Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[N:22]1[CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:6]
Reactant: Cc1ncc(C(CN)N2CCCOCC2)cn1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCCOCC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(1,4-oxazepan-4-yl)ethanamine.
Reaction SMILES: C(OC([NH:8][NH:9][C:10](=[S:18])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O)(C)(C)C.[ClH:19].O1CCOCC1>>[ClH:19].[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][NH2:8])=[S:18])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NNC(=S)c1ccc(F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: NNC(=S)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To N′-(4-fluoro-thiobenzoyl)-hydrazinecarboxylic acid tert-butyl ester (18.5 mmol) is added HCl (4 N) in 1,4-dioxane (185 mmol). The mixture is stirred at room temperature for 1 hour. Hexanes is added to further precipitate the product. The product is filtered off yielding 4-fluoro-thiobenzoic acid hydrazide hydrochloride salt: 1H NMR (400 MHz, CH3OD) δ 7.8-7.75 (m, 2H), 7.09 (t, J=11.6 Hz, 2H). LC/MS: (ES+) 171 (M+1)+.
Reaction SMILES: [NH2:1][C:2]([CH3:39])([CH3:38])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)([CH2:11][CH2:12][N:13]2[CH:18]3[CH2:19][CH2:20][CH:14]2[CH2:15][CH:16]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[CH2:17]3)[CH2:7][CH2:6]1)=[O:4].[Cl:40][CH2:41][C:42](Cl)=[O:43].CCN(C(C)C)C(C)C>>[Cl:40][CH2:41][C:42]([NH:1][C:2]([CH3:39])([CH3:38])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)([CH2:11][CH2:12][N:13]2[CH:18]3[CH2:19][CH2:20][CH:14]2[CH2:15][CH:16]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[CH2:17]3)[CH2:7][CH2:6]1)=[O:4])=[O:43]
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(C)(C)N)CC1
Reactant: O=C(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(C)(C)NC(=O)CCl)CC1
Yield: 49 %

Procedure:
2-Chloro-N-[2-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-1,1-dimethyl-2-oxo-ethyl]-acetamide was obtained from treating 2-(4-(3-Fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-1,1-dimethyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (0.610 g, 0.97 mmol) with HCl as outlined in the procedure for Example 890 to form 2-Amino-1-(4-(3-fluoro-phenyl)-4-{2[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-2-methyl-propan-1-one (0.510 g, 99%). 2-Amino-1-(4-(3-fluoro-phenyl)-4-{2[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-2-methyl-propan-1-one (0.050 g, 0.09 mmol, Chloro-acetyl chloride (0.010 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2-Chloro-N-[2-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-1,1-dimethyl-2-oxo-ethyl]-acetamide (0.027 g, 49%) as an oil. ES-LCMS m/z 608 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.C([Mg]Cl)(C)C.[Br:14][C:15]1[C:16]([F:23])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19]>O1CCCC1>[Br:14][C:15]1[C:16]([F:23])=[C:17]([CH:18]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[OH:19])[CH:20]=[CH:21][CH:22]=1
Reactant: O=Cc1cccc(Br)c1F
Reactant: Clc1ccccc1I
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC(c1ccccc1Cl)c1cccc(Br)c1F
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a stirring solution of 1-chloro-2-iodobenzene (7.05 g, 29.6 mmol) in tetrahydrofuran (Volume: 15 mL) at −15° C. was added isopropylmagnesium chloride (17.24 mL, 34.5 mmol). The mixture was allowed to stir for 30 minutes, at which time 3-bromo-2-fluorobenzaldehyde (5 g, 24.63 mmol) was added. The reaction mixture was stirred overnight. The reaction was quenched with saturated aqueous NH4Cl. The reaction mixture was extracted with EtOAc (3×). The organics were combined, rinsed with brine, dried over Na2SO4, filtered, and concentrated to afford the title compound (7.5 g, 96%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].O.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[CH2:16]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc2c(c1)CCN2
Reactant: ClCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCc3ccccc32)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Into a 1,000 mλ reaction flask equipped with a thermometer, a stirrer, a condenser and a dropping funnel, 119.2 g (1.0 mol) of indoline, 105 g (1.25 mols) of sodium hydrogen carbonate and 200 g of water were charged, and the temperature was raised to a liquid temperature of 90° C. Then, while stirring at the same temperature, 132.9 g (1.05 mols) of benzyl chloride was dropwise added thereto over a period of about one hour from the dropping funnel, and then stirring was continued for eight hours at from 90 to 95° C. After completion of the reaction, 400 mλ of toluene was added, and the mixture was stirred from 60 to 80° C. for a while and then left to stand still for liquid separation. From the obtained organic layer, toluene was distilled off under reduced pressure to obtain 209 g of brown 1-benzylindoline (crude yield: 100%).
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1)=[O:7].[N:16]1([C:22]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[C:31]([F:34])([F:33])[F:32])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:19]2[CH2:20][CH2:21][N:16]([C:22](=[O:23])[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[C:31]([F:34])([F:33])[F:32])[CH2:17][CH2:18]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Reactant: O=C(c1ccc(F)cc1C(F)(F)F)N1CCNCC1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccc(F)cc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-methylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(4-fluoro-2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (63.8% yield). 1H NMR (400 MHz, CDCl3) δ 8.08, 7.85, 7.48-7.46, 7.41-7.32, 7.02, 4.08-4.05, 3.95-3.88, 3.80-3.68, 3.52-3.45, 3.35, 1.73-1.68, 1.51, 0.94.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]1=2.C(OCC)C.[CH3:20][N:21]1[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH2:22]1>CCCCCC>[CH3:20][N:21]1[CH2:26][CH2:25][CH2:24][C:23]([C:10]2[S:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=2)([OH:27])[CH2:22]1
Reactant: CN1CCCC(=O)C1
Reactant: c1ccc2sccc2c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CN1CCCC(O)(c2cc3ccccc3s2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
26.5 ml of a 2N solution of n-butyllithium in hexane is added dropwise within 30 minutes to a solution of 7.0 g of benzo[b]thiophene in 50 ml of abs. diethyl ether at a reaction temperature of 5° to 10°. The solution is then stirred for a further 1 hour at 0°. There is then added dropwise, in the course of 30 minutes, a solution of 5.9 g of 1-methyl-3-piperidone in 50 ml of abs. diethyl ether, with the reaction temperature being maintained at 0° by external cooling. The reaction solution is stirred for a further 15 hours at room temperature, and is then poured, with stirring, onto 100 g of ice; the aqueous phase is separated, and extracted 3 times with 100 ml of ethyl acetate each time. The combined organic extracts are dried with sodium sulphate, filtered under suction and concentrated by evaporation. The residue is dissolved in 250 ml of 2N hydrochloric acid, and the acid solution is washed with diethyl ether. The aqueous solution is subsequently brought to a pH-value of 12 by the addition of 10 sodium hydroxide solution, and extracted with 500 ml of chloroform. The chloroform solution is dried with sodium sulphate, filtered with suction and concentrated by evaporation to obtain crude 1-methyl-3-(benzo[b]thien-2-yl)-3-piperidinol; the oxalate thereof is prepared, for example, from 1.8 g of free base in ethyl actate and 0.7 g of oxalic acid in 10 ml of ethyl acetate, and it melts at 165°-168° after recrystallisation from ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH3:10])[CH:3]=1
Reactant: CCC(=O)c1cccc(Br)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cccc(Br)c1

Procedure:
A solution of 3'-bromopropiophenone (25 g) and triethylsilane (57 ml) in trifluoroacetic acid (50ml) was heated at reflux for 16 hours. The reaction mixture was evaporated under reduced pressure and the residue was purified by chromatography eluting with isohexane. Yield 25.14 g. The subtitle compound was contaminated with 17 mole % of 3-(1-propenyl)bromobenzene. Used directly in the next step. 1H NMR: δ(CDCl3) 7.32(m,2H), 7.10(m,2H), 2.55(t,2H), 1.61(m,2H), 0.90(t3H).
Reaction SMILES: C([O:3][C:4]([NH:6][C@@H:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:8][OH:9])=O)C.C([Li])CCC.C(O)(=O)C>C1COCC1.CCCCCC>[C:10]1([C@H:7]2[CH2:8][O:9][C:4](=[O:3])[NH:6]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)N[C@H](CO)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCCCCC
Product: O=C1N[C@@H](c2ccccc2)CO1
Temperature: 0 °C
Yield: 63 %

Procedure:
To a stirred, 0° C. solution of L-phenylglycine (25.3 g, 167.4 mmol) in 60 mL of 3N aqueous NaOH was added ethyl chloroformate (8 mL) in several portions. Additional 3N aqueous NaOH (35 mL) was added to redissolve the precipitated phenylglycine, followed by ethyl chloroformate (4 mL). This process was continued with 3N aqueous NaOH (65 mL) and ethyl chloroformate (8 mL, total of 20 mL, 209 mmol) over a period of ca. 10 minutes. After stirring for 1 hour at 0° C. the solution was acidified with 6M H2SO4, and the precipitated carbamate was extracted into 8% isopropanol in dichloromethane (2×300 mL). The combined organic layers were dried (Na2SO4) and concentrated to afford 37.3 g of N-ethoxycarbonyl L-phenylglycine as a white solid. The carbamate was dissolved in 170 mL of THF, cooled to 0° C., treated with borane-dimethylsulfide (33.5 mL of a 10M solution), and stirred at room temperature for 17 hours. Excess borane was cautiously quenched with water (100 mL), and the bulk of the THF removed under reduced pressure. The white slurry was diluted with additional water (350 mL) and then extracted with dichloromethane (2×500 mL). The combined organic layers were washed with 100 mL of saturated aqueous NaHCO3, dried (Na2SO4), and concentrated to give 27.4 g of (S)-2-ethoxycarbonylamino-2-phenylethanol as a white solid. The crude alcohol was dissolved in 200 mL of THF, cooled to 0° C., and treated with n-butyllithium in hexane (6 mL of a 2M solution). After heating at 55° C. for 6 hours, the solution was treated with acetic acid (1 ml) and concentrated. The residue was dissolved in dichloromethane (300 mL), washed with 100 mL of brine, dried (Na2SO4), and concentrated to a white solid. Recrystallization from toluene gave 17.14 g (63%) of (S)-4-phenyloxazolidin-2-one; mp 132°-133° C.; [α]D20 +49.5° (c=2.1, CHCl3); IR (CHCl3) 3460, 3020, 1760, 1500, 1480, 1460, 1400, 1230 cm-1 ;
Reaction SMILES: Cl.[C:2]([NH2:6])(=[NH:5])[CH2:3][CH3:4].Cl[C:8](=[CH2:11])[C:9]#[N:10]>>[CH2:3]([C:2]1[N:6]=[C:9]([NH2:10])[CH:8]=[CH:11][N:5]=1)[CH3:4]
Reactant: CCC(=N)N
Reactant: C=C(Cl)C#N
Agent: Cl
Product: CCc1nccc(N)n1

Procedure:
This intermediate was made according to example 2, step A] via the alternative preparation method from propionamidine hydrochloride (1.45 g, obtained from propionitrile in analogy to Synth. Commun. 12 (13), 1982, 989-993 and Tetrahedron Lett. 31 (14), 1990, 1969-1972) and 2-chloro-acrylonitrile (1.17 mL). 2-Ethyl-pyrimidin-4-ylamine was obtained as a light brown solid (0.89 g): 1H NMR (δ, DMSO-d6): 7.96 (d, 1H), 6.68 (br s, 2H), 6.21 (s, 1H), 2.55 (q, 2H, 1.18 (t, 3H).
Reaction SMILES: [CH:1]1([CH2:6][C:7]([NH:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([OH:32])=[N:15][N:16]3[CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=3[O:30][CH3:31])=[CH:12][CH:11]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:33](Br)[CH:34]=[CH2:35].[H-].[Na+].C(N1C(=O)C2C(=CC(NC(=O)CC3CCCC3)=CC=2)N1CC1C=CC(C(OC)=O)=CC=1OC)C=C>CN(C)C=O>[CH2:35]([O:32][C:14]1[C:13]2[C:17](=[CH:18][C:10]([NH:9][C:7](=[O:8])[CH2:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:11][CH:12]=2)[N:16]([CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=2[O:30][CH3:31])[N:15]=1)[CH:34]=[CH2:33]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(Cn2nc(O)c3ccc(NC(=O)CC4CCCC4)cc32)c(OC)c1
Agent: C=CCn1c(=O)c2ccc(NC(=O)CC3CCCC3)cc2n1Cc1ccc(C(=O)OC)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1nn(Cc2ccc(C(=O)OC)cc2OC)c2cc(NC(=O)CC3CCCC3)ccc12

Procedure:
The starting ester methyl 4-[2-allyl-6-(2-cyclopentylacetamido)-3-oxo-2H,3H-indazol-1-ylmethyl]-3-methoxybenzoate was itself prepared as follows. Using a similar procedure to that described in Example 42, except starting from methyl 4-[6-(2-cyclopentylacetamido)-3-hydroxyindazol-1-ylmethyl]-3-methoxybenzoate (that is, reaction of this compound with allyl bromide in N,N-dimethylformamide in the presence of sodium hydride), a mixture of methyl 4-[2-allyl-6-(2-cyclopentylacetamido)-3-oxo-2H,3H-indazol-1-ylmethyl]-3-methoxybenzoate, and methyl 4-[3-allyloxy-6-(2-cyclopentylacetamido)indazol-1-ylmethyl]-3-methoxybenzoate was obtained. The mixture of compounds was heated neat at 200° C. for 18 hours, and the product isolated by flash chromatography on silica gel (60 g.), eluting with 1:30:70 v/v/v acetic acid:ethyl acetate:dichloromethane, to give methyl 4-[2-allyl-6-(2-cyclopentylacetamido)-3-oxo-2H,3H-indazol-1-ylmethyl]-3-methoxybenzoate in 81% yield, as am oil with satisfactory NMR spectral data.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[O:17]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:20][N:19]=[CH:18]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:28]([C:25]2[CH:26]=[CH:27][C:22]([C:21]3[O:17][CH:18]=[N:19][CH:20]=3)=[CH:23][CH:24]=2)(=[O:29])=[O:30])=[C:3]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccnc1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Product: O=C(c1cccnc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(-c2cnco2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-Amino-5-chloro-phenyl)-pyridin-3-yl-methanone and 122 mg of 4-oxazol-5-yl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 7.23 (m, 2H), 7.42-7.47 (m, 3H), 7.58-7.62 (m, 3H), 7.71 (dt, 1H, J=7.6 Hz, 2.0 Hz), 7.88 (s, 1H), 8.45 (b, 1H), 8.58 (bd, 1H, J=3.6 Hz), 9.67 (s, 1H). MS: m/z 458.1 (M++1)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[CH3:13][NH:14][CH3:15]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:14]([CH3:15])[CH3:13])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: CNC
Reactant: COc1cc(C(=O)O)ccc1Br
Product: COc1cc(C(=O)N(C)C)ccc1Br

Procedure:
Starting with 4-bromo-3-methoxybenzoic acid and dimethyl amine, Int02.06 was prepared analogously to the procedure for the preparation of Int02.05.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[NH:9][C:10](=[O:12])[CH3:11].[C:13](Cl)(Cl)=[O:14]>C(#N)C>[C:10]([N:9]1[C:3]2[C:4]([Br:8])=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:13]1=[O:14])(=[O:12])[CH3:11]
Reactant: CC(=O)Nc1c(N)cccc1Br
Reactant: O=C(Cl)Cl
Solvent: CC#N
Product: CC(=O)n1c(=O)[nH]c2cccc(Br)c21
Reaction time: 0.17 h

Procedure:
To a solution of N-(2-amino-6-bromophenyl)acetamide from Step A (3.5 g, 15.28 mmol) in acetonitrile (100 mL) was added phosgene (1.9 M in toluene, 8 mL, 15.2 mmol). After 10 min, the mixture was concentrated, redissolved in water, and the solid was collected by filtration, washed with H2O and dried in vacuo to give the title compound. MS: m/z=256 (M+1).
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14]C2C(C3C=CC=CC=3)=C(OCCN)N=C(SC)N=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(C)(C)C.C(S(Cl)(=O)=O)C>>[C:8]1([S:11]([NH2:14])(=[O:13])=[O:12])[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(-c2ccccc2)c(OCCN)n1
Agent: CCS(=O)(=O)Cl
Product: NS(=O)(=O)c1ccccc1

Procedure:
According to Example 4a) 100 mg 4-tert.-butyl-N-[6-(2-aminoethoxy)-2-methylsulfanyl-5-phenyl-pyrimidin-4-yl]-benzenesulfonamide was reacted with 83 mg ethanesulfonylchloride to give 56 mg 4-tert.-butyl-N-[6-(2-(ethanesulfonyl)-amino)-ethoxy)-2-methylsulfanyl-5-phenyl-pyrimidin-4-yl]-benzenesulfonamide. LC-MS: tR=5.68 min. [M−1]−=563.42.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:4][CH:3]=1.Cl[C:11]1[CH:19]=[CH:18][C:17]([S:20]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])(=[O:22])=[O:21])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Cu+2].CN(C=O)C>[CH:7]([N:6]1[C:2]([NH:1][C:11]2[C:12](=[CH:16][C:17]([S:20]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])(=[O:21])=[O:22])=[CH:18][CH:19]=2)[C:13]([OH:15])=[O:14])=[CH:3][CH:4]=[N:5]1)([CH3:9])[CH3:8]
Reactant: CC(C)n1nccc1N
Reactant: CCN(CC)S(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCN(CC)S(=O)(=O)c1ccc(Nc2ccnn2C(C)C)c(C(=O)O)c1
Yield: 62.4 %

Procedure:
A mixture of 5-amino-1-isopropylpyrazole (6.43 g, 0.051 mol), 2-chloro-5-(diethylaminosulfonyl)benzoic acid (15.0 g, 0.051 mol), K2CO3 (7.04 g, 0.051 mol), Cu(OAc)2 (1.0 g) and DMF (100 ml) is refluxed for 24 hours. The reaction mixture is concentrated in vacuo, and the residue is poured into water and neutralized with acetic acid. The mixture is extracted with CH2Cl2 and the CH2Cl2 layer is dried over MgSO4 and evaporated to afford 12.1 g of N-(1-isopropylpyrazol-5-yl)-5-(diethylaminosulfonyl) anthranilic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[N+:23]([O-])=O)[C:14]2=[O:26])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[Cl-].[NH4+].O>[Fe].ClCCl>[NH2:23][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:20]=1[CH:21]=[CH:22][N:13]([CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:9]([O:11][CH3:12])=[O:10])[C:14]2=[O:26]
Reactant: COC(=O)C(c1ccc(Cl)cc1)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(c1ccc(Cl)cc1)n1ccc2c(N)cccc2c1=O
Temperature: 80 °C

Procedure:
A round bottom flask was charged with methyl 2-(4-chlorophenyl)-2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)acetate (4.2 g, 0.011 mol) ethanol (60 mL, 1 mol) and ammonium chloride (6 g, 0.1 mol) in water (60 mL, 3 mol) was added and the reaction heated at 80° C. and iron (2 g, 0.04 mol) was added in four portions 5 minutes apart. The reaction was heated for another 1 h at that temperature and cooled to room temperature and poured into 200 ml dichloromethane and extracted. The solvent was removed to obtain the product as a light brown solid. MS m/z=343.0 (M+H).
Reaction SMILES: [CH3:1][CH:2](O)[C:3]#[CH:4].[CH3:6][O:7][CH2:8][CH2:9][NH:10][CH2:11][CH3:12]>>[CH2:11]([N:10]([CH2:9][CH2:8][O:7][CH3:6])[CH:2]([CH3:1])[C:3]#[CH:4])[CH3:12]
Reactant: C#CC(C)O
Reactant: CCNCCOC
Product: C#CC(C)N(CC)CCOC

Procedure:
In analogy to example 37.5 and 37.6, 3-Butyn-2-ol and N-(Methoxyethyl)ethylamine were converted to yield Ethyl-(2-methoxy-ethyl)-(1-methyl-prop-2-ynyl)-amine as colorless oil, MS: 155 (M).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:3][CH2:2]1.Cl.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH2:28][CH2:29][NH:30][CH2:31][CH:32]=2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH2:32][CH2:31][N:30]([C:8]([C:7]3[CH:11]=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:13]=[CH:14][C:6]=3[O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)=[O:10])[CH2:29][CH:28]=2)=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)O)c1
Reactant: Clc1ccc(C2=CCNCC2)cc1
Agent: Cl
Product: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)N2CC=C(c3ccc(Cl)cc3)CC2)c1

Procedure:
According to the procedure described for the synthesis of example 4, step f, the title compound has been synthesized from 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (CAS: 845616-03-7) and 4-(4-chloro-phenyl)-1,2,3,6-tetrahydro-pyridine hydrochloride (commercial). MS (m/e): 446.0 (MH+, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH:25]1[C:37]2[NH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]=2[CH:28]=[CH:27][CH:26]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O.CCCCCC.C1(C)C(C)=CC=CC=1>[C:19]1([C:10]2[CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]([C:5]3[CH:6]=[CH:7][C:2]([N:36]4[C:37]5[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=5[C:30]5[C:35]4=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:3][CH:4]=3)[N:9]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Brc1ccc(-n2nc(-c3ccccc3)cc2-c2ccccc2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Product: c1ccc(-c2cc(-c3ccccc3)n(-c3ccc(-n4c5ccccc5c5ccccc54)cc3)n2)cc1

Procedure:
In a 100 mL three-necked flask were placed 1.5 g (4.0 mmol) of 1(4-bromophenyl)-3,5-diphenyl-1H-pyrazol, 0.70 g (4.2 mmol) of 9H-carbazole, and 0.80 g (8.2 mmol) of sodium tert-butoxide, and the atmosphere in the flask was replaced with nitrogen. To this mixture was added 40 mL of xylene. The mixture was degassed by being stirred under reduced pressure, and then to this mixture were added 0.10 mL of a 10% hexane solution of tri(tert-butyl)phosphine and 50 mg (0.086 mmol) of bis(dibenzylideneacetone)palladium(0). The resulting mixture was stirred under a nitrogen stream at 140° C. for 6 hours. After a certain time, water was added to the mixture, and an aqueous layer was extracted with toluene. The obtained extracted solution and the organic layer were combined, washed with water, a saturated aqueous solution of sodium hydrogen carbonate, and saturated saline, and dried with magnesium sulfate. The filtrate obtained by gravity filtering the obtained mixture was concentrated to give an oily substance. The obtained oily substance was purified by silica gel column chromatography (a developing solvent was a mixed solvent of toluene:hexane=1:1) to give an oily substance. To the oily substance was added hexane, and suction filtration was performed on a precipitated solid, so that 1.3 g of a white powder, which was the object of the synthesis, was obtained at a yield of 68%.