Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:19])C(=O)C1.C(=O)(O)[O-].[Na+]>CC#N>[Br:19][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][C:7]=1[C:10]#[N:11])[NH:1][CH2:2][CH2:3]2
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc2c(c1)NCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1cc2c(cc1Br)CCN2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.4 %

Procedure:
A solution of 2,3-dihydro-1H-indole-6-carbonitrile (2.5 g, 17.34 mmol) in MeCN (69 mL) was cooled to 0° C. and treated with NBS (3310 mg, 17.7 mmol). The light red reaction mixture was stirred at room temperature for 20 minutes, and was then poured into saturated aqueous sodium bicarbonate (200 mL). The product was extracted with ethyl acetate (2×200 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified using flash chromatography eluting with heptanes/ethyl acetate (95:5 to 60:40) to give the title compound (2.26 g, 58%) as a white solid. MS (ES−): 219.0, 221.0 (79Br M+H, 81Br M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:35]=[CH:34][C:9]([C:10]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C@H:15]([N:22]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:23](=[O:25])[CH3:24])[CH2:14][C@@H:13]2[CH3:33])=[O:11])=[CH:8][CH:7]=1.Br[CH2:37][C:38]([O:40]CC)=[O:39].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:23]([N:22]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C@H:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]([C:10]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][CH2:37][C:38]([OH:40])=[O:39])=[CH:35][CH:34]=2)=[O:11])[C@@H:13]([CH3:33])[CH2:14]1)(=[O:25])[CH3:24]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCN)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCNCC(=O)O)cc2)c2ccccc21
Temperature: 50 °C

Procedure:
{[3-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)propyl]amino}acetic acid was prepared from (2S,4R)-N-{1-[4-(3-amino-propoxy)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-N-(4-chloro-phenyl)-acetamide. (2S,4R)-N-{1-[4-(3-amino-propoxy)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-N-(4-chloro-phenyl)-acetamide (0.036 g, 0.07 mmol) was dissolved in dimethylformamide, ethyl bromoacetate (0.008 mL, 0.07 mmol) and potassium carbonate (0.021 g, 0.14 mmol) were added. The reaction was heated to 50° C. for 17 h. The reaction was concentrated down and purified using 50% ethyl acetate/50% hexane to 100% ethyl acetate.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:70][CH:71]([CH3:75])[C@H:72]([NH2:74])[CH3:73]>CN(C=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:74][C@H:72]([CH3:73])[CH:71]([CH3:75])[CH3:70])=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CC(C)[C@@H](C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)N[C@H](C)C(C)C)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and (2R)-3-methyl-2-butanamine (10.5 uL, 0.09 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (14 mg, 40%). LC-MS m/z 591 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH2:7][O:6][C:5](=[O:8])[CH:4]=1.[CH3:9][O:10][P:11]([O:14]C)[O:12][CH3:13]>>[O:8]=[C:5]1[CH:4]=[C:3]([CH2:2][P:11](=[O:14])([O:12][CH3:13])[O:10][CH3:9])[CH2:7][O:6]1
Reactant: O=C1C=C(CBr)CO1
Reactant: COP(OC)OC
Product: COP(=O)(CC1=CC(=O)OC1)OC

Procedure:
A solution 15.0 g of 4-bromomethyl-2-oxo-[5H]-furan (Martin R. et al., Helv.Chim. Acta, 1976, 59, 2724) in 100 ml of trimethylphosphite was refluxed for 2 hrs, while a stream of nitrogen was bubbled vigorously into the solution. The mixture was then evaporated to dryness and the residue was purified by chromatography (SiO2 ; ethyl acetate/diethylether 50/50) to give 16.0 g of dimethyl (2-oxo-[5H]-4-furyl)methyl-phosphonate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9]O.P(Br)(Br)[Br:12]>COCCOC.O>[Br:12][CH2:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: OCc1cc(F)ccc1Cl
Reactant: BrP(Br)Br
Solvent: O
Solvent: COCCOC
Product: Fc1ccc(Cl)c(CBr)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2-chloro-5-fluorophenyl)methanol (24, 25.5 g, 159 mmol) in dry DME (200 mL) at 0° C. was added a solution of PBr3 (25.8 g, 95.2 mmol) in dry DME (150 mL) dropwise. The mixture was then slowly warmed up to RT and stirred at RT for another 3 h. The mixture was diluted with water (300 mL), and extracted with 1:1 petroleum-ether-EtOAc (200 mL×2). The combined extracts were washed with saturated NaHCO3 and brine, dried over MgSO4, and concentrated to give 2-(bromomethyl)-1-chloro-4-fluorobenzene (25).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@H:24]1[C@@H:28]([N:29]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:27][C@@H:26]([C:40]([O:42][CH3:43])=[O:41])[CH2:25]1)[N:17]=[CH:16]2.O.NN>CCO>[NH2:29][C@@H:28]1[C@H:24]([NH:23][C:18]2[N:17]=[CH:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:3]4[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[Cl:1])[CH:14]=3)[N:19]=2)[CH2:25][CH:26]([C:40]([O:42][CH3:43])=[O:41])[CH2:27]1
Reactant: COC(=O)[C@H]1C[C@@H](Nc2ncc3cc(-c4c(Cl)c(OC)cc(OC)c4Cl)ccc3n2)[C@@H](N2C(=O)c3ccccc3C2=O)C1
Agent: NN
Solvent: CCO
Solvent: O
Product: COC(=O)C1C[C@H](N)[C@H](Nc2ncc3cc(-c4c(Cl)c(OC)cc(OC)c4Cl)ccc3n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
(1S,3R,4S)-methyl 3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-4-(1,3-dioxoisoindolin-2-yl)cyclopentanecarboxylate (0.500 g, 0.805 mmol) was taken up in EtOH (20 ml) and hydrazine monohydrate (0.079 ml, 1.61 mmol) was added. The reaction was stirred overnight at room temperature. A white precipitate was filtered off and solvent was removed under reduced pressure. The precipitate was triturated with ether, followed by removal of the solvent under reduced pressure to give methyl (3S,4R)-3-amino-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)cyclopentane-1-carboxylate (0.395 g, 0.805 mmol) in quantative yield, which was carried on without further purification. MS (ES+) C23H24Cl2N4O4 requires: 491, found: 492 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:3]=1[C:4]([N:6]=[S:7]([CH2:10][CH3:11])[CH2:8][CH3:9])=[O:5].[Cl:18][C:19]1[C:20]([N:25]2[C:29]([C:30](Cl)=[O:31])=[CH:28][C:27]([C:33]([F:36])([F:35])[F:34])=[N:26]2)=[N:21][CH:22]=[CH:23][CH:24]=1>N1C=CC=CC=1>[Cl:18][C:19]1[C:20]([N:25]2[C:29]([C:30]([NH:1][C:2]3[C:3]([C:4](=[O:5])[N:6]=[S:7]([CH2:8][CH3:9])[CH2:10][CH3:11])=[CH:12][C:13]([Cl:17])=[CH:14][C:15]=3[Cl:16])=[O:31])=[CH:28][C:27]([C:33]([F:36])([F:34])[F:35])=[N:26]2)=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCS(CC)=NC(=O)c1cc(Cl)cc(Cl)c1N
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Solvent: c1ccncc1
Product: CCS(CC)=NC(=O)c1cc(Cl)cc(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 1 h
Yield: 28.4 %

Procedure:
To a solution of 2-amino-3,5-dichloro-N-(diethyl-sulfanylidene)benzamide (8.82 g, 25.6 mmol) in pyridine (30 mL) was added N,N-dimethylamino pyridine (312 mg, 2.56 mmol, 10.0 mol %). At 90° C., a solution of 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carbonyl chloride (10.90 g, 29.12 mmol, 1.100 equiv.) in pyridine (50 mL) was added dropwise and the mixture was stirred for 1 h. The mixture was cooled and concentrated in vacuum. Water was added and the mixture was extracted with ethyl acetate. Combined organic layers were washed with water and brine, dried over sodium sulphate, filtered and concentrated in vacuum. Flash-chromatography on silica gel yielded the title compound (4.12 g, 28%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[N:11]([CH3:17])[C:12](=[O:16])[O:13][CH2:14][CH3:15].[OH:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>>[NH2:23][C:22]1[CH:24]=[CH:25][C:19]([O:18][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=2[N:11]([CH3:17])[C:12](=[O:16])[O:13][CH2:14][CH3:15])=[CH:20][CH:21]=1
Reactant: Nc1ccc(O)cc1
Reactant: CCOC(=O)N(C)c1c(Cl)ccnc1[N+](=O)[O-]
Product: CCOC(=O)N(C)c1c(Oc2ccc(N)cc2)ccnc1[N+](=O)[O-]
Yield: 11.2 %

Procedure:
Method A was used with ethyl 4-chloro-2-nitropyridin-3-yl-methyl-carbamate (400 mg, 1.5 mmol) and 4-hydroxyaniline (196 mg, 1.8 mmol) to afford the title compound (56 mg, 12%) after purification by column chromatography, eluent gradient DCM to DCM:AcOEt 1:1. 1H-NMR (δ, ppm, DMSO-d6): 1.06+1.23 (t+t, rotamers, 3H, CH3,Et), 3.18+3.23 (s+s, rotamers, 3H, NCH3), 4.04+4.12 (q+q, rotamers, 2H, CH2,Et), 5.44 (s, 2H, NH2,Ph), 5.97 (s, 2H, NH2,Py2), 6.92 (d, 2H, Harom,Ph,3+5, J=8.79 Hz), 6.92 (d, 2H, Harom,Ph,2+6, J=8.82 Hz), 7.04 (d, 1H, HPy,5, J=5.60 Hz), 8.33 (d, 1H, HPy,6, J=5.59 Hz). LC-MS (m/z): 332 (M+, 100).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:54])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3].[C:55]([O:59][C:60]([NH:62][C@H:63]([C:65]([NH:67][C@H:68]([C:70](O)=[O:71])[CH3:69])=[O:66])[CH3:64])=[O:61])([CH3:58])([CH3:57])[CH3:56]>ClCCl>[C:55]([O:59][C:60]([NH:62][C@H:63]([C:65]([NH:67][C@H:68]([C:70]([NH:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:54])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3])=[O:71])[CH3:69])=[O:66])[CH3:64])=[O:61])([CH3:58])([CH3:57])[CH3:56]
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)N
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Yield: 75 %

Procedure:
from N-(2-L-alanyl-amino-2-deoxy-β-D-glucopyranosyl)-N-octadecyl-oleamide and N-tert-butyloxycarbonyl-L-alanyl-L-alanine. Yield 75%. [α]D =+17.9° (c=0.96, dichloromethane).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1>CO>[CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=[CH:20][CH:19]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Reactant: Nc1ccnc2ccccc12
Solvent: CO
Product: O=C(Nc1ccnc2ccccc12)c1cc(NC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 4-aminoquinoline (Tyger), the title compound was obtained as a red solid after trituration in methanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:19])CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([F:19])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Br)cc2)CCC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: FC1(c2ccc(Br)cc2)CCC1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 64.1 %

Procedure:
To a solution of 5.66 g of 1-(4-bromophenyl)-cyclobutanol (24.92 mmol, described in example S2-A) in 70 ml DCM were added 4.23 g of (diethylamino)sulfur trifluoride (95%, 24.92 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 35 min, then sat. NaHCO3— solution was added and the resulting mixture was extracted with DCM. The combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give a residue which was purified by flash column chromatography (100% pentane) to give 1-bromo-4-(1-fluoro-cyclobutyl)-benzene (3.66 g, 64%) as a colorless liquid.
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH2:11][CH3:12])[C:4](=[O:9])[C:5]([O:7]C)=[O:6])[CH3:2].[OH-].[Na+]>CO.O>[CH2:1]([N:3]([CH2:10][CH2:11][CH3:12])[C:4](=[O:9])[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCCN(CC)C(=O)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCN(CC)C(=O)C(=O)O
Yield: 38 %

Procedure:
870 mg (5.0 mmole) of methyl N-ethyl-N-n-propyloxamate was dissolved in 20 ml of methanol. The resulting mixture was stirred under ice-cooling over an ice bath. 594 mg (15 mmole) of sodium hydroxide was dissolved in 10 ml of water and the resulting solution was added dropwise to said mixture. After completion of the dropwise addition, the ice bath was removed and the reaction mixture was stirred for 1 hour at room temperature. After adding 10 ml of 1N aqueous solution of hydrochloric acid, the solvent was distilled off from the reaction solution under reduced pressure. The residue was added with 80 ml of ethanol and the insoluble solids as formed were filtered off. The organic solution after the filtration was concentrated to afford 305 mg (1.9 mmole) of N-ethyl-N-n-propyloxamic acid as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH3:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([CH3:13])[NH:9]1>>[CH3:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([CH3:13])[N:9]1[CH2:2][C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)CBr
Reactant: C[C@H]1CC[C@H](C)N1
Product: COC(=O)CN1[C@@H](C)CC[C@@H]1C

Procedure:
By a procedure analogous to Example 6, methyl bromoacetate is reacted with trans-2,5-dimethylpyrrolidine (J. Amer. Chem. Soc. 1951, 73, 5230) to give methyl (trans-2,5-dimethylpyrrolidin-1-yl)acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7](=O)[CH3:8].[CH2:13]([O:15][C:16](=[O:21])[CH2:17][C:18](=[NH:20])[NH2:19])[CH3:14].C(O)(C)C>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[CH:5]([C:4]2[CH:10]=[CH:11][CH:12]=[C:2]([Cl:1])[CH:3]=2)[CH:6]=[C:7]([CH3:8])[NH:20][C:18]=1[NH2:19])=[O:21])[CH3:14]
Reactant: CCOC(=O)CC(=N)N
Reactant: CC(=O)C=Cc1cccc(Cl)c1
Solvent: CCO
Solvent: CC(C)O
Product: CCOC(=O)C1=C(N)NC(C)=CC1c1cccc(Cl)c1
Yield: 56 %

Procedure:
After heating a solution of 18.1 g of 3-chlorobenzylideneacetone and 13.0 g of amidinoacetic acid ethyl ester in 150 ml of ethanol for 3 hours, 2-amino-6-methyl-4-(3-chlorophenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester of melting point 140°C (isopropanol) is obtained. Yield: 56 percent of theory.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:23])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:24]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH2:25][CH2:26][CH3:27]>>[CH2:24]([N:28]1[CH2:33][CH2:32][N:31]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:23])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH3:22])(=[O:19])=[O:20])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:30][CH2:29]1)[CH2:25][CH2:26][CH3:27]
Reactant: CNS(=O)(=O)c1ccc(NC(=O)Nc2cccc(C#N)c2)cc1
Reactant: CCCCN1CCNCC1
Product: CCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NC)cc3)c2)CC1
Yield: 1 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-methylbenzenesulfonamide following procedure C and using 2.2 equivalents of n-butylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:19]([O:21][C:22](=[O:32])[CH2:23][NH:24][CH:25]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH3:20].C(OCC)(=O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:19]([O:21][C:22](=[O:32])[CH2:23][N:24]([C:16](=[O:18])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH:25]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH3:20]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)CNC1CCCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C1CCCCCC1
Temperature: 25 °C

Procedure:
CBZ-L-Valine (10.05 g, 0.04 mol) was dissolved in CH2Cl2 (300 mL) and the following reagents were added in equal molar amounts in the stated order: 4-Dimethylaminopyridine, ethyl-N-(cycloheptyl)glycinate and WSCDI. Used additional 100 mL CH2Cl2 to wash down the reagents. The reaction mixture was allowed to stir at room temperature over night. Evaporation of the solvent yielded a viscous semisolid which was treated with ethyl acetate and then 1N HCl and separated. The organic extract was washed with 1N HCl followed by 5% aqueous Na2CO3 and saturated aqueous NaCl-solution. After drying over MgSO4, filtration and evaporation under reduced pressure yielded the titled compound as an oil (11.2 g) which was used as is for saponification.
Reaction SMILES: [OH:1][C:2]1[C:10](=[O:11])[N:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH:17](N(CC)C(C)C)(C)C.C[Si](C=[N+]=[N-])(C)C>CO.C(#N)C>[CH3:17][O:1][C:2]1[C:10](=[O:11])[N:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1=C(O)C(=O)N2CCCCC12
Reactant: CCN(C(C)C)C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC#N
Product: CCOC(=O)C1=C(OC)C(=O)N2CCCCC12
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
At 0° C. to a solution of Intermediate 22C (30 mg, 0.13 mmol) and N,N-diisopropylethylamine (35 μL, 0.20 mmol) in methanol (0.15 mL) and acetonitrile (1.35 mL) was added (trimethylsilyl)diazomethane (0.10 mL, 2.0 M in diethyl ether, 0.20 mmol). The reaction mixture was stirred at rt for 2 h, concentrated and the residue was purified by ISCO chromatography (ethyl acetate/hexane 0-100%, column, 4 g) to afford Intermediate 22D (20 mg, 63%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.25-1.41 (5H, m), 1.50-1.61 (1H, m), 1.76-1.98 (2H, m), 2.44-2.52 (1H, m), 2.79-2.90 (1H, m), 3.95 (1H, dd, J=11.4, 3.6 Hz), 4.23-4.38 (6H, m).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@@H:3]([C:14]([OH:16])=[O:15])[NH:2]1.O=S(Cl)Cl.[CH2:21](O)[CH3:22]>>[CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@@H:3]([C:14]([O:16][CH2:21][CH3:22])=[O:15])[NH:2]1
Reactant: CCO
Reactant: O=C(O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Yield: 68 %

Procedure:
(3S)-1,2,3,4-Tetrahydro-β-carboline-3-carboxylic acid (32.5 g) is suspended in ethanol (500 ml) and thereto is added dropwise SOCl2 (13.0 ml) at 0° C. The mixture is refluxed for 8 hours and then distilled to remove the solvent. The residue is dissolved in water and is made alkaline with NH4OH and extracted with ethyl acetate. The extract is dried and distilled to remove the solvent. The residue is recrystallized from ethyl acetate-isopropyl ether to give the title compound (24.86 g, 68%) as colorless needles, m.p. 135°-137° C.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([S:14][C:15]1[N:16]=[C:17]2[S:22][CH:21]([CH3:23])[C:20](=[O:24])[N:18]2[N:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S(OC)(OC)(=O)=O>CN(C)C=O>[CH2:7]([S:14][C:15]1[N:16]=[C:17]2[S:22][C:21]([CH3:23])=[C:20]([O:24][CH3:1])[N:18]2[N:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC1Sc2nc(SCc3ccccc3)nn2C1=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COc1c(C)sc2nc(SCc3ccccc3)nn12
Reaction time: 0.17 h

Procedure:
Potassium t-butoxide (2.6 g) was added to a solution of the product of stage (b) in dimethylformamide (30 ml) with stirring and cooling. After 10 minutes, this solution was treated with dimethyl sulphate (2.8 g) and stirring was continued for 4 hours. Addition to ice/water/ether and filtration gave 2.3 g of desired product, mp 101°-103° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.Cl.[Cl:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O>[ClH:13].[N:16]1([CH2:15][CH2:14][O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 250 mL 3 neck flask with mechanical stirring and condenser, and a heating apparatus consisting of an RTD probe in the flask hooked via a temperature controller to a heating mantle and under nitrogen atmosphere, the following was added: 7.61 g of methyl 4-hydroxybenzoate, 11.05 g of β-chloroethyl-piperidine hydrochloride, 16.59 g of powdered potassium carbonate and 60 mL of ethyl acetate. The mixture was heated slowly to reflux. After overnight reflux, the mixture was cooled to ambient temperature, after which 60 mL of deionized water was added. The aqueous layer was separated and discarded. The organic layer was extracted with 4N hydrochloride (3 aliquots of 20 mL). The combined acid extracts were heated to reflux. After 1 hour at reflux, HPLC indicated the saponification to be 609 complete. After 4 hours, the reaction was near 100% complete. The mixture was cooled to 0° C.-5° C. and stirred. The resulting crystals were filtered, rinsed with acetone and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[C:24]([O:30][CH2:31][CH3:32])=[N:25][C:26]([CH3:29])=[N:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1.[N:33]1([C:39](=[O:47])[CH2:40][N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:44]3[CH2:45][CH2:46][N:41]([CH2:40][C:39]([N:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)=[O:47])[CH2:42][CH2:43]3)=[O:21])[C:10]([C:23]3[C:24]([O:30][CH2:31][CH3:32])=[N:25][C:26]([CH3:29])=[N:27][CH:28]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1nc(C)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Product: CCOc1nc(C)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1

Procedure:
cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 16) was reacted with 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) to give cis-2-{4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C33H38N7O4Cl2 [(M+H)+] 666.2357, observed 666.2358.