1)) to give 4-(4-bromobenzyl)morpholine (1.55 g). 4-(4-Bromobenzyl)morpholine (1.55 g), 1-(tert-butoxycarbonyl)piperazine (1.27 g), 2-(di-tert-butylphosphino)biphenyl (37 mg), tris(dibenzylideneacetone)dipalladium (57 mg) and sodium tert-butoxide (1.2 g) were added to toluene (13 ml), and the mixture was heated under reflux for 5 hr. The insoluble material was filtered through a Celite (trademark) filter, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography. The obtained 4-[4-(morpholine-4-ylmethyl)phenyl]piperazine-1-carboxylic acid tert-butyl ester was dissolved in dichloromethane, trifluoroacetic acid was added and the mixture was stirred overnight at room temperature. The mixture was neutralized with an aqueous sodium hydroxide solution, and extracted with dichloromethane. The organic layer was dried and the solvent was evaporated under reduced pressure to give 4-(4-piperazin-1-ylbenzyl)morpholine (1.06 g, yield 51%).
Reaction SMILES: C[NH:2]C(C1N(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)N=CN=1)=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[N:39][N:38]3[C:43]=2[CH2:44][N:45]2[C:49]([C:50]([O:52]C)=O)=[N:48][CH:47]=[N:46]2)=[CH:31][CH:30]=1.N>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[N:39][N:38]3[C:43]=2[CH2:44][N:45]2[C:49]([C:50]([NH2:2])=[O:52])=[N:48][CH:47]=[N:46]2)=[CH:31][CH:30]=1
Reactant: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Reactant: COC(=O)c1ncnn1Cc1c(-c2ccc(Cl)cc2)nc2cccnn12
Agent: N
Product: NC(=O)c1ncnn1Cc1c(-c2ccc(Cl)cc2)nc2cccnn12

Procedure:
The title compound was prepared according to the procedure described for compound 68 from methyl 1-((2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)-1H-1,2,4-triazole-5-carboxylate and ammonia. 1H-NMR (CDCl3, 400 MHz, δ) 8.74 (s, 1H), 8.56 (dd, J=1.4, 4.5 Hz, 1H), 8.08 (dd, J=1.5, 9.3 Hz, 1H), 8.02 (d, J=8.5 Hz, 2H), 7.57 (d, J=8.5 Hz, 2H), 7.37 (dd, J=4.5, 9.2 Hz, 1H), 6.01 (s, 2H) ppm; m/e 354 (M+H)−.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.C(N)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].ClCC(Cl)=O.[CH2:27]([NH:34][C:35](=[O:38])[CH2:36][Cl:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([N:34]([CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1)[C:35](=[O:38])[CH2:36][Cl:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: ClCc1cscn1
Reactant: O=C(CCl)NCc1ccccc1
Agent: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: NCc1ccccc1
Product: O=C(CCl)N(Cc1ccccc1)Cc1cscn1
Temperature: 80 °C
Yield: 85.7 %

Procedure:
4-Chloromethylthiazole (1.33 g, 10.0 mmol) and benzylamine (2.2 mL, 20.0 mmol) were mixed together and heated to 80° C. for 24 hours and allowed to cool to room temperature. The solid mass was treated with 2M aqueous sodium carbonate and stirred until the mass was broken up and the mixture was extracted with 2 portions of ethyl ether. The combined organic extracts were dried (Na2SO4), filtered, and concentrated. The residue was dissolved in 40 mL of dichloromethane, cooled to 0° C., and 40 mL of saturated, aqueous NaHCO3 was added. To this stirred biphasic mixture was added chloroacetyl chloride (1.8 mL, 22.0 mmol) dropwise and mixture was stirred for an additional 2 hours at 0° C. The layers were separated and the organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, 30% -50% ethyl acetate/hexanes) to provide first, 0.58 g (21%) N-benzylchloroacetamide followed by 0.76 g (27%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:36])(=[N:27][C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])=[O:26])=[CH:21][CH:20]=1>>[N:30]1([C:28]([N:27]=[S:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:2]3[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)=[CH:4][N:3]=3)=[CH:20][CH:21]=2)([CH3:36])=[O:26])=[O:29])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: CS(=O)(=NC(=O)N1CCOCC1)c1ccc(N)cc1
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Product: C[C@H](CO)Nc1nc(Nc2ccc(S(C)(=O)=NC(=O)N3CCOCC3)cc2)ncc1-c1cccs1
Yield: 7 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (49.2 mg, 0.18 mmol) with (RS)—S-(4-aminophenyl)-N-(morpholine-4-carbonyl)-S-methylsulphoximide (47 mg, 0.17 mmol) according to procedure 5c, the desired product is obtained in 7% yield (6 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol) and HPLC).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][O:9][CH2:10][C:11]#[CH:12])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(O)(=O)/C=C/C(O)=O>>[CH2:10]([O:9][CH2:8][CH2:7][N:6]1[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=[C:2]1[N:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1)[C:11]#[CH:12]
Reactant: C#CCOCCn1c(Cl)nc2ccccc21
Reactant: CN1CCNCC1
Agent: O=C(O)/C=C/C(=O)O
Product: C#CCOCCn1c(N2CCN(C)CC2)nc2ccccc21

Procedure:
In the same manner as described in Example 1 using 2-chloro-1-[2-(propargyloxy)ethyl]benzimidazole (3.00 g), N-methylpiperazine (2.70 g) and fumaric acid (1.52 g), there are obtained crude crystals, which are recrystallized from ethyl acetate-ethanol to give 1-[2-(propargyloxy)ethyl]-2-(4-methyl-1-piperazinyl)benzimidazole.3/2 fumarate (2.80 g) as colorless plates, m.p. 145°-146.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][C:10]=2[Cl:12])[N:5]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:3]=1.[C:19]1([N:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Na+]>CN(C)C=O>[Cl:12][C:10]1[CH:9]=[C:8]([Cl:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:1][C:26]([N:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27])=[CH:3][C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:5]2
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1cc(N)c2c(Cl)cc(Cl)cc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(NC(=O)N(c2ccccc2)c2ccccc2)c2c(Cl)cc(Cl)cc2n1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
5-L three-neck flask was charged with a cold (<10° C.) solution of Compound 5 (about 0.59 mole, 168.95 g) in N,N-dimethylformamide (DMF) (about 2 L). Diphenylcarbamoyl chloride (0.73 mole, 168.92 g) then was added to the solution. The resulting mixture was maintained below 10° C., sodium hydride (NaH; 1.19 mole, 28.45 g) was added, in portions, over about 1.3 hours, and the reaction mixture was allowed to warm to ambient temperature overnight. Thin layer chromatography (TLC) indicated that some unreacted Compound 5 remained. The reaction mixture was recooled to about 10° C., and additional NaH (about 0.3 mole, 7.11 g) was added. The subsequent reaction was quenched with saturated aqueous ammonium chloride (NH4Cl; about 1.3 L) followed by the addition of 10% aqueous acetic acid (AcOH; 1 L), 20% AcOH (0.5 L), and EtOAc (4 L) to obtain a mixture having a pH of about 4 to 5. The solids present in the flask then were filtered, rinsed with EtOAc (500 mL) and DI water (500 mL), and dried by lyophilization to afford about 229 g of crude Compound 6 and a crude filtrate containing additional Compound 6. The crude Compound 6 was dissolved in dichloromethane (CH2Cl2; 3 L), back extracted with deionized (DI) water (500 mL) and brine (500 mL). The organic phase was dried over Na2SO4 (323.30 g) and filtered to afford a solution containing the bulk of the crude Compound 6.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1.C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O.[Na+]>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([CH3:24])=[C:2]([NH:1][C:31]([C:30]5[N:26]([CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=5)=[O:32])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)n(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a solution of N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (213 mg, 0.659 mmol) in tetrahydrofuran (10 mL) were added a solution of 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (136 mg, 0.856 mmol) in tetrahydrofuran (0.5 mL) and triethylamine (200 mg, 1.98 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution, and extracted three times with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was filtrated and washed with ethyl acetate/hexane to give the title compound (222 mg, 77%) as a white powder. melting point 223° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24](I)[CH3:25]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([CH2:24][CH3:25])=[C:15]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(Cl)cc2)on1
Product: CCc1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccc(Cl)cc1
Yield: 61 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-chlorophenyl)isoxazole (0.4 g) and ethyl iodide (0.11 ml) were subjected to reaction and post-treatment in a similar manner to that described in Example 14(a) to obtain the title compound (0.26 g, 61%) as a colorless oil.
Reaction SMILES: BrCCCCCCCCCC[O:12]C1C=CC(C(O)=O)=CC=1.C1(C=CC=C(O)C=1)O.[CH2:30]([O:41][C:42]1[CH:58]=[CH:57][C:45]([C:46]([O:48][C:49]2[CH:54]=[CH:53][C:52]([CH:55]=[O:56])=[CH:51][CH:50]=2)=[O:47])=[CH:44][CH:43]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH2:40].[O-]Cl=O.[Na+]>>[CH2:30]([O:41][C:42]1[CH:58]=[CH:57][C:45]([C:46]([O:48][C:49]2[CH:54]=[CH:53][C:52]([C:55]([OH:12])=[O:56])=[CH:51][CH:50]=2)=[O:47])=[CH:44][CH:43]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH2:40]
Reactant: C=CCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Reactant: O=C(O)c1ccc(OCCCCCCCCCCBr)cc1
Agent: Oc1cccc(O)c1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Product: C=CCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)O)cc2)cc1

Procedure:
Synthesized as described above for compound 7. Quantities: resorcinol (1.71 g, 16 mmol), 13 (5.07 g, 13 mmol), NaH2PO4·H2O (5.32 g, 39 mmol), NaClO2 (6.71 g, 74 mmol). Yield 5.34 g (quant.). 1H NMR: δH (CDCl3; 300 MHz): 1.24-1.52 (12 H, m, CH2), 1.83 (2 H, m, O—CH2—CH2), 2.04 (2 H, m, CH2═CH—CH2), 4.05 (2 H, t, 3J=6.5 Hz, O—CH2), 4.95 (2 H, m, CH2═CH), 5.82 (1 H, m, CH2═CH), 6.99 (2 H, d, 3J=8.9 Hz, Ar—H), 7.34 (2 H, d, 3J=8.6 Hz, Ar—H), 8.16 (2 H, d, 3J=8.9 Hz, Ar—H), 8.20 (2 H, d, 3J=8.6 Hz, Ar—H). 13C NMR: δC (CDCl3; 75 MHz): 26.0, 28.9, 29.1, 29.3, 29.4, 29.5, 33.8, 68.4, 114.1, 114.4, 121.0, 122.0, 126.5, 131.9, 132.4, 139.2, 155.5, 163.8, 170.6.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:28][O:29][C:30]1[C:31](=O)[C:32](=[O:36])[C:33]=1[O:34]C>>[CH3:28][O:29][C:30]1[C:33](=[O:34])[C:32](=[O:36])[C:31]=1[NH:2][C:3]1[CH:4]=[C:5]([CH:9]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(C(NC(=O)c2ccc(F)cc2)c2cccc(N)c2)cc1
Reactant: COc1c(OC)c(=O)c1=O
Agent: Cl
Product: COc1ccc(C(NC(=O)c2ccc(F)cc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Yield: 49.7 %

Procedure:
In a similar manner to that described in Example (46e) N-[(3-aminophenyl)-(4-methoxyphenyl)methyl]-4-fluorobenzamide hydrochloride (674 mg) [prepared as described in step (b) above] and 3,4-dimethoxy-3-cyclobutene-1,2-dione (250 mg) were reacted, to afford the title compound (399 mg) as a yellow solid.