Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[C:27](Cl)(=[O:29])[CH3:28].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:27](=[O:29])[CH3:28])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cccc(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To a solution of [4-(3-amino-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (30 mg, 0.079 mmol) and acetyl chloride (9.2 mg, 0.119 mmol) in tetrahydrofuran (3 mL) was added triethylamine (16 mg, 0.158 mmol) at 0° C. After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by flash column (gradient elution, 0-5% methanol in dichloromethane) to afford [4-(3-acetylamino-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (24 mg, 72%) as a white solid. MS cald. for C19H24N4O5S 420, obsd. (ESI+) [(M+H)+] 421.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([S:12]CC2C=CC(OC)=CC=2)[C:6]=1[CH3:22])(=O)C.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>>[CH3:22][C:6]1[C:7]([SH:12])=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=1[OH:4]
Reactant: COc1ccc(CSc2cc(C)cc(OC(C)=O)c2C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1cc(O)c(C)c(S)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
To a mixture of 3-((4-methoxybenzyl)sulfanyl)-2,5-dimethylphenyl acetate (509.1 mg) and anisole (1.5 mL) was added TFA (5.0 mL) at 0° C. The mixture was stirred at 0° C. for 1 h and warmed to room temperature. Then the mixture was stirred at room temperature for 4 h. The mixture was concentrated. The residue was neutralized with 1N NaOH, and the mixture was extracted with EtOAc. The aqueous layer was acidified with 1N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (128 mg).
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH2:5][CH2:4]1)#[N:2].[Cl:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=1[O:26][CH:27]([CH3:29])[CH3:28])/[C:19](=[N:21]/O)/[NH2:20].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:15][C:16]1[CH:17]=[C:18]([C:19]2[N:21]=[C:10]([C:9]3[CH:8]=[CH:7][C:6]([C:3]4([C:1]#[N:2])[CH2:4][CH2:5]4)=[CH:14][CH:13]=3)[O:12][N:20]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)Oc1ccc(/C(N)=N/O)cc1Cl
Reactant: N#CC1(c2ccc(C(=O)O)cc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(C4(C#N)CC4)cc3)n2)cc1Cl
Temperature: 160 °C
Yield: 23.7 %

Procedure:
A 20 mL microwave vial was charged with 4-(1-cyanocyclopropyl)benzoic acid (720 mg, 3.85 mmol), (Z)-3-chloro-N′-hydroxy-4-isopropoxybenzimidamide (880 mg, 3.85 mmol), DCC (873 mg, 4.23 mmol), HOBT (648 mg, 4.23 mmol), ACN (10 ml), and DIEA (1.478 ml, 8.46 mmol). The vial was capped and heated to 160° C. via microwave irradiation for 25 minutes (max 300 W). Solvent was removed under reduced pressure and crude oil was purified by flash column chromatography (Analogix system, heptane/ethyl acetate, 0-45% ethyl acetate over 30 min; 80 g column, 60 mL/min flow rate). Fractions containing product were combined, rotovapped, and dried in a vacuum oven overnight to give 1-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)cyclopropanecarbonitrile (347 mg, 23.8%) as a yellow solid. LCMS (Table 1, Method c) Rt=3.19 min, m/z 380.43 (M+H)+; 1H NMR (400 MHz, DMSO)) δ ppm 8.22-8.12 (m, 2H), 8.05 (d, 1H), 7.99 (dd, 2.14 Hz, 1H), 7.62-7.55 (m, 2H), 7.38 (d, 1H), 4.82 (td, 1H), 1.90 (q, 2H), 1.67 (q, 2H), 1.38-1.33 (m, 6H).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.[F:29][C:30]1([F:57])[C:38]2[C:33](=[CH:34][CH:35]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:37]=2)[N:32]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[C:31]1=[O:56]>>[F:29][C:30]1([F:57])[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:2]3[N:7]4[CH:8]=[C:9]([CH2:11][CH2:12][C:13]5[CH:22]=[CH:21][C:20]6[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=6)[N:14]=5)[N:10]=[C:6]4[C:5]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:4][CH:3]=3)[CH:37]=2)[N:32]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:53])[CH3:54])[C:31]1=[O:56]
Reactant: CC1(C)OB(c2ccc3c(c2)C(F)(F)C(=O)N3COCC[Si](C)(C)C)OC1(C)C
Reactant: Brc1cnc(N2CCOCC2)c2nc(CCc3ccc4ccccc4n3)cn12
Product: C[Si](C)(C)CCOCN1C(=O)C(F)(F)c2cc(-c3cnc(N4CCOCC4)c4nc(CCc5ccc6ccccc6n5)cn34)ccc21

Procedure:
Compound 3a was subjected to Suzuki coupling conditions with 3,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2(trimethylsilyl)ethoxy)methyl)indolin-2-one to obtain compound 37b using the method described in the Example 21, Step D. Mass Spectrum (LCMS, ESI pos.) Calcd. For C35H38F2N6O3Si: 657.2 (M+H). Found 657.5.
Reaction SMILES: [Cl-].[Na+].[OH:3][C:4]1[C:11]([CH3:12])=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([CH3:13])[CH:5]=1.[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[OH:3][C:4]1[C:11]([CH3:12])=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([CH3:13])[C:5]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(C=O)c(C)cc1O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Product: Cc1cc(C=O)c(C)c([N+](=O)[O-])c1O
Reaction time: 0.5 h

Procedure:
To a −10° C. (ice and sodium chloride) solution of 4-hydroxy-2,5-dimethylbenzaldehyde (1.0 g, 6.65 mmol) in concentrated sulfuric acid (10 mL) was added dropwise 70% (concentrated) nitric acid (0.598 g, 6.65 mmol) in 2 mL concentrated sulfuric acid. The reaction stirred for approximately 30 minutes. The reaction was then poured onto crushed ice. The precipitate was collected and washed with water. The solid was then dried on a high vacuum pump to yield a white solid. Microanalysis (C9H9N1O4): calculated: C=55.39, H=4.65, N=7.18; found: C=55.60, H=4.65, N=7.02. MS: M+−1=194.1 Da.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]2[N:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:3]1=[O:17].[H-].[Na+].[CH2:20]([N:27]([CH3:31])[CH2:28][CH2:29]Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH2:20]([N:27]([CH3:31])[CH2:28][CH2:29][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3](=[O:17])[C:4]2[CH:16]=[CH:15][CH:14]=[N:13][C:5]1=2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN(CCCl)Cc1ccccc1
Reactant: CN1C(=O)c2cccnc2Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCN1c2ccccc2N(C)C(=O)c2cccnc21)Cc1ccccc1
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 75.2 %

Procedure:
18.1 gm (0.08 mol) of 6,11-dihydro-6-methyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one were dissolved in 180 ml of dimethylformamide at room temperature, 2.88 gm (0.096 mol) of 80% sodium hydride in mineral oil were added to the solution, and the mixture was stirred at 60° C. for 45 minutes. Then, 17.7 gm (0.096 mol) of 2-(N-benzyl-methylamino)-ethyl chloride were added dropwise, and the resulting mixture was stirred at 120° C. for 30 minutes. After evaporation in vacuo, the residue was dissolved in chloroform/dilute acetic acid, and the aqueous phase was separated and made alkaline with concentrated ammonia. The base, which precipitated as an oil, was taken up in chloroform, the solvent was distilled off in vacuo and the oily residue was distilled, yielding 22.4 gm (75% of theory) of 11-[2'-(N-benzyl-methylamino)-ethyl]-6,11-dihydro-6-methyl-5-H-pyrido [2,3-b][1,5]benzodiazepin-5-one, b.p. 212°-216° C. at 0.05 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.[NH2:12][C:13]1[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=1[CH3:20].C(Cl)CCl>C(Cl)Cl>[NH2:12][C:13]1[CH:18]=[C:17]([NH:19][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=2)[CH:16]=[CH:15][C:14]=1[CH3:20]
Reactant: Cc1ccc(N)cc1N
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1ccc(NC(=O)c2ccc(Cl)c(Cl)c2)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3,4-dichlorobenzoic acid (200 mg, 1.05 mmol), 2,4-diaminotoluene (513 mg, 4.20 mmol), and EDC (403 mg, 2.10 mmol) was added CH2Cl2 (40 mL). The mixture was stirred overnight at RT, concentrated, diluted with EtOAc and extracted with water. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography (n-Hexanes→50% EtOAc/n-Hexanes) yielding N-(3-amino-4-methyl-phenyl)-3,4-dichloro-benzamide. MS m/z=295, 297 [M]+ and [M+]+. Calc'd for C14H12Cl2N2O: 295.17.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([O:11]C)=[O:10])=[CH:7][CH:6]=[C:5]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=CC=2)[N:4]=1.[OH-].[Na+].[CH3:24]O>>[CH3:1][O:2][C:3]1[N:4]=[C:5]([S:13][C:14]2[CH:15]=[CH:20][C:19]([CH3:24])=[CH:18][CH:21]=2)[CH:6]=[CH:7][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1ccc(SCc2ccc(C)cc2)nc1OC
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: COc1nc(Sc2ccc(C)cc2)ccc1C(=O)O
Temperature: 25 °C

Procedure:
To a suspension of 9.25 g (31.96 mmol) of methyl 2-methoxy-6-(4-methyl benzylthio)pyridine-3-carboxylate in 80 mL of methanol was added 38.36 mL (38.36 mmol) of 1N-sodium hydroxide aqueous solution, and the mixture was refluxed for 1 hour. After the reaction mixture was cooled to the room temperature, the solvent was removed under reduced pressure and the residue was diluted with water. Then 2N-HCl was added to the solution and the resultant precipitate was collected to obtain 8.92 g (quantitative) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:14][C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27]C(=O)OC(C)(C)C)=[CH:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[ClH:35]>O1CCOCC1.CCOCC>[ClH:35].[NH2:27][C@H:22]1[C:23]2[C:19](=[C:18]([C:15]3[O:14][C:13]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:12])[CH3:11])=[C:3]([CH:4]=4)[C:1]#[N:2])=[N:17][CH:16]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:20][CH2:21]1
Reactant: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CC[C@H]4NC(=O)OC(C)(C)C)o2)cc1C#N
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CC[C@H]4N)o2)cc1C#N
Temperature: 60 °C
Yield: 78 %

Procedure:
To a stirring solution of (R)-tert-butyl 4-(2-(3-cyano-4-isopropoxyphenyl)oxazol-5-yl)-2,3-dihydro-1H-inden-1-ylcarbamate INT-42 (48 mg, 0.1 mmol) in 1,4-dioxane (1 mL) was added a 4N HCl solution in 1,4-dioxane (1 mL). The reaction mixture was heated at 55-65° C. for 48 h. The cooled reaction mixture was diluted with Et2O (10 mL). The resulting solid was collected and dried under high vacuum to yield 32 mg (78%) of (R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)oxazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 59 as a white solid. LCMS-ESI (m/z) calculated for C22H21N3O2: 359.4; found 343.1 [M−NH2]+, tR=2.40 min. 1H NMR (400 MHz, DMSO) δ 8.55 (br s, 2H), 8.43 (dd, J=6.5, 2.4 Hz, 1H), 8.32 (ddd, J=6.7, 6.1, 2.9 Hz, 1H), 8.00 (t, J=13.5 Hz, 1H), 7.72 (s, 1H), 7.66 (d, J=7.5 Hz, 1H), 7.49 (dd, J=8.5, 6.3 Hz, 2H), 4.93 (dt, J=12.1, 6.0 Hz, 1H), 4.81 (s, 1H), 3.43-3.25 (m, 1H), 3.23-3.04 (m, 1H), 2.67-2.55 (m, 1H), 2.11 (ddd, J=14.2, 9.0, 5.9 Hz, 1H), 1.36 (dd, J=13.8, 7.0 Hz, 6H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][NH2:24])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2].[O-:26][C:27]#[N:28].[K+]>C(O)(=O)C.O>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][NH:24][C:27]([NH2:28])=[O:26])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(CN)ccc2-3)n(C(C)C)n1
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(CNC(N)=O)ccc2-3)n(C(C)C)n1

Procedure:
Following the procedures for 542, C-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-methylamine 532 was reacted with potassium cyanate in acetic acid and water to give 524. MS(ESI+) 399.1. 1H NMR (400 MHz, DMSO) δ 8.27 (d, J=8.2 Hz, 1H), 7.07 (dd, J=8.2, 1.3 Hz, 1H), 6.95 (br, 1H), 6.44 (t, J=6.1 Hz, 1H), 5.83-5.68 (m, 1H), 5.54 (s, 2H), 4.35 (t, J=5.0 Hz, 2H), 4.18 (d, J=6.1 Hz, 2H), 3.42 (t, J=5.0 Hz, 2H), 2.32 (s, 3H), 1.52 (d, J=6.6 Hz, 6H).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li][CH2:15][CH2:16]CC.ICC>>[CH2:15]([CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH3:16]
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Solvent: CCI
Product: CCC1c2ccccc2-c2ccccc21
Yield: 97.5 %

Procedure:
Fluorene (5.0 g, 30.1 mmol), n-BuLi (16 ml, 40 mmol, 2.5 M in hexane), RX=iodoethane (7.04 g, 45.1 mmol). 41 was isolated as yellow oil (5.7 g, 97%). Analytical data were identical to those in the literature (K. D. Bartle, P. M. G. Bavin, D. W. Jones, R. L'Amie, Tetrahedron 1970, 26, 911).
Reaction SMILES: [CH2:1]([O:6][CH:7]([CH3:11])[CH2:8][CH2:9][OH:10])[CH2:2][CH2:3][CH2:4][CH3:5].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.[OH-].[Na+].Cl>C1C=CC=CC=1.N1C=CC=CC=1>[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([O:10][CH2:9][CH2:8][CH:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH3:11])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCOC(C)CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCCOC(C)CCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 35 %

Procedure:
5.0 g of 3-pentyloxybutanol, 3.98 g of p-toluenesulfonyl chloride, 1.65 g of pyridine, and 8 ml of benzene were charged in a 30 ml-reaction vessel and, under N2 stream, stirred for 23 hours at room temperature. Then, into the reaction mixture, 6.3 ml of hot conc. NaOH aqueous solution was added and stirred for 5 min. The mixture was poured in 280 ml of cold 10%-hydrochloric acid solution and extracted with hexane. The hexane layer was washed successively with cold 5%-hydrochloric acid solution, saturated NaCO3 aqueous solution and water and dried with anhydrous MgSO4, followed by distilling-off of the solvent to 6.0 g of a crude product, which was purified by alumina column chromatography (hexane) to obtain 2.3 g of 3-pentyloxybutyl p-toluenesulfonate.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([CH2:30][CH3:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[N:24]1[CH:23]=[CH:22][C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[CH:29]=[C:28]([CH2:30][CH3:31])[S:27][C:17]=3[N:18]=2)=[CH:26][CH:25]=1
Reactant: CCc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCCc1ccc2c(c1)OCCO2
Product: CCc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH3:14])[CH:6]([NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:7])[CH3:2].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH3:14])[CH:6]([N:8]([C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)C(C)NC1CCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(C)C(C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
A solution of 1.07 g (0.005 mole) of (rac)-3-cyclopentylamino-2-methyl-butanoic acid ethyl ester in 30 mL of water was added dropwise to a solution of 0.97 g (0.005 mole) of 2,4-dichloro-5-nitro-pyrimidine in 30 mL of ethyl ether. At 0 degrees, 1.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-80:20) gave 1.4 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-2-methyl-butanoic acid ethyl ester (IV-41).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:19])[C@@H:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)[CH2:6][OH:7].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH2:20]([O:7][CH2:6][C@H:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=1)[CH:4]([CH3:19])[CH3:3])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)[C@H](CO)Nc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[C@H](COCc1ccccc1)Nc1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Sodium hydride (10 mg) and (2R)-3-methyl-2-{[4-(trifluoromethyl)phenyl]amino}butan-1-ol (30 mg), which is the compound obtained in Step 1 of Example 2, were dissolved in dimethylformamide (1 mL), and then benzyl bromide (0.052 mL) was added. The mixture was stirred at 50° C. for 3 hrs, and the title compound (37.5 mg) was obtained by purification step A.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:12][CH2:11]1)[CH3:8])([CH3:4])([CH3:3])C.Cl.ClC(OC1C=[CH:32][C:31]([Cl:34])=[CH:30]C=1)=O>CO.O>[Cl:34][C:31]1[CH:32]=[CH:3][C:1]([O:5][C:6](=[O:22])[N:7]([CH2:9][C@H:10]2[CH2:11][CH2:12][C@H:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:14][CH2:15]2)[CH3:8])=[CH:4][CH:30]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CN(C[C@H]1CC[C@H](OCCCCO)CC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Solvent: CO
Product: CN(C[C@H]1CC[C@H](OCCCCO)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the sequence described in examples 1.5 and 1.7, trans-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester was treated with hydrogen chloride solution in methanol/water followed by acylation with 4-chlorophenyl chloroformate giving trans-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 370 (MH+, 1Cl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH:3]=1>[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(/C=C/c2cccc(F)c2)cc1
Agent: [Pd]
Product: Nc1ccc(CCc2cccc(F)c2)cc1

Procedure:
In an analogous manner to that described in Example 18b), the hydrogenation of (E)-1-fluoro-3-[2-(4-nitrophenyl)ethenyl]-benzene [Example 18a)] using palladium on carbon (10%) during 5 hours and simultaneous reduction of the double bond yields quantitatively 4-[2-(3-fluoro-phenyl)-ethyl]-phenylamine as a yellow solid. MS: m/e=215 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[F:13].O=S(Cl)Cl.[CH3:18][CH2:19]O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([O:11][CH2:18][CH3:19])=[O:10])=[CH:4][C:3]=1[F:13]
Reactant: CC(C(=O)O)c1ccc(N)c(F)c1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C)c1ccc(N)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of 2-(4-Amino-3-fluorophenyl)propionic acid (1 g, 5.459 mmol) in EtOH was added SOCl2 (0.6 ml, 8.189 mmol) at 0° C. The mixture was stirred for 2 hours at room temperature and then SOCl2 was removed under reduced pressure. The residue was diluted with EtOAc and washed with a saturated NaHCO3 solution. The resulting mixture was dried over MgSO4 and concentrated. The residue was purified by column chromatography to afford ethyl 2-(4-amino-3-fluorophenyl)propanoate (1 g, 87%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]([CH3:39])([CH3:38])[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=O)[CH2:31][CH2:30]1.[NH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([N:50]2[CH2:59][CH2:58][C:57]3[N:56]=[C:55]([CH3:60])[N:54]([CH2:61][C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)[C:53]=3[C:52]3[CH:68]=[CH:69][CH:70]=[CH:71][C:51]2=3)=[O:49])=[CH:44][C:43]=1[CH3:72].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:61]([N:54]1[C:53]2[C:52]3[CH:68]=[CH:69][CH:70]=[CH:71][C:51]=3[N:50]([C:48]([C:45]3[CH:46]=[CH:47][C:42]([CH2:41][NH:40][C:35]([CH:32]4[CH2:31][CH2:30][N:29]([CH2:28][CH2:27][C:26]([CH3:25])([CH3:39])[CH3:38])[CH2:34][CH2:33]4)=[O:37])=[C:43]([CH3:72])[CH:44]=3)=[O:49])[CH2:59][CH2:58][C:57]=2[N:56]=[C:55]1[CH3:60])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: CC(C)(C)CCN1CCC(C(=O)O)CC1
Reactant: Cc1cc(C(=O)N2CCc3nc(C)n(Cc4ccccc4)c3-c3ccccc32)ccc1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2CCc3nc(C)n(Cc4ccccc4)c3-c3ccccc32)ccc1CNC(=O)C1CCN(CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
HBTU (175 mg, 0.46 mmol) was added to a solution of 1-(3,3-dimethyl-butyl)-piperidine-4-carboxylic acid (86 mg, 0.34 mmol) in DMF (5 ml). The mixture was stirred at room temperature for 2 h then (4-aminomethyl-3-methyl-phenyl)-(1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone from Example E121.2 (100 mg, 0.23 mmol) and DIEA (0.12 ml, 0.69 mmol) were added. The mixture was stirred at room temperature for 18 h then solvents were removed in vacuo and azeotroped with toluene. The residue was purified by flash chromatography on silica gel through an isolute (eluant; 5% methanol:95% dichloromethane then 10% methanol:90% dichloromethane) to give a yellow foam identified as the title compound (114 mg, 79%).
Reaction SMILES: [CH2:1]([CH:3]1[C:9](=[O:10])[N:8]2[CH:4]1[S:5][C:6](=[S:24])[CH:7]2[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])[CH3:2].[CH2:25](N(C(C)C)C(C)C)[CH3:26].BrCC>O1CCOCC1>[CH2:1]([CH:3]1[C:9](=[O:10])[N:8]2[CH:4]1[S:5][C:6]([S:24][CH2:25][CH3:26])=[C:7]2[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])[CH3:2]
Reactant: CCC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=S)SC12
Reactant: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCBr
Product: CCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(CC)C2S1

Procedure:
To a solution of 0.5 g of 4-nitrobenzyl 6-ethyl-7-oxo-3-thioxo-4-thia-1-azabicyclo[3,2,0]heptane 2-carboxylate in 2 ml of dioxane was added, in one batch, 0.57 ml of N-ethyldiisopropylamine, then 0.10 ml of bromoethane. When the reaction was complete, the solution was evaporated in vacuo and chromatographed on silica gel, eluting with ethyl acetate/hexane mixtures to give the title product. (Yield 0.300 g)