Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[S:34](Cl)(=[O:36])=[O:35].O>C(Cl)Cl>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[S:34]([O:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:9])([CH3:10])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](COS(=O)(=O)c2cc(Cl)ccc2Cl)OC(C)(C)O1
Reaction time: 3.5 h
Yield: 137.9 %

Procedure:
To a stirring 0°-5° C. solution of the (4R-cis)-1,1-dimethylethyl 6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (European Patent Application 0319,847) (10 g, 38 mmol) in methylene chloride (250 mL) containing triethylamine (10 mL, 72 mmol) is added 2,5-dichlorobenzenesulfonyl chloride (14.7 g, 57.5 mmol). Stirring is continued at 0°-5° C. for 3.5 hours, the solution is poured onto 200 mL of water, and the layers separated. The upper aqueous layer is extracted with 200 mL of methylene chloride and the combined organic layers are washed with 200 mL each of saturated sodium bicarbonate solution to ensure complete removal of 2,5-dichlorobenzenesulfonyl chloride and then saturated sodium chloride solution. Drying the solution with magnesium sulfate and concentration in vacuo gives 24.6 g of the product as a yellow-orange oil.
Reaction SMILES: [Li].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][CH2:21]I>>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([C:8]2([C:4]3[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:10][CH:11]=1)#[N:14]
Reactant: ClCCCCI
Reactant: N#Cc1ccc(Cc2cccnc2)cc1
Agent: [Li]
Product: N#Cc1ccc(C2(c3cccnc3)CCCC2)cc1

Procedure:
Using procedure described in Example 36, the lithium salt of 4-(3-pyridylmethyl)-benzonitrile is treated with 1-chloro-4-iodobutane and the intermediate cyclized to obtain 1-(4-cyanophenyl)-1-(3-pyridyl)-cyclopentane.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[NH:9][CH2:10][CH2:11][C:12]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]1>O1CCOCC1.C(OCC)(=O)C>[ClH:1].[ClH:1].[ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[NH:9][CH2:10][CH2:11][C:12]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1
Reactant: CCOC(=O)C1(CCNc2cnccc2C)CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(CCNc2cnccc2C)CCCNC1
Reaction time: 2 h

Procedure:
Hydrogen chloride in 1,4-dioxane (4.0 M, 2.0 mL) was added to a solution of 1-tert-butyl 3-ethyl 3-{2-[(4-methylpyridin-3-yl)amino]ethyl}piperidine-1,3-dicarboxylate (0.036 g, 0.000092 mol) in ethyl acetate (0.5 mL) and the mixture was stirred for 2 h. Then the solvent was removed in-vacuo to afford the product. LC-MS: 292.3 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[N:20][N:21]([C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=3)[C:22]=2[OH:23])=[C:14]([CH3:33])[CH:13]=1)#[N:11].C(O)=O>>[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[N:20][N:21]([C:24]3[CH:32]=[CH:31][C:27]([C:28]([N:2]([CH3:1])[CH:3]4[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]4)=[O:29])=[CH:26][N:25]=3)[C:22]=2[OH:23])=[C:14]([CH3:33])[CH:13]=1)#[N:11]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CNC1CCN(C)CC1
Solvent: O=CO
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N(C)C3CCN(C)CC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 284 using N,1-dimethylpiperidin-4-amine and 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid to give a formic acid salt (42 mg, 0.088 mmol, 70.6%) as a white solid. MS: 431 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.71 (d, J=11.6 Hz, 2 H) 1.78-1.95 (m, 2 H) 2.35 (s, 3 H) 2.78 (s, 3 H) 2.92-3.83 (m, 7 H) 4.34 (br. s., 1 H) 7.43 (d, J=8.3 Hz, 1 H) 7.48 (s, 1 H) 7.76-7.88 (m, 2 H) 8.06-8.11 (m, 1 H) 8.38 (br. s., 1 H) 8.43 (d, J=8.8 Hz, 1 H).
Reaction SMILES: [CH:1]([Si:3]([Cl:6])([Cl:5])[Cl:4])=[CH2:2].[Cl:7][Si:8]([Cl:15])([Cl:14])[CH2:9][CH2:10][SiH:11]([Cl:13])[Cl:12]>>[Cl:4][Si:3]([Cl:6])([Cl:5])[CH2:1][CH2:2][Si:11]([Cl:13])([Cl:12])[CH2:10][CH2:9][Si:8]([Cl:15])([Cl:14])[Cl:7]
Reactant: C=C[Si](Cl)(Cl)Cl
Reactant: Cl[SiH](Cl)CC[Si](Cl)(Cl)Cl
Product: Cl[Si](Cl)(Cl)CC[Si](Cl)(Cl)CC[Si](Cl)(Cl)Cl
Reaction time: 12 h

Procedure:
Vinyltrichlorosilane (16.8 g, 104 mmol) was heated to 60° C. and 100 μL 10% H2PtCl6/IPA-solution was added. 1,1,1,4,4-pentachloro-1,4-disilabutane (20.4 g, 77.7 mmol) was added slowly during 20 min so that the temperature did not exceed 100° C. The reaction was allowed to proceed for 12 hours at 100° C., after which it was distilled under vacuum at 115-130° C./<1 mbar. The yield was 31.5 g (74.3 mmol, 96%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH2:16][C@H:17]([NH:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[CH3:18])=[CH:11][C:12]=2[C:14]#[N:15])[CH2:7][CH2:6]1.[OH-].[Na+].OO.S([O-])([O-])=[O:40].[Na+].[Na+]>CS(C)=O.O>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH2:16][C@H:17]([NH:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][C:31]([F:34])([F:32])[F:33])[CH3:18])=[CH:11][C:12]=2[C:14]([NH2:15])=[O:40])[CH2:7][CH2:6]1
Reactant: C[C@H](Cc1cc(C#N)c2c(c1)CCN2CCCO)NCCOc1ccccc1OCC(F)(F)F
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](Cc1cc2c(c(C(N)=O)c1)N(CCCO)CC2)NCCOc1ccccc1OCC(F)(F)F
Temperature: 22.5 °C
Reaction time: 5 h

Procedure:
1-(3-Hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carbonitrile(6.00 g) was dissolved in dimethylsulfoxide (75 mL), and to the solution was added 5 mol/L aqueous sodium hydroxide solution(4.50 mL). To the reaction mixture, 30% hydrogen peroxide (2.63 mL) was added little by little at not more than 25° C. The reaction mixture was stirred at 20 to 25° C. for 5 hours. To the reaction mixture, an aqueous sodium sulfite solution of sodium sulfite (2.1 g) dissolved in water (150 mL) was added carefully. The reaction mixture was extracted twice with ethyl acetate (50 mL). The combined ethyl acetate layer was extracted twice with 2 mol/L hydrochloric acid. The aqueous hydrochloric acid solution extracted was neutralized with sodium bicarbonate, and extracted twice with ethyl acetate (50 mL). The combined ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was cooled to give 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]-ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide (4.49 g).
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:17]=[CH:16][S:15][C:14]=1[CH3:18].[CH2:19]1[O:21][CH2:20]1.B(F)(F)F.CCOCC>C1COCC1>[CH3:18][C:14]1[S:15][CH:16]=[CH:17][C:13]=1[CH2:19][CH2:20][OH:21]
Reactant: C1CO1
Reactant: Cc1sccc1Br
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1sccc1CCO
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1.6M BuLi in hexane (98.4 mL, 157.5 mmol) and THF (150 mL) was added at −78° C. a solution of 3-bromo-2-methyl-thiophene (CAS 30319-05-2, 26.6 g, 150 mmol) in THF (50 mL) and stirring at −78° C. was continued for 1 h. 2.0M ethylene oxide in THF (112.5 mL, 225 mmol) and then BF3-Et2O (20.4 mL, 165 mmol) was added dropwise at −70° C. and the yellow solution was stirred at −78° C. for 1 h. After warming to 0° C. the reaction mixture was quenched with 10% brine (400 mL) and extracted with ethyl acetate (400+200 mL). The organic layers were washed with 10% brine, dried (Na2SO4) and evaporated affording 18.6 g crude product as a yellow oil. Purification by chromatography over silica with hexane-ethyl acetate 5:1 gave 14.9 g (70%, GC 94.7%) yellow oil.
Reaction SMILES: C(OC(NCC1(O)CCNC1)=O)(C)(C)C.Cl[CH2:17][CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([N:28]3[CH:32]=[N:31][N:30]=[CH:29]3)[CH:26]=2)[NH:21][CH:20]=1.[CH2:33]([NH:40][CH2:41][C:42]1([OH:65])[CH2:47][CH2:46][N:45]([CH2:48]CCC2C3C(=CC=C(N4C=NN=C4)C=3)NC=2)CC1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C2C(=CC=CC=2)C=C1>O.CS(C)=O>[CH2:33]([NH:40][CH2:41][C:42]1([OH:65])[CH2:47][CH2:46][N:45]([CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N:28]4[CH:32]=[N:31][N:30]=[CH:29]4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:48]1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: ClCCc1c[nH]c2ccc(-n3cnnc3)cc12
Reactant: OC1(CNCc2ccccc2)CCN(CCCc2c[nH]c3ccc(-n4cnnc4)cc23)CC1
Agent: CC(C)(C)OC(=O)NCC1(O)CCNC1
Agent: c1ccc2[nH]ccc2c1
Solvent: O
Solvent: CS(C)=O
Product: OC1(CNCc2ccccc2)CCN(CCc2c[nH]c3ccc(-n4cnnc4)cc23)C1

Procedure:
The title compound was prepared from 3-(t-butyloxycarbonylamino) methyl-3-hydroxypyrrolidine and 1-chloro-2-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]ethane (prepared from 2-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]ethanol), followed by deprotection and functionalisation as described for 4-(benzylamino)methyl-4-hydroxy-1-(3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl)piperidine. mp>56° C. MS, ES+, m/z=417 for (M+H)+ ; δ (360 MHz, D6 -DMSO) 1.60-1.68 (1H, m, CH), 1.80-1.88 (1H, m, CH), 2.40-2.76 (8H, m, 4×CH2N), 2.84 (2H, t, J=7 Hz, CH2 -indole), 3.72 (2H, s, NHCH2Ar), 4.56 (1H, s, OH), 7.17-7.36 (7H, m, Ar--H), 7.47 (1H, d, J=8 Hz, Ar--H), 7.78 (1H, d, J=2 Hz, Ar--H), 9.01 (2H, s, triazole-H), 11.07 (1H, s, indole-NH). (Found: C, 67.40; H, 6.68; N, 19.54. C24H28N6O.0.5 H2O requires C, 67.74; H, 6.87; N, 19.75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[N:12]=[N:13][N:14]=[C:7]1[NH:6][CH:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+].CI.[CH:25](OC(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[N:12]=[N:13][N:14]=[C:7]1[N:6]([CH3:25])[CH:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)OC(C)C
Reactant: Clc1ccc2c(c1)C(c1ccccc1)Nc1nnnn1-2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1c2nnnn2-c2ccc(Cl)cc2C1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.4 g of 7-chloro-4,5-dihydro-5-phenyltetrazolo[1,5-a]quinazoline in 20 ml of dimethylformamide was added 0.07 g of 50% sodium hydride. After the mixture was stirred at room temperature for 1 hour, 0.4 g of methyl iodide was added thereto. The resulting mixture was stirred at room temperature for 2 hours and then poured into ice-water. The mixture was stirred with a small quantity of isopropyl ether, and the resulting precipitate was collected by filtration, washed successively with water and isopropyl ether, and dried to give 0.26 g of 7-chloro-4,5-dihydro-4-methyl-5-phenyltetrazolo[1,5-a]quinazoline as pale yellow crystals. Recrystallization from ethanol gave colorless scales, m.p. 282°-283° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:9][C:10]([C:12]1[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=1)=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7].[N:20]1([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:9][C:10]([C:12]1[N:13]=[N:14][C:15]([N:23]2[CH2:24][CH2:25][N:20]([C:26](=[O:27])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:35])[F:36])[CH2:21][CH2:22]2)=[CH:16][CH:17]=1)=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: COC(=O)C(CC(C)C)NC(=O)c1ccc(Cl)nn1
Product: COC(=O)C(CC(C)C)NC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 2-[(6-chloropyridazine-3-carbonyl)amino]-4-methylpentanoic acid methyl ester in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)-methanone, the title compound was obtained as a white solid (36% yield). 1H NMR (400 MHz, CDCl3) δ 8.16, 8.04, 7.85, 7.66-7.53, 7.28, 7.00, 4.82-4.77, 4.14-3.68, 3.58-3.51, 1.83-1.60, 1.03-0.95.
Reaction SMILES: CN([CH2:4][CH2:5][N:6]([CH3:8])[CH3:7])C.[Li][CH2:10][CH2:11][CH2:12][CH3:13].Cl[P:15]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CCCCCC>[C:5]1([N:6]2[C:8]3[C:21](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:20]=[C:7]2[P:15]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:4]=1
Reactant: [Li]CCCC
Reactant: ClP(C1CCCCC1)C1CCCCC1
Reactant: CN(C)CCN(C)C
Solvent: CCCCCC
Product: c1ccc(-n2c(P(C3CCCCC3)C3CCCCC3)cc3ccccc32)cc1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
1.6 ml (15 mmol.) of TMEDA are added to 1.93 g (10 mmol.) of 1 in 30 ml of hexane. A solution (1.6 M in hexane) of n-BuLi (6.25 ml, 10 mmol.) is added dropwise. After 3 hours, reflux (75° C.), the colour has deepened from yellow to orange. Without cooling, a solution of 2.2 ml (10 mmol.) of chlorodicyclohexylphosphane in 20 ml of hexane is added dropwise. Refluxing is carried out for a further one hour, the colour of the mixture lightening again and a white solid precipitating. After cooling, 30 ml of water are added to the mixture. The aqueous phase is extracted 3 times using 20 ml of hexane each time. The combined organic phases are washed with 10 ml of water, dried over Na2SO4 and concentrated in vacuo (45° C.). The yellow residue is boiled for 30 minutes in 30 ml of MeOH. After cooling to RT, the resulting product is filtered off (660 mg, 17%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH2:19][CH3:20])[CH:12]=[CH:11][C:10]=1[N:21]1[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)O[O:31]1>CC(C)=O.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]2[CH:16]([CH2:17][CH2:18][CH2:19][CH3:20])[O:31]2)[CH:12]=[CH:11][C:10]=1[N:21]1[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OO1
Reactant: CCCC/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCCCC1OC1c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-[2-benzyloxy-4-((E)-hex-1-enyl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (10 mg, 0.275 mmol) in acetone (10 mL) is added a solution of DMDO (0.56 mM, 4.9 mL, 0.413 mmol) in acetone. This mixture is stirred at RT for 1 h, at which point LCMS of the reaction shows clean conversion to the desired epoxide. The reaction mixture is diluted with EtOAc and concentrated 3× to fully remove the volatile DMDO. The remaining EtOAc is removed under reduced pressure to afford the title compound which is used directly in the next step.
Reaction SMILES: [Br:1]Br.Cl.[C:4]([C:7]1[CH:8]=[CH:9][C:10]([NH2:17])=[C:11]([CH:16]=1)[CH2:12][N:13]([CH3:15])[CH3:14])(=[O:6])[CH3:5].N>C(O)(=O)C>[C:4]([C:7]1[CH:8]=[C:9]([Br:1])[C:10]([NH2:17])=[C:11]([CH:16]=1)[CH2:12][N:13]([CH3:14])[CH3:15])(=[O:6])[CH3:5]
Reactant: CC(=O)c1ccc(N)c(CN(C)C)c1
Reactant: BrBr
Agent: Cl
Agent: N
Solvent: CC(=O)O
Product: CC(=O)c1cc(Br)c(N)c(CN(C)C)c1

Procedure:
9.0 gm of bromine were added dropwise to a solution of 12.8 gm of 5-acetyl-2-amino-N,N-dimethyl-benzylamine hydrochloride in 100 ml of 80% acetic acid. Subsequently, the reaction mixture was made alkaline with 2 N ammonia, extracted twice with chloroform, and the organic extract was evaporated. By recrystallization of the residue from ethanol/water, 5-acetyl-2-amino-3-bromo-N,N-dimethyl-benzylamine, m.p. 92°-95° C, was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:29])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[CH:10]=2)[N:5]=[C:4]([C:30](OC)=[O:31])[CH:3]=1.[Cl-:34].[Na+].O>O1CCCC1.C(OCC)(=O)C>[ClH:34].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:29])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:20][O:21][C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[CH:10]=2)[N:5]=[C:4]([CH2:30][OH:31])[CH:3]=1
Reactant: [Cl-]
Reactant: COC(=O)c1cc(N)c2cc(NC(=O)c3ccccc3COc3ccc(C)cc3)ccc2n1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(OCc2ccccc2C(=O)Nc2ccc3nc(CO)cc(N)c3c2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
To a solution of N-(4-amino-2-methoxycarbonyl-6-quinolyl)-2-[(4-methylphenoxy)methyl]benzamide (170 mg, 0.385 mmol) obtained in Example 131, Step 5 in tetrahydrofuran (10 ml) was added, by small portions, lithium tetrahydroboroate (42 mg, 1.927 mmol) under ice-cooling in an argon stream. After 10 min, the mixture was warmed to room temperature and the mixture was stirred for 2 hr. The reaction mixture was diluted with saturated brine and ethyl acetate to separate the layers. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained yellow residue was dissolved in ethyl acetate and 4N hydrochloric acid—dioxane solution (0.5 ml) was added to precipitate hydrochloride. This salt was collected by filtration and dried under reduced pressure at 80° C. to give the title compound (116 mg, 67%, pale-yellow crystals).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[C:16]([S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:17]=1>CN(C=O)C>[C:22]([NH:21][S:18]([C:16]1[CH:17]=[C:12]([NH:11][CH:1]=[O:3])[CH:13]=[CH:14][C:15]=1[S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])(=[O:19])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=CO
Reactant: CCS(=O)(=O)c1ccc(N)cc1S(=O)(=O)NC(C)(C)C
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: CCS(=O)(=O)c1ccc(NC=O)cc1S(=O)(=O)NC(C)(C)C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
0.82 ml of formic acid is added dropwise to 1.85 ml of acetic anhydride. After the mixture has been stirred at 50° C. for 2 hours, a solution of 2.5 g of 5-amino-N-tert-butyl-2-ethylsulfonylbenzenesulfonamide in 10 ml of DMF is added dropwise at room temperature. This mixture is first stirred at 50° C. for 3 hours and then concentrated under a high vacuum. The residue is taken up in water and the mixture is extracted with ethyl acetate. After the organic phase been dried over magnesium sulfate, the solvent is distilled off. The residue (3.0 g) contains the desired product and is of adequate purity for further reactions.
Reaction SMILES: [CH:1]([C:3]([CH2:5][CH3:6])=[O:4])=[CH2:2].[CH2:7]=[CH:8][C:9](=[CH2:11])[CH3:10].Cl(O)(=O)(=O)=O.C([C@@H]1N[C@H](C2OC(C)=CC=2)N(C)C1=O)C1C=CC=CC=1>>[CH3:11][C:9]1[CH2:8][CH2:7][C@@H:1]([C:3](=[O:4])[CH2:5][CH3:6])[CH2:2][CH:10]=1
Reactant: C=CC(=C)C
Reactant: C=CC(=O)CC
Agent: Cc1ccc([C@H]2N[C@@H](Cc3ccccc3)C(=O)N2C)o1
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCC(=O)[C@H]1CC=C(C)CC1
Reaction time: 72 h
Yield: 79 %

Procedure:
Prepared according to general procedure B from ethyl vinyl ketone (70 μL, 0.70 mmol), isoprene (140 μL, 1.40 mmol), 70% aqueous perchloric acid (12.1 μL, 0.14 mmol) and (2S, 5S)-5-benzyl-3-methyl-2-(5-methyl-furan-2-yl)-imidazolidin-4-one (38 mg, 0.14 mmol) neat for 3 days at −20° C. Then, another portion of isoprene (100 μL, 1.00 mmol) was added and the solution was allowed to stir for an additional 3 days. Purification by silica gel chromatography (10:1 pentane:ether) provided the title compound as a single regioisomer (as judged by GLC analysis) in 79% yield (84 mg, 0.55 mmol) and 85% ee. IR (film) 2967, 2928, 2836, 1710, 1452, 1413, 1377, 1343, 1217, 1149, 1126, 952.6, 915.1, 871.9, 800.0 cm−1; 1H NMR (300 MHz, CDCl3) δ 5.34 (m, 1H, C═CH), 2.46 (m, 3H, CH2CO and CHCO), 2.09 (m, 2H, CH2CH═C(CH3)), 1.94 (m, 2H, CH2C(CH3)═CH), 1.86 (m, 1H, one of CH2CH2CH), 1.54 (m, 1H, one of CH2CH2CH), 0.99 (dd, J=7.5, 7.5 Hz, 3H, CH2CH3); 13C NMR (75 MHz, CDCl3) δ 214.4, 133.8, 119.6, 46.6, 34.1, 29.9, 27.6, 25.4, 23.7, 8.1; HRMS (CI) exact mass calc'd for (C10H16O) requires m/z 152.1201, found m/z 152.1201. [α]D=+37.8 (c=1.0, CHCl3). Product ratios were determined by GLC analysis (100° C., 23 psi); (R) isomer tr=16.1 min, and (S) isomer tr=15.4 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].Cl.C[N:17](C)[CH:18]=[C:19]([N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)[C:20]#N>C(O)C>[NH2:17][C:18]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])[N:14]=[CH:20][C:19]=1[N:22]1[CH:26]=[N:25][CH:24]=[N:23]1
Reactant: CN(C)C=C(C#N)n1cncn1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: CCO
Product: Nc1c(-n2cncn2)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 95.5 %

Procedure:
19 g (0.075 mole) of 2,6-dichloro-4-trifluoromethyl-phenylhydrazine and 16 g (0.075 mole) of 3-dimethylamino-2-(1,2,4-triazol-1-yl)-acrylonitrile hydrochloride in 200 ml of ethanol are heated at 75° C. to 78° C. for 5 hours, with stirring. For working up, the solvent is distilled off and the residue is triturated with water and dried over clay. 26 g (96% of theory) of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(1,2,4-triazol-1-yl)-pyrazole of melting point 170°-174° C. are obtained.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:28])[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])=[C:4]([CH3:29])[C:3]=1[F:30].[C:31]([O:35][C:36]([NH:38][CH:39]1[CH2:43][CH2:42][NH:41][CH2:40]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].[C:44](OC(N[C@@H]1CCNC1)=O)(C)(C)C>>[C:31]([O:35][C:36]([NH:38][CH:39]1[CH2:43][CH2:42][N:41]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:28])[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][N:9]3[CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[O:21][CH3:22])=[C:4]([CH2:29][CH3:44])[C:3]=2[F:30])[CH2:40]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(Cl)c(F)c(C)c2c1=O
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3CCC(NC(=O)OC(C)(C)C)C3)c(F)c(CC)c2c1=O

Procedure:
This example was prepared by substituting ethyl 7-chloro-1-(2,4-dimethoxybenzyl)-6-fluoro-5-ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate for ethyl 7-chloro-1-(2,4-dimethoxybenzyl)-6-fluoro-5-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate and 3-(tert-butoxycarbonylamino)pyrrolidine for (3R)-3-(tert-butoxycarbonylamino)pyrrolidine in EXAMPLE 1E.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([N:10]=[C:11]=[O:12])[CH2:7][CH2:8][CH2:9][C:2]1=2.[CH3:13][NH:14][CH3:15]>C(OCC)C>[CH3:13][N:14]([CH3:15])[C:11]([NH:10][CH:6]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH2:9][CH2:8][CH2:7]1)=[O:12]
Reactant: O=C=NC1CCCc2sccc21
Reactant: CNC
Solvent: CCOCC
Product: CN(C)C(=O)NC1CCCc2sccc21

Procedure:
A solution of 6.27 grams of 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate in 200 ml. of diethyl ether is charged with gaseous dimethylamine introduced via a capillary tube with stirring. After 0.5 hour of bubbling, the gas flow is terminated, and the mixture is evaporated to dryness to give a solid residue. This is crystallized from acetone-hexane-ether to give 1,1-dimethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea melting at 117° C. to 120° C.