Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[NH2:8]
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)c(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(N2CCCCC2)c(F)c1

Procedure:
The product from Example 10A (12.7 mmol) was hydrogenated (balloon) as a solution in ethyl acetate over 5% Pd/C overnight at room temperature. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 6.72–6.78 (m, 1H), 6.26–6.34 (m, 2H), 4.92 (br s, 2H), 2.76 (m, 4H), 1.56–1.63 (m, 4H), 1.42–1.49 (m, 2H); MS (APCI+) m/z 195.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[O:13][CH3:14])(=[O:3])[CH3:2].C1(P(=[CH:34][C:35]([O:37][CH3:38])=[O:36])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:34][C:35]([O:37][CH3:38])=[O:36])=[CH:7][C:6]=1[O:13][CH3:14])(=[O:3])[CH3:2]
Reactant: COc1cc(C=O)ccc1NC(C)=O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C=Cc1ccc(NC(C)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.6 %

Procedure:
To a solution of 4-acetamido-3-methoxybenzaldehyde (388 mg) in tetrahydrofuran (10 ml) was added methyl (triphenylphosphoranylidene)acetate (739 mg), and the mixture was stirred for 2 hours at ambient temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol=30:1, V/V) to give methyl 4-acetamido-3-methoxycinnamate (113 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: CC(C)(C)OC(=O)N1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and N-(tert-butoxy carbonyl)piperazine according to conditions described in general procedure C. Mp: 175-177° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.36 (s, 9 H), 1.58-1.59 (m, 6 H), 3.24-3.31 (m, 8 H), 3.47 (s, 4 H), 6.22 (d, J=5.5 Hz, 1H), 6.96 (d, J=12.4 Hz, 1 H), 7.15 (d, J=9.1Hz, 1 H), 7.41 (d, J=8.0 Hz, 1 H), 7.47 (s, 1 H), 7.50-7.62 (m, 3 H), 7.82-7.84 (m, 1 H), 7.98 (d, J=7.7 Hz, 1 H), 8.27 (d, J=5.5 Hz, 1 H), 10.43 (s, 1 H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:12][CH2:11][CH:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[CH:20]=3)[CH:15]=[CH:14]2)[CH2:9][CH2:8]1.Br[CH2:28][CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1>CN(C)C=O>[N:32]1[CH:33]=[CH:34][CH:35]=[C:30]([CH2:29][CH2:28][N:7]2[CH2:8][CH2:9][CH:10]([N:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[CH:20]=4)[CH:15]=[CH:14]3)[CH2:11][CH2:12]2)[CH:31]=1
Reactant: BrCCc1cccnc1
Reactant: CC(=O)NCc1ccc2ccn(C3CCNCC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc2ccn(C3CCN(CCc4cccnc4)CC3)c2c1
Yield: 43.2 %

Procedure:
Potassium carbonate (0.5 g) was added to a solution of 1-(piperidin-4-yl)-6-acetamidomethylindole (0.10 g) obtained in Example 386-1) and 3-(2-bromoethyl)pyridine (0.07 g) obtained in Production Example 26-2 in N,N-dimethylformamide (5 ml) and the resultant mixture was stirred at 70° C. for 6 hr. Then the reaction mixtures were concentrated under reduced pressure and the residue was partitioned between ethyl acetate (40 ml) and water (15 ml) followed by extraction with ethyl acetate. The ethyl acetate layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol system) to give the title compound (0.06 g) as a pale yellow wax (yield: 75.5%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([CH2:14][C:15]([OH:17])=O)[C:10]2=O)=[CH:5][CH:4]=1.[C:20]1([NH:26][NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[C:20]1([N:26]2[C:15](=[O:17])[CH2:14][CH:9]3[C:10]([C:11]4[CH:12]=[C:3]([C:2]([F:1])([F:19])[F:18])[CH:4]=[CH:5][C:6]=4[CH2:7][CH2:8]3)=[N:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)CC1CCc2ccc(C(F)(F)F)cc2C1=O
Reactant: NNc1ccccc1
Solvent: CCO
Product: O=C1CC2CCc3ccc(C(F)(F)F)cc3C2=NN1c1ccccc1

Procedure:
After a mixture of 7-trifluoromethyl-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetic acid and phenylhydrazine in ethanol is refluxed under heating for 10 hours, the ethanol is distilled off. To the residue is added acetic acid and the mixture is refluxed under heating for 7 hours. After the acetic acid is distilled off, the residue is extracted with chloroform and the extract is washed with water and dried over magnesium sulfate anhydride. The chloroform is distilled off to give 2-phenyl-9-trifluoromethyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4](Cl)Cl.[OH2:11]>[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]=[O:11]
Reactant: O
Reactant: Clc1ccccc1C(Cl)Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: O=Cc1ccccc1Cl
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
195.3 g (1.0 mol) of 2-chlorobenza1 chloride are initially charged at 120° C. At this temperature 20 ml (21.8 g, 1.09 mol of water) of a 10% strength aqueous zinc chloride solution are metered in over a period of 5 hours. The mixture is stirred for a further 30 minutes at 120° C. After cooling to room temperature the reaction mixture is extracted with 1×10 ml and 2×5 ml of water. The organic phase is subsequently free of chloride and is worked up by distillation. 136.0 g (97% of theoretical) of 2-chlorobenzaldehyde (b.p.: 90° C./16 torr) with a purity of >99.9% are obtained. The combined aqueous phases (20 ml, 22.0 g) are used in Example 2 as catalyst solution.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:18][CH2:19][OH:20])[C:7]([CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:20][CH2:19][CH2:18][N:6]1[C:5]2[CH:21]=[CH:22][C:2]([Br:1])=[CH:3][C:4]=2[N:8]=[C:7]1[CH2:9][NH:10][C:11]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:17])(=[O:33])=[O:32]
Reactant: CC(C)(C)OC(=O)NCc1nc2cc(Br)ccc2n1CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1nc2cc(Br)ccc2n1CCOS(C)(=O)=O
Reaction time: 2 h
Yield: 106.2 %

Procedure:
tert-Butyl ((5-bromo-1-(2-hydroxyethyl)-1H-benzo[d]imidazol-2-yl)methyl)carbamate (648 mg, 1.75 mmol) was stirred in methylene chloride (25 mL), and triethylamine (530 mg, 0.74 mL, 5.3 mmol) and methanesulfonyl chloride (400 mg, 0.27 mL, 3.5 mmol) were added. The mixture was stirred for 2 h and then washed with water, dried over sodium sulfate and concentrated to provide the title compound (833 mg, quant) as a yellow solid: ESI MS m/z 448 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]3)=[CH:6][N:5]=[CH:4][C:3]=1[CH2:20][NH:21][C:22]([C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][N:25]=1)=[O:23].[H-].[Na+].[CH3:33]I>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]3)=[CH:6][N:5]=[CH:4][C:3]=1[CH2:20][N:21]([CH3:33])[C:22]([C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][N:25]=1)=[O:23]
Reactant: CN1C(=O)CCc2cc(-c3cncc(CNC(=O)c4ncccc4Cl)c3Cl)ccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CN(Cc1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1Cl)C(=O)c1ncccc1Cl

Procedure:
In analogy to the procedure described for the preparation of example 195, 3-chloro-pyridine-2-carboxylic acid [4-chloro-5-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-pyridin-3-ylmethyl]-amide (example 220) has been reacted with sodium hydride and methyl iodide to give the title compound as off-white solid. MS: 455.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][CH3:11].[CH2:12]([O:14][C:15]1[C:16](=O)[C:17](=[O:22])[C:18]=1[O:19]CC)[CH3:13]>C(#N)C.C(OCC)(=O)C>[O:19]=[C:18]1[C:17](=[O:22])[C:16]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH2:10][CH3:11])=[C:15]1[O:14][CH2:12][CH3:13]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: CCc1cc(C#N)ccc1N
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOc1c(Nc2ccc(C#N)cc2CC)c(=O)c1=O
Temperature: 150 °C
Yield: 34 %

Procedure:
4-Amino-3-ethylbenzonitrile (0.86 g, 5.88 mmol) and 3,4-diethoxy-3-cyclobutene-1,2-dione (1.0 g, 5.88 mmol) in acetonitrile (2 mL) was heated in an oil bath at 110° C. for 21 hours. 3,4-Diethoxy-3-cyclobutene-1,2-dione (0.5 g, 2.9 mmol) was added to the reaction mixture and the temperature of the oil bath increased to 150° C. After 48 hours the reaction mixture was cooled to room temperature, then diluted with ethyl acetate and filtered. The filtrate was concentrated and the resulting solid was taken up in ethyl acetate (5 mL) and sonicated. Filtration gave 0.54 g (34%) of 4-(3,4-dioxo-2-ethoxy-cyclobut-1-enylamino)-3-ethylbenzonitrile as a light brown solid: 1H NMR (DMSO-d6): δ 10.56 (br s, 1H), 7.70 (br s overlapping a doublet at δ 7.69, 2H), 7.30 (d, 1H), 4.71 (q, 2H), 2.74 (q, 2H), 1.37 (t, 3H), 1.15 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[NH:7][C:8](=[N:23][C:24](=[O:41])[CH2:25][C:26]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH:39]=[CH2:40])=[CH:33][CH:32]=1)=[N:27][O:28][CH2:29][CH3:30])[CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:18](=[O:21])[CH2:19]Br)=[C:12]([Cl:22])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:44]([NH2:48])[CH2:45][CH:46]=[CH2:47].C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6](=[O:42])[NH:7][C:8](=[N:23][C:24](=[O:41])[CH2:25][C:26]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH:39]=[CH2:40])=[CH:33][CH:32]=1)=[N:27][O:28][CH2:29][CH3:30])[CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:18](=[O:21])[CH2:19][NH:48][CH2:44][CH2:45][CH:46]=[CH2:47])=[C:12]([Cl:22])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCOc1ccc(C(CC(=O)N=C(Cc2cc(Cl)c(NC(=O)CBr)c(Cl)c2)NC(=O)OC(C)(C)C)=NOCC)cc1
Reactant: C=CCCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCNCC(=O)Nc1c(Cl)cc(CC(=NC(=O)CC(=NOCC)c2ccc(OCC=C)cc2)NC(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl-1-(3-(4-(allyloxy)phenyl)-3-(ethoxyimino)-propanoylimino)-2-(4-(2-bromoacetamido)-3,5-dichlorophenyl)ethylcarbamate (100 mg) in dichloromethane (0.30 mL) at room temperature was added but-3-en-1-amine hydrochloride (45 mg) and diisopropylethylamine (97 μL), and the resulting solution was stirred at room temperature for 2 h. The solvents were removed in vacuo to give the title compound as a white solid, which was used for Step B without purification. retention time: 2.11 min (method A). MS (ESI) (M+H)+ 689.20.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][S:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2]1.[NH:24]1[CH:31]=[CH:30][C:28]([NH2:29])=[N:27][C:25]1=[O:26].C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>CN(C)C=O>[OH:1][CH:3]([CH2:4][S:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2][N:24]1[CH:31]=[CH:30][C:28]([NH2:29])=[N:27][C:25]1=[O:26]
Reactant: Nc1cc[nH]c(=O)n1
Reactant: CCCCCCCCCCCCCCCCCCSCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCSCC(O)Cn1ccc(N)nc1=O
Temperature: 25 °C

Procedure:
rac-1,2-Epoxy-3-octadecylthiopropane (2.0 g, 5.83 mmol) is added to a mixture of cytosine (1.0 g, 9.0 mmol) and anhydrous potassium carbonate (40 mg) in dimethyl formamide (25 mL) over a 30 minute period under a nitrogen atmosphere. The resultant mixture is stirred at 80°-90° C. (oil bath temperature) for 48 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo to leave a residue. The residue is stirred with chloroform (50 mL). The undissolved material is filtered in vacuo, and the filtrate concentrated in vacuo, purified by chromatography and dried in vacuo to afford 1-[2'-hydroxy-3'-octadecylthiopropyl]-cytosine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH3:29])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[S:19][CH:20]=[C:21]([CH2:23]Cl)[N:22]=4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.O>CCO>[Cl:1][C:2]1[C:3]([N:27]([CH3:28])[CH3:29])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[S:19][CH:20]=[C:21]([CH2:23][N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[N:22]=4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CCl)cs3)c1)=N2
Reactant: C1COCCN1
Solvent: CCO
Solvent: O
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CN4CCOCC4)cs3)c1)=N2
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 8-chloro-4-[3-(4-chloromethyl-thiazol-2-yl)-phenyl]-7-dimethylamino-1,3-dihydro-benzo[b][1,4]diazepin-2-one (89 mg) (Example 191a), morpholine (0.17 mL) and KI (3 mg) in EtOH (0.5 mL) was stirred at 60° C. for 3 h. H2O (25 mL) was added to the cooled solution and the precipitate was collected by filtration and purified by chromatography on silica gel using AcOEt/acetone (1:1) as eluent. The product was stirred with 20% aqueous MeOH (20 mL) The pH of the mixture was set to 11 by addition of 1N NaOH and the solid was subsequently isolated by filtration to give the title compound (55 mg) as yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=3)[N:10]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:31]([O:33][CH3:34])=[O:32]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=3)[N:10]([CH:18]3[CH2:23][CH2:22][N:21]([C:31]([O:33][CH3:34])=[O:32])[CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(c1)c(-c1ccc(F)cc1)cn2C1CCNCC1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)N1CCC(n2cc(-c3ccc(F)cc3)c3cc(C)ccc32)CC1

Procedure:
A mixture of 3-(4-fluorophenyl)-5-methyl-l-(4-piperidyl)-1H-indole 3d (6.0 g). K2CO3 (3.0 g) and dichloromethane (50 ml) was cooled to 0°-5° C. and a solution of methyl chloroformate (2.2 g)in dichloromethane (50 ml) was added during 0.5 h. After reaction for further 2 h at room temperature the reaction mixture was washed with water (2×100 ml) and dried (MgSO4). Evaporation of the solvents in vacuo afforded the title compound, which was used without further purification. Yield: 6.7 g, (oil).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[C:26]([C:28]1[C:29](=[O:48])[N:30]([CH2:43][C:44]([O:46][CH3:47])=[O:45])[CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)#[N:27].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:26]([C:28]1[C:29](=[O:48])[N:30]([CH2:43][C:44]([O:46][CH3:47])=[O:45])[CH:31]=[C:32]([C:2]2[C:3]([CH3:25])=[CH:4][CH:5]=[C:6]([NH:8][C:9]([C:11]3([C:14]4[CH:24]=[CH:23][C:17]5[O:18][C:19]([F:21])([F:22])[O:20][C:16]=5[CH:15]=4)[CH2:12][CH2:13]3)=[O:10])[N:7]=2)[CH:33]=1)#[N:27]
Reactant: COC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(C#N)c1=O
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)Cn1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cc(C#N)c1=O
Temperature: 80 °C
Yield: 46.7 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (150 mg, 0.41 mmol), methyl 2-(3-cyano-2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-1(2H)-yl)acetate (244 mg, 0.61 mmol) and tetrakis(triphenylphosphine)palladium (0) (47 mg, 0.041 mmol) in 1,2-dimethoxyethane (4.5 mL), 2 M Na2CO3 (613.5 μL, 1.23 mmol) was added. The reaction mixture was stirred and heated at 80° C. for 22 hours under N2 atmosphere. The reaction mixture was diluted with ethyl acetate (5 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-100% ethyl acetate in hexane) to yield methyl 2-(3-cyano-5-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-2-oxopyridin-1(2H)-yl)acetate (100 mg, 46.8%). ESI-MS m/z calc. 522.5. found 532.5 (M+1)+. Retention time 1.86 minutes.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.Cl>N1C=CC=CC=1>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:16][C:13]2[S:14][CH:15]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=3)[N:12]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3cccc([N+](=O)[O-])c3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A mixture of 0.5 g of 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrochloride with 0.42 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 50 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and dissolved in a mixture of 10 ml of ethanol and 10 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated upon neutralization with concentrated hydrochloric acid. Recrystallization from 40 ml of 50% ethanol yielded 0.35 g of 4-methyl-N-[4-(3-nitro-phenyl)-thiazol-2-yl]-benzenesulfonamide as yellowish crystals.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.Br[CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(#N)C>[C:23]1([CH:17]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C1CCNCC1
Reactant: CCOC(=O)C(Br)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(c1ccccc1)N1CCCCC1

Procedure:
DIPEA (0.86 ml, 4.94 mmol) and piperidine (0.49 ml, 4.94 mmol) were sequentially added to a solution of ethyl 2-bromo-2-phenylacetate (0.72 ml, 4.11 mmol) in acetonitrile (13 ml). The pale yellow solution was stirred at room temperature monitoring by TLC (petroleum ether/EtOAc=9/1). After 1.5 hours complete conversion into the desired product was detected. Solvent was evaporated and the residue (pale yellow solid) was triturated with Et20 (30 ml). The solid was filtered off and the ethereal solution was evaporated to dryness. The residue was purified by flash chromatography (petroleum ether/EtOAc=95/5) to collect ethyl 2-phenyl-2-(piperidin-1-yl)acetate (990 mg, 97% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[OH-].[Na+].Br[CH2:8][CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]>>[CH2:1]([NH:4][CH2:8][CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[CH2:2][CH3:3]
Reactant: CCCN
Reactant: CCOC(CBr)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCNCC(OCC)OCC

Procedure:
Propylamine (100 ml) and 1-bromo-2,2-diethoxyethane (50 ml) were charged into a glass reaction flask equipped with a stirrer, thermometer, heater and reflux condenser. The reaction mixture was then heated at reflux for a period of one hour with stirring. After this time the mixture is treated with 50% by weight aqueous sodium hydroxide and was then distilled under reduced pressure to yield the desired product N-propyl-N-(2,2-diethoxyethyl)amine.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([NH:11][C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl[C:22](=[O:26])[CH:23]([Cl:25])[CH3:24]>ClCCCl>[S:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[C:12]1[NH:11][C:5]1[CH:6]=[CH:7][C:8]([C:22](=[O:26])[CH:23]([Cl:25])[CH3:24])=[CH:9][CH:10]=1
Reactant: c1ccc(Nc2nc3ccccc3s2)cc1
Reactant: CC(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(Cl)C(=O)c1ccc(Nc2nc3ccccc3s2)cc1
Temperature: 80 °C
Yield: 96.7 %

Procedure:
Aluminium(III)chloride (0.666 mol) was added portionwise at RT to a solution of N-phenyl-2-benzothiazolylamine (0.222 mol) and 1,2dichloro-1-propanone (0.233 mol) in 1,2-dichloroethane (500 ml) and the mixture was stirred and heated at 80° C. for 2 hours. The mixture was poured into ice and extracted with CH2Cl2. The organic layer was decanted, dried filtered and the solvent was evaporated, yielding 68 g of (±)-1-[4-(2-benzothiazolylamino)phenyl]-2-chloro-1-propanone (95.7%) (interm. 22).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[O:28])[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[BH4-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[OH:28])[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2=O)C(=O)Nc2cnccn2)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2O)C(=O)Nc2cnccn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 79.4 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(2-oxo-cyclopentyl)-N-pyrazin-2-yl-propionamide (prepared as in Example 30, 13.5 mg, 0.03 mmol) in ethanol (0.32 mL) cooled to 0° C. was treated with sodium borohydride (1.2 mg, 0.03 mmol). The reaction mixture was stirred at 0° C. for 20 min. At this time, the reaction was diluted with water (25 mL). The layers were separated. The aqueous layer was extracted with ethyl acetate 3×30 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(2-hydroxy-cyclopentyl)-N-pyrazin-2-yl-propionamide (10.1 mg, 75.5%) as a white foam: EIHRMS m/e calcd for C19H22ClN3O4S (M+Na)+ 446.0912. found 446.0916.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=1>>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH:5]2[CH2:4][CH2:3][NH:2][CH2:7][CH2:6]2)=[CH:12][CH:11]=1
Reactant: CN1CCC(=O)CC1
Reactant: Cc1ccc(CCN)cc1
Product: Cc1ccc(CCNC2CCNCC2)cc1

Procedure:
1-Methyl-4-piperidone (1.1 ml, 7.4 mmol, 1.0 eq.), 2-(4-methylphenyl)ethylamine (1.0 g, 1.0 eq.).