Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37](O)=[O:38])=[CH:29][CH:28]=1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:37]([C:30]3[C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:27]=[CH:28][CH:29]=3)=[O:38])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)c1ccnc2ccccc12
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccnc2ccccc12

Procedure:
The title compound, yellow solid (106 mg, 88%), MS (ISP) m/z=482.3 [(M+H)+], mp 169° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and quinoline-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][C:27]=1[C:28](O)=[O:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][C:27]=1[C:28]([N:15]1[CH2:16][CH2:17][N:12]([C:3]2[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=2[F:1])[CH2:13][CH2:14]1)=[O:29])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CS(=O)(=O)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Reactant: CS(=O)(=O)c1ccc(N2CCNCC2)c(F)c1
Product: CS(=O)(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OCc3ccccc3)CC2)c(F)c1

Procedure:
The title compound was prepared in analogy to example 5 from 1-(2-Fluoro-4-methanesulfonyl-phenyl)-piperazine (commercial) and 2-Benzyloxy-5-methanesulfonyl-benzoic acid (compound 7.5). MS (m/e): 547.4 (MH+, 100%)
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH:10]1([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([NH2:30])=[N:25][CH:26]=[C:27]([CH3:29])[N:28]=3)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1COCC1>[CH:10]1([O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[C:24]4=[N:30][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:25]4[CH:26]=[C:27]([CH3:29])[N:28]=3)=[CH:21][CH:22]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: Cc1cnc(N)c(-c2ccc(OC3CCCCC3)cc2)n1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=CN2CCS(=O)(=O)N=C2C(c2ccc(OC3CCCCC3)cc2)=N1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 5.29 g) in THF (dry) (100 mL) was added 2-chloroethanesulfonyl chloride (5.57 ml) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-(4-(cyclohexyloxy)phenyl)-5-methylpyrazin-2-amine (7.5 g) in THF (dry) (75 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen for 2 days. The mixture was quenched with water/THF at 0° C. carefully and water was added to form precipitates which were washed with EtOAc and water and dried in vacuo to give crude title compound (4.7 g). The part of this material (ca. 4.3 g) was crystallized from DMSO (200 mL)-EtOH (40 mL)/water (400 mL) to give 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide as light-yellow crystals (3.6 g), which was recrystallized from DMSO (100 mL)-EtOH (15 mL)/water (100 mL) at 80° C. to room temperature to give the title compound (3.09 g) as light-yellow crystals.
Reaction SMILES: [C:1]([C:4]1[CH2:5][CH2:6][N:7](CC2C=CC=CC=2)[CH2:8][CH:9]=1)(=[O:3])[CH3:2].[CH2:17]([O:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[C:1]([C:4]1[CH2:9][CH2:8][N:7]([C:25]([O:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:26])[CH2:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(=O)C1=CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Product: CC(=O)C1=CCN(C(=O)OCc2ccccc2)CC1

Procedure:
To a solution of 4-acetyl-1-benzyl-1,2,3,6-tetrahydropyridine (9.63 g) and benzyloxycarbonyl chloride (9.06 ml) in toluene was heated at 85° C. for 8 hours. After the solvent was removed in vacuo, the residual solution was dissolved in ethyl acetate (100 ml), washed with saturated aqueous sodium hydrogen carbonate (100 ml×3) and brine (100 ml) successively. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo to give an oil, which was chromatographed on silica gel (500 ml) eluting with a mixture of hexane and ethyl acetate (1:1, V/V) to give 4-acetyl-1-benzyloxycarbonyl-1,2,3,6-tetrahydropyridine (10.2 g).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[F:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29]([CH:33]=1)[C:30](O)=[O:31]>>[F:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29]([CH:33]=1)[C:30]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:31]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: COc1ccc(F)cc1C(=O)O
Product: COc1ccc(F)cc1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(C)sc1-c1cccc(C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 5-Fluoro-2-methoxy-benzoic acid. LC-MS (basic): tR=0.92 min; [M+H]+=480.1.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](#[N:19])[CH:17]=[CH2:18].N12CCCN=C1CCCCC2>O1CCOCC1>[C:10]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH:8]=[O:9])[CH2:18][CH2:17][C:16]#[N:19])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C=CC#N
Reactant: O=CC(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: N#CCCC(C=O)(c1ccccc1)c1ccccc1

Procedure:
To a stirred solution of diphenylacetaldehyde (11.0 mL) and acrylonitrile (4.5 mL) in dioxane (125 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (10.5 mL). The solution was heated under reflux overnight and then concentrated in vacuo. The residue was purified by a silica gel column eluting with (95:5) hexane/ethyl acetate. The desired product (8.115 g) was obtained a colorless crystals, mp 80-82° C.: MS showed (M+NH4)+ @ 267; 1H-NMR (CDCl3, δ): 2.05-2.15 (m, 2H), 2.65-2.75 (m, 2H). 7.11-7.45 (m, 10 H), 9.80 (s, 1H); Anal. Calcd for C17HI5NO: C, 81.90; H, 6.60; N, 5.61. Found: C, 81.83; H, 6.64; N, 5.65.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=1.[Al+3].[Cl-:15].[Cl-].[Cl-]>>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[Cl:15]
Reactant: [Cl-]
Reactant: Cc1ccc(C)cc1
Agent: CS(=O)(=O)Cl
Agent: [Al+3]
Product: Cc1ccc(C)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A mixture of 2.3 g (0.02 mole) of methanesulfonyl chloride, 20 ml (0.16 mole) of p-xylene, and 3.1 g (0.023 mole) of AlCl3 was stirred for one hour at 25° C. The product was worked up as described above in Example 1. 2,5-dimethylchlorobenzene was obtained in a 70% yield. NMR and VPC analysis of the crude product showed the presence of less than 1% of 2,5-dimethylphenyl methyl sulfone.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].C1(C)C=CC=CC=1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]#[CH:27])=[CH:22][CH:21]=1)([O-:19])=[O:18]>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.C(N(CC)CC)C>[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[C:2]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[NH:8][N:9]=2)=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: C#Cc1ccc([N+](=O)[O-])cc1
Reactant: NNc1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Cc2n[nH]c3ccccc23)cc1
Yield: 19.3 %

Procedure:
Into a dry reaction vessel, 10.3 g (44 mmol) (2-iodophenyl)hydrazine, 100 mL toluene, 50 mL triethylamine, 8.41 g (57.2 mmol) p-nitro phenylacetylene, 500 mg (Ph3P)2PdCl2, 250 mg cuprous iodide were respectively added, and reacted at 110° C. under protection of nitrogen for 4.5 h. It was cooled, rotate evaporated to dryness to remove the solvent, chromatographed on a column to obtain a red liquid 2.15 g (8.50 mmol), at a yield of 19.3%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].C1C(=O)N([Br:20])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>ClC1C=CC=CC=1>[Br:20][CH2:12][C:4]1[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COc1cccc(C(=O)O)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: COc1cccc(C(=O)O)c1CBr

Procedure:
for the synthesis of the title compound, 6.64 g (0.040 mol) of 3-methoxy-2-methylbenzoic acid, 7.1 g (0.040 mol) of NBS and 0.25 g of AIBN in 150 ml of chlorobenzene are reacted by method H (variant 1).
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.Cl.[F:13][C:14]([F:30])([F:29])[O:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][O:24][CH2:25][C:26]([NH2:28])=[NH:27])[CH:19]=[CH:20][CH:21]=1>>[F:11][C:4]1[CH:5]=[CH:6][C:7]2[C:8](=[O:10])[NH:28][C:26]([CH2:25][O:24][CH2:23][CH2:22][C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([O:15][C:14]([F:13])([F:29])[F:30])[CH:17]=3)=[N:27][C:2]=2[N:3]=1
Reactant: N=C(N)COCCc1cccc(OC(F)(F)F)c1
Reactant: O=C(O)c1ccc(F)nc1F
Agent: Cl
Product: O=c1[nH]c(COCCc2cccc(OC(F)(F)F)c2)nc2nc(F)ccc12

Procedure:
The title compound was prepared in analogy to example 85 from 2,6-difluoropyridine-3-carboxylic acid and 2-[2-(3-trifluoromethoxy-phenyl)-ethoxy]-acetamidine hydrochloride (example 81.2). Light brown solid. MS: m/e=384.1 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C@H:4]([CH2:38][OH:39])[NH:5][C:6](=[O:37])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:36])[C@H:13]([CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1)[NH:14][C:15](=[O:29])[C@H:16]([C@H:25]([CH2:27][CH3:28])[CH3:26])[NH:17]C(OC(C)(C)C)=O.[ClH:41]>O1CCOCC1>[ClH:41].[CH3:1][O:2][C:3](=[O:40])[C@H:4]([CH2:38][OH:39])[NH:5][C:6](=[O:37])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:36])[C@H:13]([CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1)[NH:14][C:15](=[O:29])[C@H:16]([C@H:25]([CH2:27][CH3:28])[CH3:26])[NH2:17]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)OC
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@H](C)[C@H](N)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)OC

Procedure:
8.5 g of t-butoxycarbonylisoleucylhistidylprolylserine methyl ester is dissolved in 51 ml of dioxane. To this solution is added 25.5 ml of 6 N hydrochloric acid in dioxane. The reaction is allowed to stand for ten minutes and the solvent is removed under vacuum to afford isoleucylhistidylprolylserine methyl ester hydrochloride.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.C(=O)([O-])[O-].[Na+].[Na+].[CH2:11]([N:13]1[C:17](=[O:18])[NH:16][N:15]=[N:14]1)[CH3:12]>CN(C)C=O.O>[Br:1][CH2:2][CH2:3][N:16]1[C:17](=[O:18])[N:13]([CH2:11][CH3:12])[N:14]=[N:15]1
Reactant: BrCCBr
Reactant: CCn1nn[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nnn(CCBr)c1=O
Reaction time: 8 h
Yield: 22 %

Procedure:
To a stirred solution of 109 parts of 1,2-dibromoethane and 21.2 parts of sodium carbonate in 5 parts of water and 18 parts of N,N-dimethylformamide were added dropwise a solution of 22.5 parts of 1-ethyl-1,4-dihydro-5H-tetrazol-5-one in 5 parts of water and 27 parts of N,N-dimethylformamide at about 40° C. Upon completion, stirring was continued overnight at 40° C. The organic phase was separated, dried and distilled, yielding 9.8 parts (22%) of 1-(2-bromoethyl)-4-ethyl-1,4-dihydro-5H-tetrazol-5-one; bp. 110° C. at 0.1 mm pressure (interm. 47).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([OH:23])=[C:18]([Cl:24])[CH:17]=1)(=[O:14])=[O:13].[H-].[Na+].Cl[C:28]1[S:29][C:30]2[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:31]=2[N:32]=1>CN(C=O)C.CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][C:28]2[S:29][C:30]3[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:31]=3[N:32]=2)=[C:18]([Cl:24])[CH:17]=1)(=[O:13])=[O:14]
Reactant: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Reactant: O=S(=O)(Nc1cc(Cl)c(O)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2nc(Oc3c(Cl)cc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4Cl)cc3Cl)sc2c1
Reaction time: 0.17 h
Yield: 73.5 %

Procedure:
To a solution of 2-chloro-N-(3,5-dichloro-4-hydroxy-phenyl)-4-trifluoromethyl-benzenesulfonamide (421, 1.52 g, 3.41 mmol) in 10 mL of DMF, was added NaH (Aldrich, 288 mg, 60%, 7.2 mmol). The mixture was stirred for 10 min, then 2-chloro-6-nitrobenzothiazole (411, 765 mg, 3.56 mmol) was added. The reaction mixture was stirred until no 421 remained by TLC. The mixture was diluted with EtOAc and 2N HCl, extracted 3× with EtOAc (100 mL). The organic layers were washed twice with a brine solution (100 mL), dried over Na2SO4 and concentrated. The residue was purified by chromatography (15%-20% EtOAc/hexanes) to give 1.5 g (74%) of product. 1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 9.08 (d, J=2.4 Hz, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.26 (dd, J=9.0, 2.4 Hz, 1H), 8.22 (s, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.87 (d, J=9.0 Hz, 1H), 7.33 (s, 2H). MS (EI): m/z 596 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([O:17]C)=O)=[C:13]([CH2:19]Br)[NH:12][C:11]3[CH2:21][O:22][CH2:23][C:24](=[O:25])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:26].CO>>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[C:15](=[O:17])[NH:26][CH2:19][C:13]=3[NH:12][C:11]3[CH2:21][O:22][CH2:23][C:24](=[O:25])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N
Reactant: COC(=O)C1=C(CBr)NC2=C(C(=O)COC2)C1c1ccc(F)c(Br)c1
Solvent: CO
Product: O=C1COCC2=C1C(c1ccc(F)c(Br)c1)C1=C(CNC1=O)N2
Temperature: 25 °C
Reaction time: 60 h

Procedure:
The product from Example 25B (0.22 g, 0.46 mmol) was treated with 1:1 ammonia/methanol mixture (60 mL) in a metal Parr stirred reactor for 2.5 days at ambient temperature. The solvent was allowed to evaporate and the residue was purified by chromatography on silica gel (5% and then 10% methanol in methylene chloride) to provide the title compound (0.026 g) as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:10]([O:14][C:15](=[O:22])[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])([CH3:13])([CH3:12])[CH3:11].[BH4-].[Na+]>CO>[C:10]([O:14][C:15](=[O:22])[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:8][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: Cc1cccnc1C=O
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccnc1CNCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87 %

Procedure:
Using General Procedure B, 3-methyl-pyridine-2-carbaldehyde (2.87 g, 23.7 mmol) in dry MeOH (10 mL) was added to a solution (4-amino-butyl)-carbamic acid tert-butyl ester (4.47 g, 23.7 mmol) (Krapcho, A. et al. Synth. Commun. 1990, 20, 2559-2564) in dry MeOH (50 mL) and warmed to 50° C. under N2 for 17 h. The mixture was cooled to ambient temperature and NaBH4 (1.35 g, 35.7 mmol) was added, resulting in bubbling. The mixture was stirred for 90 min. under N2 when the bubbling subsided. A solution of saturated NaHCO3 (50 mL) and CH2Cl2 (150 mL) were added to the MeOH solution and the layers were separated. The aqueous layer was extracted with CH2Cl2 (3×100 mL), dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography on silica gel (130 g) with CH2Cl2/MeOH (96:4) to CH2Cl2/MeOH/NH4OH (88:8:4) afforded the title compound (6.05 g, 87%) as an orange oil which solidified on standing. 1H NMR (CDCl3) δ 1.35-1.50 (m, 4H), 1.43 (s, 9H), 2.05 (bs, 1H), 2.30 (s, 3H), 2.72 (t, 2H, J=6.5 Hz), 3.00-3.20 (m, 2H), 3.86 (s, 2H), 4.76 (bs, 1H), 7.07 (dd, 1H, 7.5, 4.5 Hz), 7.42 (d, 1H, J=7.5 Hz), 8.38 (d, 1H, J=4.5 Hz); 13C NMR (CDCl3) δ 18.06, 27.45, 27.89, 28.43, 40.48, 49.54, 52.18, 78.89, 121.78, 130.84, 137.52, 146.41, 156.03, 157.25; ES-MS m/z 194 (M+H). Anal Calcd. For C16H27N3O2.0.2(H2O): C, 64.70; H, 9.30; N, 14.15. Found: C, 65.07; H, 9.35; N, 14.29.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].Cl.Cl.Cl[CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:22]1([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][CH2:13][S:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH2:2][OH:1])[CH2:21][CH2:20]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OCc1ccccc1S
Reactant: ClCCCN1CCN(c2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCc1ccccc1SCCCN1CCN(c2ccccc2)CC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 89.7 %

Procedure:
A mixture of 1.56 g of 2-(hydroxymethyl)thiophenol, 3.77 g of 1-(3-chloropropyl)-4-phenylpiperazine dihydrochloride, 5.02 g of potassium carbonate and 40 ml of dimethylformamide is stirred at 50° C. for 6 hours. Insoluble materials are filtered off, and the filtrate is concentrated under reduced pressure to remove solvent. Water is added to the residue, and the aqueous mixture is extracted with ethyl acetate. The extract is washed with water, dried and concentrated under reduced pressure to remove solvent. The residue is digested with n-hexane and collected by filtration. 3.42 g of 2-[3-(4-phenylpiperazin-1-yl)propylthio]benzylalcohol are obtained. Yield: 91%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)/[S:6][C:5]1=[O:32].[C:33]([NH:36][C:37]1[S:38][C:39]([S:43](Cl)(=[O:45])=[O:44])=[C:40]([CH3:42])[N:41]=1)(=[O:35])[CH3:34]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:16]2[C:17]3[C:13](=[CH:12][C:11](/[CH:10]=[C:7]4/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][S:43]([C:39]5[S:38][C:37]([NH:36][C:33](=[O:35])[CH3:34])=[N:41][C:40]=5[CH3:42])(=[O:44])=[O:45])[C:5](=[O:32])[S:6]/4)=[CH:19][CH:18]=3)[CH:14]=[N:15]2)=[C:22]([C:28]([F:30])([F:29])[F:31])[CH:23]=1
Reactant: NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)NCCN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)s1

Procedure:
N-[5-({2-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}sulfamoyl)-4-methyl-1,3-thiazol-2-yl]acetamide was prepared from 3-(2-aminoethyl)-(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (from Example 49) and 2-acetamido-4-methyl-5-thiazolesulfonyl chloride following General Procedure U.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[S:23][C:13]=2[N:14]=1
Reactant: NCCc1ccccc1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: FC(F)(F)c1cc2c(NCCc3ccccc3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyrazin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-phenethylamino-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:8]=1[C:9]([O:11]C)=O)=[C:2]=[S:3].[CH3:19][C:20]1[N:24]([CH2:25][CH2:26][CH2:27][NH2:28])[CH:23]=[N:22][CH:21]=1>>[CH3:19][C:20]1[N:24]([CH2:25][CH2:26][CH2:27][N:28]2[C:9](=[O:11])[C:8]3[CH:7]=[C:6]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[S:5][C:4]=3[NH:1][C:2]2=[S:3])[CH:23]=[N:22][CH:21]=1
Reactant: COC(=O)c1cc(-c2ccccc2)sc1N=C=S
Reactant: Cc1cncn1CCCN
Product: Cc1cncn1CCCn1c(=S)[nH]c2sc(-c3ccccc3)cc2c1=O

Procedure:
The compound was synthesized starting from methyl 2-isothiocyanato-5-phenylthiophene-3-carboxylate (0.10 g, 0.36 mmol) and 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (5) (0.051 g, 0.36 mmol) as described above.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:37]C)=[C:6]([C:8]([CH3:36])([CH3:35])[CH2:9][C:10]([C:31]([F:34])([F:33])[F:32])([OH:30])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[N:18]3)[CH:7]=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:37])=[C:6]([C:8]([CH3:35])([CH3:36])[CH2:9][C:10]([C:31]([F:32])([F:34])[F:33])([OH:30])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[N:18]3)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2nc(CN3CCOCC3)ccc12)C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(CC(O)(CNc1cccc2nc(CN3CCOCC3)ccc12)C(F)(F)F)c1cc(F)ccc1O

Procedure:
Analogously to Example 38, 80 mg (0.15 mmol) of 4-(5-fluoro-2-methoxyphenyl)-1-(2-(morpholin-4-ylmethyl)quinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol is mixed with 3.0 ml (3.0 mmol) of a 1 M boron tribromide solution in dichloromethane. After working-up and purification on silica gel with hexane-ethyl acetate (0-100%) as well as ethyl acetate-methanol (0-20%), 53 mg (68% of theory) of the product is obtained.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:6]2[S:14][CH:13]=[C:12]([CH2:15][CH3:16])[C:7]=2[N:8]=[C:9](Cl)[N:10]=1)[CH:2]=[CH2:3].[CH2:17]([NH2:20])[CH:18]=[CH2:19].C(=O)([O-])O.[Na+]>>[CH2:17]([NH:20][C:9]1[N:10]=[C:5]([NH:4][CH2:1][CH:2]=[CH2:3])[C:6]2[S:14][CH:13]=[C:12]([CH2:15][CH3:16])[C:7]=2[N:8]=1)[CH:18]=[CH2:19]
Reactant: C=CCNc1nc(Cl)nc2c(CC)csc12
Reactant: C=CCN
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCC=C)c2scc(CC)c2n1
Yield: 86.3 %

Procedure:
304 mg (1.2 mmol) of 4-allylamino-2-chloro-7-ethylthieno[3,2-d]pyrimidine and 1.10 g (19.2 mmol) of allylamine were heated in a sealed tube at 140° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 284 mg (yield: 86.3%) of the title compound.