Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20](Br)[S:21][C:17]=2[C:16]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=O)C(C)(C)C.[Br:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.CO.[OH-].[Na+]>O1CCOCC1>[Br:33][C:34]1[CH:35]=[C:36]([C:20]2[S:21][C:17]3[C:16]([C:26]4[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=4)=[C:15]([C@H:9]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:8][OH:7])[C:24]([CH3:25])=[CH:23][C:18]=3[N:19]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Cc1cc2nc(Br)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc2nc(-c3cccc(Br)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 90 °C
Yield: 35.9 %

Procedure:
To a solution of (S)-2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (310 mg, 0.577 mmol) in dioxane (5 mL), was added 3-bromophenylboronic acid (173 mg, 0.865 mmol), Ph(PPh3)4 (33 mg, 0.029 mmol) 2N K2CO3 (850 μL) in sealed tube. The reaction mixture was heated at 90° C. for 3hs. Then the reaction was cooled down and to the mixture was added MeOH (5 mL), 2N NaOH (1.5 mL) and heated at 45° C. After the reaction was finished, the reaction was washed by water, extracted by EtOAc. The organic phase was dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-50% EtOAc in hexanes to give the product (110 mg, 36%). LCMS-ESI+: calc'd for C26H25BrClNO2S: 530.0 (M+H+); Found: 530.2 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=5)[CH:17]=4)[N:12]([S:27]([C:30]4[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[N:37]1([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:20]=[CH:21][C:22]([CH2:23][N:40]6[CH2:41][CH2:42][N:37]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38][CH2:39]6)=[CH:25][CH:26]=5)[CH:17]=4)[N:12]([S:27]([C:30]4[CH:31]=[CH:32][C:33]([CH3:34])=[CH:35][CH:36]=4)(=[O:29])=[O:28])[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(-c4ccc(C=O)cc4)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(-c4ccc(CN5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Reaction time: 1 h
Yield: 92.7 %

Procedure:
4-(3-(1H-indol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzaldehyde (2.1 g) was suspended in anhydrous dichloromethane (15 mL), treated with tert-butyl piperazine-1-carboxylate (1.6 g), and stirred for one hour. To the resulting mixture was added sodium triacetoxy borohydride 1.36 g in three portions. The reaction was stirred for 3 hours, diluted with water and extracted with dichloromethane. The organic layers were washed with brine, dried over MgSO4, and purified by MPLC silica gel chromatography (30-60% EtOAc in hexane) to yield 2.62 g of the title compound (M+H 662).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1([CH:20]=[CH:19][CH:18]=[CH:17][CH2:16]1)[CH2:14][OH:15].O>N1C=CC=CC=1>[C:1]([O:15][CH2:14][C:13]1([C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH2:20]1)(=[O:3])[CH3:2]
Reactant: OCC1(c2cccs2)C=CC=CC1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCC1(c2cccs2)C=CC=CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (5 ml) was added to a solution of 1-(2-thienyl)benzyl alcohol in pyridine. The resultant solution was stirred at 70° C. for 3h. Water (50 ml) was added and the reaction mixture was stirred at room temperature for 2h. This was extracted with ethyl acetate (2×50 ml) and the combined organic layers dried over anhydrous MgSO4. Removal of the solvent gave crude product, which was purified by passing through silica gel using 3:1 hexane/ethyl acetate mixture to give 1-(2-thienyl)benzyl acetate.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:21]1([C:26]2[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH3:20][C:13]1([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([N:21]5[CH2:22][CH2:23][CH2:24][CH2:25]5)[CH:27]=4)[N:3]=3)[NH:8][CH:9]=2)=[O:12])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: OB(O)c1cccc(N2CCCC2)c1
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCCC1
Product: CC1(C(=O)c2c[nH]c3ncc(-c4cccc(N5CCCC5)c4)nc23)CCCCCC1

Procedure:
(1-Methyl-cycloheptyl)-[2-(3-pyrrolidin-1-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cycloheptyl)-methanone and 3-(1-pyrrolidinyl)phenylboronic acid following general procedures as described in these Examples. MP 192-193° C., M+H=403.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]#[N:11])[C:4]=2[CH:3]=[CH:2]1.C1C(=O)N([Cl:19])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Cl:19][C:3]1[C:4]2[C:5]([C:10]#[N:11])=[CH:6][CH:7]=[CH:8][C:9]=2[NH:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1cccc2[nH]ccc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cccc2[nH]cc(Cl)c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.8 %

Procedure:
To 1H-indole-4-carbonitrile (514.0 mg, 3.61 mmol) in anhydrous DMF (2.8 mL) at 0° C. was added dropwise NCS (517.3 mg, 3.80 mmol) dissolved in DMF (8.5 mL). The reaction mixture was slowly warmed to RT. After stirring for 20 h, the mixture was diluted with EtOAc. The organic layer was washed with satd. aq. NaHCO3 solution, water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by SiO2 chromatography eluting with heptane:EtOAc to afford 3-chloro-1H-indole-4-carbonitrile as a white solid (630 mg, 98.7%). MS (ESI) m/z: 177.1 [M+1]+. 1H NMR (400 MHz, DMSO) 11.99 (br s, 1H), 7.80 (d, J=2.8 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.61 (d, J=7.2 Hz, 1H), 7.37-7.26 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:10][N:11]([CH3:15])[C:12](Cl)=[O:13].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:12]([N:11]([CH3:15])[CH3:10])=[O:13])=[N:6][CH:7]=1
Reactant: NNc1ccc(F)cn1
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)NNc1ccc(F)cn1
Yield: 77 %

Procedure:
A solution of (5-fluoro-pyridin-2-yl)-hydrazine (500 mg, 3.93 mmol), dimethylcarbamyl chloride (505 mg, 4.72 mmol) and DIPEA (1.01 g, 7.86 mmol) in DCM (20 mL) was stirred at reflux for 16 h. The reaction mixture was applied to an SCX-2 cartridge (25 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo and then trituration with diethyl ether gave the title compound (600 mg, 77%). 1H NMR (400 MHz, CDCl3): 2.99 (6H, s), 6.46 (2H, m), 6.75 (1H, dd, J 9.1, 3.5), 7.22-7.32 (1H, m), 8.03 (1H, d, J 2.7).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:21]([O:24][C:25](Cl)=[O:26])[CH2:22][CH3:23]>ClCCl>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:25]([O:24][CH2:21][CH2:22][CH3:23])=[O:26])[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of 5.0 g tert-butyl 1-piperazinecarboxylate in 64 ml dichloromethane were added 8.2 ml triethylamine. The solution was cooled to 0° C. and 3.3 ml propylchloroformate were added dropwise at this temperature. After stirring for 12 h the reaction mixture was diluted with dichloromethane and washed with 0.1 M HCl and saturated NaHCO3. The crude product obtained after evaporation of the solvent was directly used in the next reaction step.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:19]=[C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:17][C:16]=3[C:24]([NH2:26])=[O:25])=[CH:11][CH:10]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.[CH2:27]([S:31](Cl)(=[O:33])=[O:32])[CH2:28][CH2:29][CH3:30]>C1COCC1>[CH2:27]([S:31]([NH:26][C:24]([C:16]1[S:17][C:18]([CH2:20][CH:21]([CH3:22])[CH3:23])=[CH:19][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)=[CH:10][CH:11]=1)=[O:25])(=[O:33])=[O:32])[CH2:28][CH2:29][CH3:30]
Reactant: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(C(N)=O)s1
Reactant: CCCCS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCS(=O)(=O)NC(=O)c1sc(CC(C)C)cc1-c1ccc(Cn2ccnc2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
NaH (55%, 12 mg, 0.28 mmol) was added to a solution of 3-(4-imindazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-carboxamide (46 mg, 0.136 mmol, see step (e) above) in THF (1 mL). The mixture was stirred at 50° C. for 0.5 hours. Butanesulfonyl chloride (29 μL, 0.223 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated and purified using silica gel chromatography (CH2Cl2:MeOH, 9:1) to give 31 mg of the title compound as a white powder (yield: 50%).
Reaction SMILES: [C:1](C1C=C(C(=O)CSCC)C=C(C(C)(C)C)C=1O)(C)(C)C.[C:22]([C:26]1[CH:27]=[C:28]([C:37](=[O:43])[CH2:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:29]=[C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:31]=1[OH:32])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:27]=[C:28]([C:37](=[O:43])[CH2:38][S:39]([CH2:42][CH3:1])(=[O:41])=[O:40])[CH:29]=[C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:31]=1[OH:32])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1cc(C(=O)CS(C)(=O)=O)cc(C(C)(C)C)c1O
Reactant: CCSCC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Product: CCS(=O)(=O)CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
This material is prepared from impure 1-(3,5-di-t-butyl-4-hydroxyphenyl)-2-(ethylsulfanyl)ethanone (following the method of 1-(3,5,-di-t-butyl-4-hydroxyphenyl)-2-(methylsulfonyl)ethanone). Crystallization (of the crude product) from EtOAc/hexanes followed by a second crystallization then a flash chromatography with EtOAc followed by a third crystallization with refrigeration gives white crystals, mp=119.5°-120.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19](=[O:20])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH:14]=[O:15])=[CH:4][CH:3]=2)=[CH:25][CH:24]=1)[CH3:17]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Product: CCOC(=O)CCc1ccc(-c2ccc(-c3onc(C)c3C=O)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and [4-(2-ethoxycarbonylethyl)phenyl]boronic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:7][N:6]=1.Cl[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[C:29]([NH2:36])[N:28]=1>CO.C(Cl)Cl>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:9]1[C:8]([CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:7][N:6]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[C:29]([NH2:36])[N:28]=2)[N:10]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: NCCNc1ncc(CN2CCOCC2)c(-c2ccc(Cl)cc2Cl)n1
Solvent: ClCCl
Solvent: CO
Product: Nc1nc(NCCNc2ncc(CN3CCOCC3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Yield: 60 %

Procedure:
Using the conditions described in Example 139, (2-aminoethyl)[4-(2,4-dichlorophenyl)-5-(morpholin-4-ylmethyl)pyrimidin-2-yl]amine and 10.6 mg (0.061 mmol) of 2-chloro-5-nitro-6-aminopyridine afforded 191 mg (60%) of [4-(2,4-dichlorophenyl)-5-(morpholin-4-ylmethyl)pyrimidin-2-yl]{2-[(5-nitro-6-amino(2-pyridyl))amino]ethyl}amine as a yellow solid following chromatography (silica gel, 5% methanol/methylene chloride).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]=[N+:14]=[N-:15])[C@H:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[C:21]([F:28])=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]=[N+:14]=[N-:15])[C@H:9]1[C:16](=[O:18])[NH:24][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([Cl:19])[C:21]=1[F:28])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1cccc(Cl)c1F
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H]1C(=O)NCc1cccc(Cl)c1F
Reaction time: 20 h

Procedure:
To (2S,3R)-3-azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (170 mg, 0.663 mmol) in CH2Cl2 (12 mL) were added successively 3-chloro-2-fluorobenzylamine (0.092 mL, 0.730 mmol), HBTU (377 mg, 0.995 mmol) DIPEA (0.232 mL, 1.33 mmol) and stirring was continued at RT for 20 h. The reaction mixture was diluted with CH2Cl2 and the organics were washed with 1N aqueous HCl (2×), aqueous 1N NaOH 1N (2×) and brine, dried (Phase separator) and concentrated in vacuo. The crude product was purified in two steps: first by preparative HPLC (Macherey-Nagel Nucleosil 100-10 C18, 5 μm, 40×250 mm; flow: 20 mL/min; eluent: 20-100% CH3CN/H2O for 20 min, 100% CH3CN for 2 min, CH3CN and H2O containing 0.1% TFA) and subsequently by flash column chromatography on silica (EtOAc/c-hexane gradient 1:3 to 1:1) to afford the title compound as a colorless wax. TLC Rf (EtOAc/c-hexane 1:1)=0.41; MS (LC/MS): 420 [M+Na]+, 342 [MH−tBu]+, 298 [MH−Boc]+; tR (HPLC conditions b): 4.66 min.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15]CSC3C=CN=CC=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[N:26]1[CH:31]=[CH:30][C:29]([S:32]CCCCN2CC=C(C3SC=CC=3)CC2)=[CH:28][CH:27]=1>>[C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][S:32][C:29]3[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=3)[CH2:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1=C(c2ccccc2)CCN(CCCCSc2ccncc2)C1
Reactant: C1=C(c2cccs2)CCN(CCCCSc2ccncc2)C1
Agent: Cl
Product: C1=C(c2ccccc2)CCN(CCCSc2ccncc2)C1

Procedure:
1,2,3,6-Tetrahydro-4-phenyl-1-[4-(4-pyridinylthio)butyl]pyridine and 1,2,3,6-tetrahydro-1-[4-(4-pyridinylthio)butyl]-4-(2-thienyl)pyridine, dihydrochloride; or a pharmaceutically acceptable acid addition salt thereof.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][S:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:16]=[CH:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[CH:12](O)[C:11]=2[CH:22]=1>C1C=CC=CC=1>[Cl:3][CH:12]1[C:11]2[CH:22]=[C:7]([S:6][CH3:5])[CH:8]=[CH:9][C:10]=2[CH:16]=[CH:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]1=2
Reactant: O=S(Cl)Cl
Reactant: CSc1ccc2c(c1)C(O)c1ccccc1C=C2
Solvent: c1ccccc1
Product: CSc1ccc2c(c1)C(Cl)c1ccccc1C=C2

Procedure:
Molar excess (5 milliliters) of thionyl chloride was added to a solution of the 3-methylthio-5H-dibenzo[a,d]cyclohepten-5-ol intermediate in 45 milliliters of benzene and the resulting mixture heated under reflux for two hours to obtain a 5-chloro-3-methylthio-5H-dibenzo[a,d]cycloheptene (chloro compound) intermediate in the reaction mixture. The reaction mixture was subjected to reduced pressure to co-evaporate benzene and unreacted thionyl chloride, and the procedure repeated with several additions of benzene to obtain a purified chloro compound intermediate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[N:6]=1)=[O:4].S(Cl)([Cl:22])(=O)=O>C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:9]([Cl:22])=[C:8]([O:10][CH3:11])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[N:6]=1)=[O:4]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)c1cc(OC)n(-c2ccccc2F)n1
Solvent: CC(=O)O
Product: COC(=O)c1nn(-c2ccccc2F)c(OC)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.6 %

Procedure:
300 mg (1.2 mmol) of 1-(2-fluoro-phenyl)-5-methoxy-1H-pyrazole-3-carboxylic acid methyl ester was dissolved in 3 ml of acetic acid. 162 mg (1.2 mmol) of sulfuryl chloride were added and the mixture stirred for 4 h at room temperature. The solvent was removed in vacuo and the residue subjected to acidic aqueous work-up. The obtained crude title compound (330 mg) was used in the hydrolysis step without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].C(=O)([O-])[O-].[Na+].[Na+].Cl.[F:19][C:20]([F:28])([F:27])[C:21]([NH:23][CH2:24][CH2:25][NH2:26])=[O:22].CN1CCCC1=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:26][CH2:25][CH2:24][NH:23][C:21](=[O:22])[C:20]([F:28])([F:27])[F:19])=[C:3]([CH3:11])[CH:4]=1)([O-:10])=[O:9]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: NCCNC(=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])ccc1NCCNC(=O)C(F)(F)F
Temperature: 90 °C
Yield: 65.2 %

Procedure:
1.55 g (0.01 mol) of 2-fluoro-5-nitrotoluene, 2.65 g (0.025 mol) of sodium carbonate, 2.11 g (0.011 mol) of 2-(trifluoroacetamido)ethylamine hydrochloride and 10 ml of N-methyl-pyrrolidone were introduced into a three-necked flask under nitrogen. The mixture was heated to 90° C. After reaction for 48 hours, the reaction mixture was cooled and 30 ml of distilled water were then added slowly with vigorous stirring. A yellow precipitate appeared. This precipitate was filtered off, washed several times with water and then with pentane, and dried under vacuum. 1.9 g of expected nitro derivative (1) were obtained in the form of a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]=O)[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].Cl.[CH3:27][O:28][NH2:29]>N1C=CC=CC=1>[CH3:27][O:28][N:29]=[CH:19][C:4]1[C:3]([S:21][C:22]([F:25])([F:24])[F:23])=[C:2]([NH2:1])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:17])[F:16])=[CH:9][C:8]=2[Cl:18])[N:5]=1
Reactant: Nc1c(SC(F)(F)F)c(C=O)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Temperature: 25 °C
Reaction time: 26 h
Yield: 42.5 %

Procedure:
A mixture of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-trifluoromethylthio-1H-pyrazole-3-carboxaldehyde (0.66 g), methoxyamine hydrochloride (0.2 g) and pyridine was stirred at room temperature for 26 hours. Pyridine was evaporated and the residue dissolved in ethyl acetate/acetonitrile, washed with 1% aqueous HCl, dried (MgSO4) and evaporated. The residue was purified by silica gel column chromatography, eluting with hexane/ethyl acetate, to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-trifluoromethylthio-1H-pyrazole-3-carboxaldehyde O-methyloxime (0.3 g) as a white solid m.p. 129-131.5° C. Compound 9.
Reaction SMILES: [CH2:1]([N:3]1[N:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:10]2=[O:38])[CH:5]=[N:4]1)[CH3:2].[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>C(Cl)Cl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[CH2:1]([N:3]1[N:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:10]2=[O:38])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1ncc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
A solution of tert-butyl 4-{1-[(2-ethyl-2H-1,2,3-triazol-4-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (2.10 g; compound B21) in DCM (50 ml) is reacted with trifluoroacetic acid (10 ml) according to the procedure described in example B43 to afford the title compound as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]([CH2:5][CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:4].CCN=C=N[CH2:25][CH2:26][CH2:27][N:28](C)C.C(N(CC)CC)C>ClCCl>[CH:27]1([NH:28][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([C:9]#[C:8][CH2:7][CH2:6][CH2:5][C:3](=[O:4])[N:2]([CH3:1])[CH3:19])[CH:11]=2)[CH2:25][CH2:26]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CN(C)C(=O)CCCC#Cc1cccc(C(=O)O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)CCCC#Cc1cccc(C(=O)NC2CC2)c1
Temperature: 25 °C
Yield: 89.5 %

Procedure:
To a solution of 3-(5-dimethylcarbamoyl-pent-1-ynyl)-benzoic acid (0.100 g, 0.38 mmol) in dry dichloromethane (1.5 mL) under a nitrogen atmosphere at room temperature, EDCI (0.0728 g, 0.38 mmol) was added followed by triethylamine (0.162 mL, 1.14 mmol), the resulting mixture was stirred at room temperature for further minutes. Cyclopropyilamine (0.027 g, 0.38 mmol) was then added and the mixture stirred at room temperature for 16 hrs. The reaction mixture was washed with a mixture of saturated brine and saturated sodium bicarbonate (1:1; 2×150 mL) followed by saturated brine solution (100 mL). The organic layer was separated and dried over magnesium sulfate and the solvent evaporated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM:MeOH, 95% to 5% methanol gradient) to afford N-cyclopropyl-3-(5-dimethylcarbamoyl-pent-1-ynyl)benzamide (25) (0.10 g, 0.34 mmol, 91% yield).
Reaction SMILES: C(O)=O.[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][C@@H:14]([NH:29]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:15][NH:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])=[CH:5]1>C(Cl)Cl>[NH2:29][C@H:14]([CH2:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][CH:5]=1)[CH2:15][NH:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27]
Reactant: COc1ccccc1CCC(=O)NC[C@@H](Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Solvent: ClCCl
Product: COc1ccccc1CCC(=O)NC[C@H](N)Cc1c[nH]c2ccccc12
Reaction time: 4 h
Yield: 90 %

Procedure:
Formic acid (9.0 ml, 238.540 mmol) was added to a stirring solution of (R)-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]-2-(N-triphenylmethylamino)propane (14.11 g, 23.763 mmol) in anhydrous methylene chloride under a nitrogen atmosphere at 0° C. After 4 hours, the reaction mixture was concentrated to an oil on a rotary evaporator and redissolved in diethyl ether and 1.0 N hydrochloric acid. The aqueous layer was washed twice with diethyl ether and basified with sodium hydroxide to a pH greater than 12. The product was extracted out with methylene chloride (4×). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated on a rotary evaporator to a white foam. The compound (R)-2-amino-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane (7.52 g, 21.397 mmols) was isolated giving a 90% yield. No further purification was necessary.