Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[O:19])[NH:9]2)[CH:7]=1.C(N(CC)CC)C.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[CH:37])[CH:31]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[Cl:29][C:30]1[CH:31]=[C:32]([C:36]#[C:37][C:2]2[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]3([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[O:19])[NH:9]3)[CH:7]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(Br)ccc2F)C1(F)F
Reactant: C#Cc1cccc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)OCC(=O)N[C@](C)(c2cc(C#Cc3cccc(Cl)c3)ccc2F)C1(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.6 %

Procedure:
A dried pressure tube was charged with (R)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one (intermediate B6.1) (250 mg, 622 μmol) and dimethylformamide (2 ml). The solution was flushed with argon, thereafter, successively bis(triphenylphosphin)palladium(II)chloride (31.2 mg, 43.5 μmol), triphenylphoshine (3.26 mg, 12.4 μmol), triethylamine (126 mg, 1.24 mmol), 1-chloro-3-ethynylbenzene (175 mg, 1.24 mmol), and copper(i) iodide (3.6 mg, 18.7 μmol) were added. The tube was sealed and the reaction mixture stirred at room temperature for 10 minutes, then it was heated at 60° C. for 16 hours. For the workup, the reaction mixture was cooled and evaporated at reduced pressure. The residue was directly purified by chromatography on an amine-silica phase using a gradient of heptane/ethyl acetate=100:0 to 60:10 as the eluent. The (R)-5-[5-(3-chloro-phenylethynyl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (235 mg, 90% yield) was obtained as a green foam. MS (ISP): m/z=422.1 [M+2+H]+ and 424.2 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:13]=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].Br[C:18]1[S:22][C:21]([C:23]2[N:27]([CH2:28][C:29]([F:32])([F:31])[F:30])[N:26]=[CH:25][N:24]=2)=[CH:20][C:19]=1[Cl:33].CC([O-])=O.[K+]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].CC([O-])=O.CC([O-])=O.[Pd+2].C(OP(OCC(Br)CBr)(OCC(Br)CBr)=O)C(Br)CBr.CN1C(=O)CCC1>[Cl:33][C:19]1[CH:20]=[C:21]([C:23]2[N:27]([CH2:28][C:29]([F:31])([F:30])[F:32])[N:26]=[CH:25][N:24]=2)[S:22][C:18]=1[C:13]1[N:8]2[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]2=[N:15][C:14]=1[CH3:16]
Reactant: CCC(CC)c1cc(C)nn2cc(C)nc12
Reactant: FC(F)(F)Cn1ncnc1-c1cc(Cl)c(Br)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN1CCCC1=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ncnn4CC(F)(F)F)cc3Cl)c(C)nc12
Yield: 78.1 %

Procedure:
Using a procedure analogous to Example 231, 8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.25 g, 1.14 mmol), 5-(5-bromo-4-chloro-thiophen-2-yl)-1-(2,2,2-trifluoro-ethyl)-1H-[1,2,4]triazole (0.47 g, 1.37 mmol), KOAc (0.56 g, 5.60 mmol), TBABr (0.37 g, 1.14 mmol), and NMP (3 mL), Pd(OAc)2 (0.013 g, 0.057 mmol) and TDBPP (0.037 g, 0.057 mmol) furnish the title compound (0.43 g, 0.89 mmol, 78%). 1H NMR (CDCl3), δ 0.88 (t, J=7.5 Hz, 6H), 1.75-1.92 (m, 4H), 2.52 (s, 3H), 2.53 (s, 3H), 3.27-3.36 (m, 1H), 4.98 (q, J=15.7, 7.9 Hz, 2H), 6.74 (s, 1H), 7.45 (s, 1H), 8.03 (s, 1H). LC/MS (m/z): calcd. for C21H22ClF3N6S (M+H)+: 483.1; found: 483.2.
Reaction SMILES: [O:1]=[C:2]1[C:10](=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][C:13]1[O:17][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][CH:14]=1.[F:23][C:24]([F:33])([F:32])[C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>C(Cl)(Cl)Cl>[O:1]=[C:2]1[N:3]([CH2:12][C:13]2[O:17][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][CH:14]=2)[C:4]2[C:9](/[C:10]/1=[N:28]/[C:27]1[CH:29]=[CH:30][CH:31]=[C:25]([C:24]([F:23])([F:32])[F:33])[CH:26]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CCOC(=O)c1ccc(CN2C(=O)C(=O)c3ccccc32)o1
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(CN2C(=O)/C(=N\c3cccc(C(F)(F)F)c3)c3ccccc32)o1
Temperature: 140 °C
Yield: 22.6 %

Procedure:
A mixture of ethyl 5-[(2,3-dioxo-2,3-dihydro-1H-indol-1-yl)methyl]-2-furoate (60 mg, 0.200 mmol) and 3-trifluoromethylaniline (32 mg, 0.200 mmol) was heated at 140° C. for 2 h. The residue was dissolved in CHCl3 (1 mL and purified by preparative TLC using EtOAc/hexane (6:4), giving the desired product (20 mg, 23%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:34])[NH:27][CH2:28][CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:22][CH:21]=1)=[O:18]>ClCCl>[CH3:31][C:30]([CH3:33])([CH3:32])[CH2:29][CH2:28][NH:27][C:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][C:17]([N:11]2[CH2:12][CH2:13][N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[CH2:9][CH2:10]2)=[O:18])=[CH:25][CH:24]=1)=[O:34]
Reactant: COc1ccc(CN2CCNCC2)cc1
Reactant: CC(C)(C)CCNC(=O)c1ccc(OC(=O)Cl)cc1
Solvent: ClCCl
Product: COc1ccc(CN2CCN(C(=O)Oc3ccc(C(=O)NCCC(C)(C)C)cc3)CC2)cc1
Reaction time: 16 h

Procedure:
The title product was prepared from 1-(4-methoxy-benzyl)-piperazine (0.35 mmol) was dissolved in dichloromethane (5 ml). 4-(3,3-Dimethyl-butylcarbamoyl)-phenyl chloroformate (0.35 mmol) was added at room temperature. The reaction mixture was stirred for 16 h and evaporated to dryness and subjected to preparative HPLC (metod C). (54%, colourless semi-crystaline oil). HPLC-MS m/z=454.3 (M+1), Rt: 2.78 min.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:26])[C:14]([C:15]3[S:19][C:18]([C:20]4[N:21]([CH3:25])[N:22]=[CH:23][N:24]=4)=[N:17][CH:16]=3)=[C:10]2[N:9]=[C:8]([CH3:27])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[Cl:28]N1C(=O)CCC1=O>ClCCl.C(#N)C>[Cl:28][C:16]1[N:17]=[C:18]([C:20]2[N:21]([CH3:25])[N:22]=[CH:23][N:24]=2)[S:19][C:15]=1[C:14]1[C:13]([CH3:26])=[N:12][N:11]2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][C:8]([CH3:27])=[N:9][C:10]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCC(CC)c1cc(C)nc2c(-c3cnc(-c4ncnn4C)s3)c(C)nn12
Solvent: ClCCl
Solvent: CC#N
Product: CCC(CC)c1cc(C)nc2c(-c3sc(-c4ncnn4C)nc3Cl)c(C)nn12
Yield: 74 %

Procedure:
Stir a mixture of 7-(1-ethyl-propyl)-2,5-dimethyl-3-[2-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiazol-5-yl)-pyrazolo[1,5-a]pyrimidine (20 mg, 0.052 mmol) and N-chlorosuccinimide (7.6 mg, 0.0569 mmol) in dichloromethane (0.5 mL) and acetonitrile (0.5 mL) at room temperature overnight in a vial. Concentrate to a residue. Purify by flash chromatography, eluting with hexanes and then with hexanes/ethyl acetate (10/1.5) to give the title compound (16 mg). ES/MS m/z (35Cl) 416.0 (M+1)+.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[OH-].[Na+].[N:9]1([C:15](Cl)=[O:16])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.Cl>O1CCCC1.O>[N:9]1([C:15]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:16])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: C[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](NC(=O)N1CCOCC1)C(=O)O
Temperature: 0 °C
Yield: 39.6 %

Procedure:
4 g(50 mmol) of L-alanine and 2 g(50 mmol) of NaOH were added to 30 ml of distilled water. The mixture was cooled to 0° C. and then stirred vigorously. To the mixture was added slowly a solution of 7.1 g(50 mmol) of morpholinecarbonyl-chloride in 30 ml of tetrahydrofuran, while adjusting the whole mixture to pH 8.5-pH 9.5 with the addition of 0.05N NaOH. After the reaction was completed, the reaction mixture was acidified to pH 2 with 6N HCl. The reaction mixture was extracted with a mixed solvent of ethyl acetate and THF(1:1) (30 ml×3) and the organic layer was concentrated under a reduced pressure to give 4 g of the title compound(yield: 40%).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:28][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[C:15]([O:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]4)=[N:16][CH:17]=[CH:18][CH:19]=3)[C:7]=2[C:6]=1[CH3:29])=[O:4].[OH-].[Li+].C1COCC1.Cl>O.CO>[OH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([O:20][C:15]2[C:14]([NH:13][C:12]3[C:7]4[C:6]([CH3:29])=[C:5]([C:3]([OH:4])=[O:2])[S:28][C:8]=4[N:9]=[CH:10][N:11]=3)=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:22][CH2:23]1
Reactant: COC(=O)c1sc2ncnc(Nc3cccnc3O[C@H]3CC[C@H](O)CC3)c2c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3O[C@H]3CC[C@H](O)CC3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 1.541 g 4-[2-(trans-4-hydroxy-cyclohexyloxy)-pyridine-3-ylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methylester, 2.00 g lithium hydroxide, 13.3 ml THF, 13.3 ml MeOH and 13.3 ml water was stirred at rt overnight. Then the mixture was acidified by addition of hydrochloric acid and extracted with DCM. The organic phase was dried, filtered and the filtrate was concentrated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].S(Cl)(Cl)=O.[CH3:20]O>>[F:1][C:2]1[CH:3]=[C:4]([CH:11]([CH3:15])[C:12]([O:14][CH3:20])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(C)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(3-fluoro-4-nitrophenyl)propanoic acid in methanol was added thionyl chloride (2.5 equiv.) at 0° C. and removed ice-bath. Reaction mixture was stirred at room temperature. After 2 h, dry over magnesium sulfate and evaporate solvent and purified by column chromatography (ethylacetate-hexane) to obtain methyl 2-(3-fluoro-4-nitrophenyl)propanoate.
Reaction SMILES: [F:1][C:2]1[CH:32]=[C:31]([N+:33]([O-])=O)[CH:30]=[CH:29][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]([NH:16][CH:17]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]3)=[O:15])[S:13][C:6]=12>CO.[OH-].[OH-].[Pd+2]>[NH2:33][C:31]1[CH:30]=[CH:29][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]([NH:16][CH:17]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:18]4)=[O:15])[S:13][C:6]=23)=[C:2]([F:1])[CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc3nccc(Oc4ccc(N)cc4F)c3s2)C1
Reaction time: 1 h
Yield: 70.5 %

Procedure:
A mixture of 289 (90 mg, 0.18 mmol) and Pd(OH)2 in MeOH (2 mL) was hydrogenated at 1 atm for 1 h. The catalyst was filtered off and the filtrate was concentrated to afford the title compound 290 (60 mg, 70% yield) as a yellowish solid. MS (m/z): 473.2 (M+H) (found).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]3[CH2:23][N:22](C(OC(C)(C)C)=O)[C@H:21]([C:31](=[O:43])[NH:32][C@H:33]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[CH2:36][CH2:35][CH2:34]4)[CH2:20]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C@H:33]1([NH:32][C:31]([C@H:21]2[NH:22][CH2:23][C@@H:19]([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]3[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]4[C:13]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[CH2:20]2)=[O:43])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1CN[C@H](C(=O)N[C@@H]2CCCc3ccccc32)C1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of (2S,4S)-tert-butyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidine-1-carboxylate (6.70 g, 11.5 mmol) in CH2Cl2 (50 mL) at rt was added TFA (15 mL) dropwise. The reaction mixture was stirred at rt for 2 h, and then concentrated in vacuo. The residue was dissolved in CH2Cl2 (200 mL) and washed with aq. K2HPO4 solution (50 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give crude (9H-fluoren-9-yl)methyl ((3S,5S)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)carbamate (5.54 g, 100%), which was used directly in the next step.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[C:4]([C:3]1[C:2]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:20][CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:26])[CH2:23][CH2:24]3)=[CH:17][CH:18]=2)=[N:10][C:9]([Cl:11])=[CH:8][CH:7]=1)(=[O:5])[NH2:6]
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Reactant: Nc1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: NC(=O)c1ccc(Cl)nc1Nc1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
To a mixture of 2,6-dichloronicotinamide (3 g, 15.71 mmol) and benzyl 4-(4-aminophenyl)piperazine-1-carboxylate (5.38 g, 17.28 mmol) in THF (100 mL) was added lithium bis(trimethylsilyl)amide (55.0 mL, 55.0 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 20 min. and at rt for 2 h. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic layers were washed with water and concentrated. The residue was purified by MPLC chromatography (ISCO, 6% NH4OH/MeOH/CH2Cl2, 40 g+12 g stacked column) to give 6.8 g of benzyl 4-(4-(3-carbamoyl-6-chloropyridin-2-ylamino)phenyl)piperazine-1-carboxylate as a brown solid. LCMS: (M+H)+=466.2, 468.2 (Cl pattern).
Reaction SMILES: ClCC(C)(C1C=CC=CC=1)C.[CH3:12][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH3:24])([CH3:23])[CH2:15][NH:14]1.C1C2C(=CC=CC=2)C=CN=1.[Cl:35][CH:36]([Cl:40])[C:37](Cl)=[O:38].[OH-].[Na+]>C(Cl)Cl.C(#N)C>[Cl:35][CH:36]([Cl:40])[C:37]([N:14]1[CH2:15][C:16]([CH3:23])([CH3:24])[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]1[CH3:12])=[O:38]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC1NCC(C)(C)c2ccccc21
Agent: CC(C)(CCl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: ClCCl
Solvent: c1ccc2cnccc2c1
Product: CC1c2ccccc2C(C)(C)CN1C(=O)C(Cl)Cl

Procedure:
By procedures described in Example 1 (Method B), 1-chloro-2-methyl-2-phenyl-propane and acetonitrile were converted to 1-methyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline. A reaction vessel was charged with 4.0 g of this isoquinoline compound and 50 ml methylene chloride. With this mixture stirred, 2 ml dichloroacetyl chloride was added dropwise to the mixture. The mixture was stirred for 20 minutes and then made alkaline with aqueous sodium hydroxide. The organic extract was dried with magnesium sulfate and stripped of solvent. The residue was recrystallized from ethanol to provide 4.2 g of a white cubic-crystal product having the elemental analysis reported in Table I.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1C(=O)C2=CC=CC=C2C1=O)=[N:8]3.O.NN>C(O)C>[NH2:18][CH2:17][CH2:16][CH2:15][CH2:14][S:13][C:7]1[C:6]2=[C:2]([CH3:1])[N:3]=[C:4]3[N:5]2[C:9](=[CH:10][CH:11]=[CH:12]3)[N:8]=1
Reactant: Cc1nc2cccc3nc(SCCCCN4C(=O)c5ccccc5C4=O)c1n23
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1nc2cccc3nc(SCCCCN)c1n23
Yield: 72.6 %

Procedure:
To a suspension of 3.90 g (10.0 mmol) of 3-methyl-[4-(phthalimido)butan-1-ylthio]-1,4,7b-triazacyclopent[cd]indene in 70 ml of ethanol was added 1.50 g (30.0 mmol) of hydrazine monohydrate. The mixture was heated for 2 hours under reflux. After cooling the resulting precipitates were filtered off. The filtrate was concentrated to give the residue, water was added, extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, then the solvent was distilled off to give 1.89 g of the desired compound (72.7%, pale brown solid)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[C:15]([C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[S:30](Cl)(=[O:32])=[O:31])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[OH-].[Na+].C(Cl)Cl>[C:15]([C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[S:30]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:32])=[O:31])(=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NCCCCCCCCCCC(=O)O
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1S(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(O)CCCCCCCCCCNS(=O)(=O)c1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
24.16 g (0.12 mole) of 11-aminoundecanoic acid in 250 ml of normal caustic soda are added to 37.9 g (0.12 mole) of 2-benzoyl-4-chlorobenzenesulphonyl chloride in 250 ml of methylene chloride, at 0° C. and with stirring.
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:2].[CH2:12]([N:19]=[C:20]=[S:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[CH2:12]([NH:19][C:20](=[S:21])[NH:11][C:8]1[CH:9]=[CH:10][C:5]([NH:4][NH:3][CH:1]=[O:2])=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: S=C=NCc1ccccc1
Reactant: Nc1ccc(NNC=O)cc1
Solvent: CCO
Product: O=CNNc1ccc(NC(=S)NCc2ccccc2)cc1

Procedure:
1-Formyl-2-(4-aminophenyl)hydrazine (1.51 g, 0.01 mole) and benzyl isothiocyanate (1.49 g. p. 0.01 mole) were mixed in ethanol (30 ml) and the mixture was refluxed for 20 minutes. The product separated from solution as a white solid. The reaction mixture was chilled in ice and the solid was collected by filtration. The product was washed thoroughly with ether and then was dried. Yield 2.5 g (83%), m.p. 152°-154° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(Cl)(Cl)Cl>[CH2:22]([O:21][C:19](=[O:20])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Br)cn1)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 2-amino-5-bromopyridine (6.92 g, 40 mmol) and 6.22 g (48 mmol) of diisopropylethylamine in 50 mL of chloroform was added dropwise to a solution of 8.19 g (48 mmol) of benzyl chloroformate in 20 mL of chloroform at about 0° C., with stirring. A voluminous white precipitate formed. After about 15 minutes, the mixture was filtered and the precipitate was washed three times with chloroform and dried to give 2.70 g of the title product, mp 184° C. (dec) (recrystallization solvent=2-propanol). 1H nmr (dimethylsulfoxide-d6): δ=10.48 (br s, 1 H), 8.37 (d, 1 H), 7.98 (d of d, 1 H), 7.81 (d, 1 H), 7.40 (m, 5 H), 5.17 (s, 2 H); ms (NH3Cl): m/z=307, 309 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19](=[O:28])(=[O:27])[CH2:18][CH2:17]2)[CH:3]=1.[O:29]1[CH2:32][C:31]([CH2:35][NH2:36])([CH2:33][NH2:34])[CH2:30]1>>[NH2:34][CH2:33][C:31]1([CH2:35][NH:36][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=3)[N:5]=[C:4]([N:16]3[CH2:22][C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[S:19](=[O:28])(=[O:27])[CH2:18][CH2:17]3)[CH:3]=2)[CH2:32][O:29][CH2:30]1
Reactant: NCC1(CN)COC1
Reactant: COC(=O)c1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: COC(=O)c1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(CN)COC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 6-1 in Scheme 52 by using methyl 4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylate and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 497, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.57 (d, 1 H), 7.95 (d, 1 H), 7.85 (m, 2 H), 7.71 (t, 1 H), 7.61 (m, 1 H), 7.46-7.38 (m, 2 H), 6.18 (s, 1 H), 5.07 (s, 2 H), 4.32 (m, 6 H), 3.80 (s, 3 H), 3.55 (m, 4 H), 2.95 (s, 2 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(N)cc2)COC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(Nc3ccc(Cl)cc3)cc2)COC1(C)C
Temperature: 110 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
In a pressure tube, (S)-4-[2-(4-amino-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.3 g), 1-bromo-4-chlorobenzene (215 mg) and cesium carbonate (458 mg) were combined with dioxane (3 ml) to give a yellow suspension. The mixture was degassed by bubbling through argon for several minutes. Xantphos (32.5 mg) and tris(dibenzylideneacetone)dipalladium chloroform complex (29.1 mg) were then added and the tube was sealed. The reaction mixture was stirred at 110° C. overnight. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography (SiO2; gradient: 0% to 100% EtOAc in hexane) to afford (S)-4-{2-[4-(4-chloro-phenylamino)-phenyl]-ethyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (228 mg, 57%) as a yellow oil. MS (EI): 432 ({37Cl}M+), 430 ({35Cl}M+H—OH+), 376 ({37Cl}[M−C4H8]+), 374 ({35Cl}[M−C4H8]), 231 ({37Cl}[ClC6H4NHC6H4CH═CH2]+), 229 ({35Cl}[ClC6H4NHC6H4CH═CH2]+), 57 ([C4H9]+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH:13]1([NH2:16])[CH2:15][CH2:14]1.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C>C1(C)C=CC=CC=1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:13]1([NH:16][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: COc1ccc(I)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(NC2CC2)c([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
To a stirred solution of 1-iodo-4-methoxy-2-nitrobenzene (0.2 g, 0.0007 mol) in toluene (6.0 mL) was added cyclopropylamine (0.068 ml, 0.0008 mol) potassium tert-butoxide (0.094 g, 0.0098 mol) and Ruphos (0.049 g, 0.00010 mol) at room temperature and purged with argon for 15 min. Then Pd2(dba)3 (0.064 g, 0.00007 mol) was added and resulting mixture was heated to 100° C. in CEM microwave for 30 min. After the reaction was complete the reaction mixture was filtered through CELITE® bed and the bed was thoroughly washed with ethyl acetate. The filtrate was washed with water brine dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound, which was purified by column chromatography to obtain title compound cyclopropyl-(4-methoxy-2-nitro-phenyl)-amine (yellow solid). C10H12N2O3; 1H NMR (400 MHz, CDCl3), δ: 7.98 (s, 1H), 7.60 (d, J=2.8 Hz, 1H), 7.30 (s, 1H), 7.19-7.16 (m, 1H), 4.12 (q, J=6.8, 1H), 3.80 (s, 1H), 0.89 (dd, J1=12.0 Hz, J2=6.0 Hz, 2H), 0.64 (t, J=6.8 Hz, 2H). MS (M+1): 209.1.