Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14](OCC)=O.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C1(OC)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:14]2[C:6]3[C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[S:9][C:5]=3[NH:4][C:3]3[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=3[N:1]=2)[CH2:26][CH2:25]1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1c(Nc2ccccc2N)sc2ccccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: CN1CCN(C2=Nc3ccccc3Nc3sc4ccccc4c32)CC1
Temperature: 25 °C

Procedure:
Ethyl 2-(2-aminoanilino)benzo[b]thiophene-3-carboxylate (3.5 g) and 1-methylpiperazine (20 ml) were dissolved in anisole (50 ml), titanium tetrachloride (3.1 ml) was added dropwise while stirring the mixture at room temperature. After the completion of dropwise addition, the mixture was stirred at 140° C. for 20 hours. The reaction mixture was cooled to 80° C. and poured into ice water. The resultant precipitate was filtrated. The filtrate was extracted with ethyl acetate (900 ml), washed with saturated brine, and dried over MgSO4. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) and the obtained oily substance was dissolved in ethyl acetate (50 ml), to which was added a solution (10 ml) of maleic acid (580 mg) in ethyl acetate. The precipitated crystals were collected by filtration and recrystallized from ethyl acetate/methanol to give 12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine.2 maleate (1.14 g).
Reaction SMILES: [CH:1]([N:4]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:7](=[O:21])[C:6]([C:22]([OH:24])=O)=[CH:5]1)([CH3:3])[CH3:2].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[S:34]([CH3:37])(=[O:36])=[O:35])[CH2:29][NH2:30].CN1CCOCC1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(OCC)(=O)C>ClCCl>[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[S:34]([CH3:37])(=[O:36])=[O:35])[CH2:29][NH:30][C:22]([C:6]1[C:7](=[O:21])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[CH:12]=2)=[C:9]([CH3:10])[N:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:24]
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)c(=O)c(C(=O)O)cn1C(C)C
Reactant: CS(=O)(=O)c1ccc(CN)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: Cc1c(-c2cccc(C(F)(F)F)c2)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)c(F)c2)cn1C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carboxylic acid (preparation 3, 60 mg, 0.177 mmol), preparation 32b (72 mg, 0.354 mmol), N-methylmorpholine (0.10 mL, 0.910 mmol) in dichloromethane (1 mL) is added at 0° C. 1-propanephosphonic acid cyclic anhydride in ethyl acetate (0.31 mL, 50%, 0.53 mmol). The reaction mixture is stirred for 18 h at room temperature. The volatiles are evaporated under reduced pressure and the remaining residue is purified by preparative reversed-phase HPLC (Sunfire, gradient of acetonitrile in water, 0.1% TFA, 60° C.). Yield: 24 mg (26% of theory); ESI mass spectrum: [M+H]+=525; Retention time HPLC: 0.86 min (005_CA01).
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]2[CH2:13][S:14][C:15](O)([CH2:16][CH2:17][CH2:18][CH2:19][C:20]34[CH2:29][CH:24]5[CH2:25][CH:26]([O:28][CH:22]([O:23]5)[O:21]3)[CH2:27]4)[C@H:11]2[N:10]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:9]1=[O:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C@H:12]2[CH2:13][S:14][C:15](=[CH:16][CH2:17][CH2:18][CH2:19][C:20]34[CH2:29][CH:24]5[CH2:25][CH:26]([O:28][CH:22]([O:23]5)[O:21]3)[CH2:27]4)[C@H:11]2[N:10]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:9]1=[O:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N(Cc2ccccc2)[C@H]2[C@H](CSC2(O)CCCCC23CC4CC(C2)OC(O4)O3)N1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1N(Cc2ccccc2)[C@@H]2C(=CCCCC34CC5CC(C3)OC(O5)O4)SC[C@@H]2N1Cc1ccccc1
Yield: 96.3 %

Procedure:
910 mg (1.68 mmol) of cis-1,3-dibenzyl-4-hydroxy-4-(4-(2,4,10-trioxaadamantyl)-butyl)-hexahydro-1H-thieno[3,4-d]imidazol-2-one (prepared in accordance with Example 1) are dissolved in 50 ml of toluene and the solution is treated with 20 mg of p-toluenesulphonic acid. The solution is heated to boiling and 20 ml of toluene are distilled off within 1 hour. Thereafter, the solution is evaporated to dryness. The residue remaining is chromatographed on silica gel. Elution with toluene, toluene/ethyl acetate (9:1) and (8:2) gives 839 mg (96% of theory) of cis-1,3-dibenzyl-4-(4-(2,4,10-trioxaadamantyl)-butylidene)-hexahydro-1H-thieno[3,4-d]imidazol-2-one in the form of a light brown oil which solidifies upon drying.
Reaction SMILES: [O:1]=[C:2]([C:6]1[N:14]2[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]2)=[CH:8][C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3](Cl)=[O:4].[O:21]=[S:22]1(=[O:35])[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.C(N(CC)CC)C>C1COCC1>[O:35]=[S:22]1(=[O:21])[CH2:23][CH2:24][N:25]([C:28]2[CH:29]=[CH:30][C:31]([NH:34][C:3](=[O:4])[C:2](=[O:1])[C:6]3[N:14]4[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]4)=[CH:8][C:7]=3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:32][CH:33]=2)[CH2:26][CH2:27]1
Reactant: Nc1ccc(N2CCS(=O)(=O)CC2)cc1
Reactant: O=C(Cl)C(=O)c1c(-c2ccccc2)cc2ccccn12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N2CCS(=O)(=O)CC2)cc1)C(=O)c1c(-c2ccccc2)cc2ccccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
A solution of oxo-(2-phenyl-indolizin-3-yl)-acetyl chloride (0.12 g, 0.42 mmol) in THF was added to a solution of 4-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-phenylamine (70 mg, 0.31 mmol) and triethylamine (85 mg, 0.85 mmol) in THF (10 mL) at 0° C., then the mixture was stirred for 8 h at r.t. The mixture was concentrated to dryness and washed with water to give a crude product which was triturated with methanol to afford the title compound (70 mg, 48%) as a solid.
Reaction SMILES: [Cl-].[C:2]([C:5]1[CH:10]=[CH:9][N+:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])[NH2:3]>[Pd].C(O)C>[C:11]1([N:8]2[CH2:9][CH2:10][CH:5]([C:2]([NH2:3])=[O:4])[CH2:6][CH2:7]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NC(=O)c1cc[n+](-c2ccccc2)cc1
Agent: [Pd]
Agent: [Cl-]
Solvent: CCO
Product: NC(=O)C1CCN(c2ccccc2)CC1
Reaction time: 48 h
Yield: 52.9 %

Procedure:
A mixture of 4-carbamoyl-1-phenylpyridinium chloride (13 g), 10% palladium-on-carbon catalyst (260 mg) and ethanol (250 ml) was hydrogenated at ambient temperature and pressure for 2 days. The solution was filtered (Celite) and the filtrate was concentrated to approximately 50 ml. This solution was cooled and the solid precipitate collected by filtration to give 1-phenylpiperidine-4-carboxamide (5.99 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([C:15]1[C:16]([O:30][CH2:31][CH3:32])=[C:17]([CH:25]2[CH2:27][CH:26]2[CH2:28][OH:29])[CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=1)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([C:15]1[C:16]([O:30][CH2:31][CH3:32])=[C:17]([CH:25]2[CH2:27][CH:26]2[CH:28]=[O:29])[CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: CCOc1c(C2CC2CO)cc(C(C)(C)C)cc1C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOc1c(C2CC2C=O)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: -35 °C
Reaction time: 0.25 h
Yield: 84.7 %

Procedure:
1.02 g of oxalyl chloride were dissolved in 37 ml of CH2Cl2 and treated with 0.86 ml of dimethyl sulfoxide at −60° C. After shortly warming to −35° C., the reaction mixture was recooled to −60° C. and treated with a solution of 1.2 g of (1RS,2SR)-[2-(3,5-di-tert.butyl-2-ethoxy-phenyl)-cyclopropyl]-methanol in 20 ml of CH2Cl2. After 15 minutes of stirring at −50° C., 1.7 ml of triethylamine were dropped in. The reaction mixture was stirred for 2 hours at room temperature, poured on icewater, extracted with ether, washed (H2O), dried (Na2SO4) and evaporated. The crude material was purified by flash chromatography (silica gel, hexane:ethyl acetate=9:1) and recrystallized from hexane to give 1.01 g of (1RS,2RS)-2-(3,5- di-tert.butyl-2-ethoxy-phenyl)-cyclopropanecarbaldehyde as white crystals, m.p. 96-97° C.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:19](Cl)(=[O:28])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1COCC1>[O:28]=[C:19]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCC(=O)Cl
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 60.4 %

Procedure:
To a solution of 25.2 g (0.142 mol) of (S)-(-)-4-benzyl-2-oxazolidinone (Aldrich Chemical Company) in 300 mL of THF cooled to -78° C. was added 97.0 mL (0.155 mol) of 1.6M n-butyllithium. The reaction mixture was stirred at -78° C. for 1 hour and nonanoyl chloride (17.4 g, 0.129 mol), dissolved in 75 mL of THF, was then added. The resulting mixture was stirred at -78° C. for 3 hours and then quenched with 5% HCl solution. The resulting mixture was extracted with ether and the combined organics were washed with water, saturated sodium bicarbonate and brine. The organics were then dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with ethyl acetate/hexanes (1:10), to provide 24.75 g (78%) of the desired product as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:18](Cl)(=[O:23])/[CH:19]=[CH:20]/[CH2:21][CH3:22]>ClCCl>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:23])/[CH:19]=[CH:20]/[CH2:21][CH3:22])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC/C=C/C(=O)Cl
Reactant: Cc1cc(N2CCNCC2)c2ccccc2n1
Solvent: ClCCl
Product: CC/C=C/C(=O)N1CCN(c2cc(C)nc3ccccc23)CC1
Reaction time: 0.25 h
Yield: 88 %

Procedure:
2-Methyl-4-piperazin-1-yl-quinoline (113.7 mg, 0.5 mmol) was dissolved in anhydrous dichloromethane (1 ml), TEA (77 μl, 0.5 mmol) followed by (E)-pent-2-enoyl chloride (65 mg, 0.55 mmol dissolved in 1 ml anhydrous dichloromethane) were added and the mixture was shaken for 15 minutes. The mixture was diluted with dichloromethane, washed with 5% sodium bicarbonate solution and water and the organic phase was evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 143 mg of a solid (0.44 mmol, 88%). MS (ES): m/z=354.2 [M+1]+.
Reaction SMILES: [C:1](=[O:15])([O:12][CH2:13][CH3:14])[O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([NH2:11])[CH:4]=1.N1C=CC=CC=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[C:1](=[O:15])([O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([NH:11][S:23]([CH3:22])(=[O:25])=[O:24])[CH:4]=1)[O:12][CH2:13][CH3:14]
Reactant: CCOC(=O)Oc1ccc(OC)c(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Oc1ccc(OC)c(NS(C)(=O)=O)c1
Reaction time: 3 h
Yield: 95.5 %

Procedure:
To a solution of 3-amino-4-methoxyphenyl ethyl carbonate (0.650 g, 3.08 mmol) and pyridine (2.2 ml, 27.2 mmol) in dry DCM (20 ml), methanesulfonyl chloride (1.0 ml, 12.83 mmol) was added at RT, and the resulting mixture was stirred for 3 hours. The volatiles were removed under reduced pressure affording crude ethyl 4-methoxy-3-(methylsulfonamido)phenyl carbonate (0.850 g, 2.94 mmol, 95% yield, MS/ESI+312.1 [MNa]+) which was used for the next step without purification.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[C:12](Br)=[CH:13][CH2:14][CH2:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20].[Li]CCCC>C1COCC1>[CH2:15]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20])[CH2:14][C:13]#[CH:12]
Reactant: N#Cc1cccc(CCC=C(Br)Br)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCCc1cccc(C#N)c1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
Sodium bis(trimethylsilyl)amide (10.7 mL, 10.7 mmol, 1 M in THF) was added dropwise to a solution of 3-(4,4-dibromobut-3-en-1-yl)benzonitrile (2.25 g, 7.14 mmol) in dry THF (45 mL) at −60° C. The reaction mixture was stirred for another 0.5 h maintaining the same temperature. The mixture was then cooled to −70° C. and n-BuLi (8.9 mL, 14.3 mmol, 1.6 M in hexane) was added dropwise. The reaction mixture was stirred for 0.5 h, quenched with saturated NH4Cl solution, and extracted with EtOAc. The combined extracts were concentrated under reduced pressure to obtain the 3-(but-3-yn-1-yl)benzonitrile (600 mg, yield 54%). 1H NMR (300 MHz, CDCl3) δ 7.55 (m, 1H), 7.53-7.51 (m, 1H), 7.48-7.39 (m, 2H), 2.90-2.85 (m, 2H), 2.54-2.48 (td, J=7.2 Hz, 2.6 Hz, 2H), 2.01-1.99 (t, J=2.6 Hz, 1H).
Reaction SMILES: [C:1](Cl)(=[O:5])C(Cl)=O.[NH2:7][C:8]1[N:13]=[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[N:22]([O:27][CH3:28])[C:21]([CH3:30])([CH3:29])[CH2:20]2)[N:11]=[C:10]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]2[CH2:41][C:40]([CH3:43])([CH3:42])[N:39]([O:44][CH3:45])[C:38]([CH3:47])([CH3:46])[CH2:37]2)[N:9]=1>>[CH3:45][O:44][N:39]1[C:40]([CH3:43])([CH3:42])[CH2:41][CH:36]([CH2:35][CH2:34][CH2:33][CH2:32][NH:31][C:10]2[N:11]=[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]3[CH2:24][C:23]([CH3:25])([CH3:26])[N:22]([O:27][CH3:28])[C:21]([CH3:30])([CH3:29])[CH2:20]3)[N:13]=[C:8]([N:7]=[C:1]=[O:5])[N:9]=2)[CH2:37][C:38]1([CH3:47])[CH3:46]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CON1C(C)(C)CC(CCCCNc2nc(N)nc(NCCCCC3CC(C)(C)N(OC)C(C)(C)C3)n2)CC1(C)C
Product: CON1C(C)(C)CC(CCCCNc2nc(N=C=O)nc(NCCCCC3CC(C)(C)N(OC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of oxalyl chloride with the compound prepared in Example 20.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4]([I:12])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O.O.C(OCC)(=O)C>[C:8]([C:6]1[C:5]([O:11][CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:4]([I:12])[C:3]([F:13])=[C:2]([Cl:1])[CH:7]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cc(Cl)c(F)c(I)c1O
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)Oc1c(C(C)=O)cc(Cl)c(F)c1I
Temperature: 60 °C
Reaction time: 3 h
Yield: 55.5 %

Procedure:
A solution of 1-(5-chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethanone (5.00 g, 15.9 mmol) in N,N-dimethylformamide (80.0 mL) was treated with potassium carbonate (4.39 g, 31.8 mmol), followed by ethyl 2-bromopropanoate (2.48 mL, 19.1 mmol), and then stirred at 60° C. for 3 h. The reaction was stirred overnight at 60° C., and then worked up per the procedure below. The reaction was then re-submitted to the reaction conditions and stirred at 90° C. for 4 h. The reaction mixture was diluted with water and ethyl acetate. The organic layer was separated and washed with brine, dried over magnesium sulfate, filtered, and concentrated to give a crude residue. Purification by flash column chromatography (100% hexanes to 10% EtOAc/hexanes) gave the desired product (3.66 g, 56%) as a mixture of enantiomers. LCMS calculated for C13H14ClFIO4 (M+H)+: m/z=415.0; found: 414.9.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([O:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-])=O.C1CCCCC=1>O1CCOCC1.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([O:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)=[C:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:10][C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: O=c1[nH]c(-c2ccccc2)c(OCCCN2CCCCC2)c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: C1COCCO1
Solvent: C1=CCCCC1
Product: Nc1ccc2c(OCCCN3CCCCC3)c(-c3ccccc3)[nH]c(=O)c2c1
Temperature: 100 °C
Yield: 39.5 %

Procedure:
To a suspension of 575 mg (1.41 mmol) of 7-nitro-3-phenyl-4-(3-piperidin-1-yl-propoxy)-2H-isoquinolin-1-one (cmpd. 35) in dioxane (15 mL), cyclohexene (5 mL, 49.4 mmol) and 250 mg of palladium on carbon (10 wt. % loading) were added and the mixture was heated at 100° C. under argon atmosphere for 3 hours. The mixture was cooled to room temperature and filtered through a celite pad, which was then washed with dioxane. The solvent was concentrated under reduced pressure and the resulting crude was purified by flash chromatography (eluant: dichloromethane/methanol/acetone/7N ammonia in methanol: 90/5/5/1) to afford 210 mg of the title compound (39%).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[N:24]1[CH:25]=[CH:26][C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[CH:29]=[C:28]([C:30]([F:32])([F:31])[F:33])[S:27][C:17]=3[N:18]=2)=[CH:22][CH:23]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][C@@H:37]5CCCO5)[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].O1CC[CH2:48][C@H:47]1[CH2:51]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:37][C@@H:36]([NH:35][CH2:34][C:32]1[CH:33]=[C:28]([C:25]2[CH:26]=[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:16]2[CH2:15][CH2:14][N:13]([S:10]([CH2:8][CH3:9])(=[O:11])=[O:12])[CH2:18][CH2:17]2)[CH:29]=[C:30]([F:42])[CH:31]=1)[CH:47]([CH3:51])[CH3:48]
Reactant: NC[C@@H]1CCCO1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC[C@@H]5CCCO5)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CN[C@H](C)C(C)C)c4)cc23)CC1
Yield: 34.9 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting (2R)-3-methyl-2-butanamine (45 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 19.5 mg of the title compound (34.9%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[CH:20]=[CH:19][N:18]([CH:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[C:14]2=[CH:15][N+:16]=1[O-])[CH3:2].COS(OC)(=O)=O.O.[C-:36]#[N:37].[K+]>C1(C)C=CC=CC=1.[OH-].[Na+]>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[CH:20]=[CH:19][N:18]([CH:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[C:14]2=[C:15]([C:36]#[N:37])[N:16]=1)[CH3:2]
Reactant: [C-]#N
Reactant: CCCC(CCC)n1ccc2cc(-c3c(CC)cccc3CC)[n+]([O-])cc21
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Product: CCCC(CCC)n1ccc2cc(-c3c(CC)cccc3CC)nc(C#N)c21
Temperature: 90 °C
Reaction time: 12 h

Procedure:
To a solution of 5-(2,6-diethyl-phenyl)-1-(1-propyl-butyl)-1H-pyrrolo[2,3-c]pyridine 6-oxide (220 mg, 0.6 mmol) in toluene (3 mL), is added dimethylsulfate (69 μL, 0.72 mmol), and the mixture is heated to 90° C. for 2 h. All volatiles are removed under reduced pressure. The residue is treated with water (2 mL), 10 M NaOH (20 drops) and KCN (200 mg, 3.1 mmol). The mixture is stirred for 12 h at room temperature. The product is extracted with EtOAc several times. The combined organic extracts are washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Chromatography of the residue on silica gel (Hexane/EtOAc, 1:1) gives 5-(2,6-diethyl-phenyl)-1-(1-propyl-butyl)-1H-pyrrolo[2,3-c]pyridine-7-carbonitrile as a colorless oil: 1H NMR (CDCl3) 7.66 (s, 7.50 (d, J=3 Hz, 1H), 7.32 (t, J=7 Hz, 1H), 7.16 (d, J=7 Hz, 2H), 6.70 (d, J=3 Hz, 1H), 5.34 (m, 1H), 2.32 (m, 4H), 1.92 (m, 4H), 1.44 (m, 2H), 1.21 (m, 2H), 1.02 (t, J=7 Hz, 6H), 0.95 (t, J=7 Hz, 6H); LCMS m/z 374.27 (3.06 min).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[C:17](=[O:19])[N:16]([CH3:20])[CH2:15][CH2:14]3)[C:5]([Cl:21])=[CH:4][N:3]=1.[F:22][CH:23]([F:31])[N:24]1[CH:28]=[C:27]([NH2:29])[C:26]([CH3:30])=[N:25]1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[C:17](=[O:19])[N:16]([CH3:20])[CH2:15][CH2:14]3)=[CH:7][C:2]([NH:29][C:27]2[C:26]([CH3:30])=[N:25][N:24]([CH:23]([F:31])[F:22])[CH:28]=2)=[N:3][CH:4]=1
Reactant: CN1CCc2cccc(Nc3cc(Cl)ncc3Cl)c2C1=O
Reactant: Cc1nn(C(F)F)cc1N
Product: Cc1nn(C(F)F)cc1Nc1cc(Nc2cccc3c2C(=O)N(C)CC3)c(Cl)cn1

Procedure:
This compound was prepared from 8-[(2,5-dichloropyridin-4-yl)amino]-2-methyl-3,4-dihydroisoquinolin-1-one and 1-(difluoromethyl)-3-methyl-pyrazol-4-amine. Column chromatography (SiO2, 50 equiv.; 50:50; EtOAc:MeOH) followed by re-crystallisation from warm MeOH (1-2 mL) furnished 64 mg of the desired product.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:9][CH2:8]1)(=[O:5])[CH3:4].I[CH3:19]>CN(C=O)C.[NH4+].[Cl-].O>[C:3]([N:6]([C:7]1([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[CH2:9][CH2:8]1)[CH3:19])(=[O:5])[CH3:4]
Reactant: CI
Reactant: COc1ccc(C2(NC(C)=O)CC2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2(N(C)C(C)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.4 %

Procedure:
To a stirred suspension of 60% sodium hydride (234 mg, 5.85 mmol) (washed with pentane) in dry DMF (20 ml) was added Compound 8 (1.00 g, 4.87 mmol) portionwise at room temperature. After 15 min., to this was added iodomethane (1.04 g, 7.31 mmol) at same temperature. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with sat. NH4Cl aq. (20 ml)-H2O (20 ml) and extracted with toluene-AcOEt (1:2). The combined solution was washed with water and brine, dried(MgSO4) and concentrated in vacuo to give crude product (1.05 g) as a yellow solid. The crude product was recrystallized from hexane-ethyl acetate to give Compound 9 (784 mg, 73%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=O.Cl.[NH2:13][OH:14].[OH-].[Na+]>CCO.O>[Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([OH:11])[C:3]=1/[CH:4]=[N:13]/[OH:14]
Reactant: O=Cc1c(O)ccc(O)c1Cl
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O/N=C/c1c(O)ccc(O)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 125.9 %

Procedure:
A mixture of 7A (25.0 g, 144.87 mmol), hydroxylamine hydrochloride (12.08 g, 173.84 mmol, 1.2 eq) and NaOH (8.69 g, 217.3 mmol, 1.5 eq) in EtOH (200 mL) and H2O (100 mL) was stirred at room temperature overnight. TLC monitored the reaction. After the reaction completed, the mixture was extracted with ethyl acetate and concentrated to give a yellow solid 7B (34.2 g, 100% yield).