Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(ON=O)CC(C)C.[Br:9][C:10]1[C:11]([CH3:17])=[N:12][C:13](N)=[N:14][CH:15]=1.CCCC(C)C.C(Br)(Br)[Br:25]>>[Br:25][C:13]1[N:12]=[C:11]([CH3:17])[C:10]([Br:9])=[CH:15][N:14]=1
Reactant: BrC(Br)Br
Reactant: Cc1nc(N)ncc1Br
Agent: CC(C)CCON=O
Solvent: CCCC(C)C
Product: Cc1nc(Br)ncc1Br
Temperature: 85 °C

Procedure:
Isoamylnitrite (21 ml) was added to a stirred suspension of 5-bromo-4-methyl-2-pyrimidinamine (1.75 g) in bromoform (30 ml) and the mixture heated at 85° C. for 4 h. After cooling, isohexane (300 ml) was added and the solution passed through a pad of silica-gel. The silica was washed with petrol (1000 ml), dichloromethane (200 ml) then the product eluted with ethylacetate. The ethylacetate layer was evaporated under reduced pressure and the residue purified by chromatography on silica eluting with 5% diethylether/isohexane, yield 0.9 g
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[C:14]([C:19]#[N:20])[CH:15]=[N:16]2)=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:33]=[C:32]2[C:28]([CH2:29][CH2:30][NH:31]2)=[CH:27][CH:26]=1.Cl.N1C=CC=CC=1>COCCO>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:24][C:25]3[CH:33]=[C:32]4[C:28]([CH2:29][CH2:30][NH:31]4)=[CH:27][CH:26]=3)=[C:14]([C:19]#[N:20])[CH:15]=[N:16]2)=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCc1ccccc1
Reactant: Nc1ccc2c(c1)NCC2
Agent: Cl
Solvent: COCCO
Solvent: c1ccncc1
Product: COc1cc2c(Nc3ccc4c(c3)NCC4)c(C#N)cnc2cc1OCc1ccccc1
Temperature: 25 °C
Yield: 27 %

Procedure:
A solution of 586 mg (1.60 mM) of 7-benzyloxy-4-chloro-6-methoxy-quinoline-3-carbonitrile, 560 mg (1.70 mM) of 6-Aminoindolin dihydrchloride salt and 208 mg (1.80 mM) of pyridine hydrochloride in 13 ml of 2-methoxyethanol was refluxed for 3 hours. The reaction was allowed to cool to room temperature and the resulting solid was isolated and washed with excess ethanol and dried under vacuum at 80° C. The resulting solid was digested in 300 ml of ethanol and the volume was reduced to 100 ml. The solid was isolated from the hot solution and the digestion process was repeated a second time. The solid was once again isolated from the hot solution to yield 206 mg of 7-benzyloxy-4-(2,3-dihydro-1H-indol-6-ylamino)-6-methoxy-quinoline-3-carbonitrile as a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:25])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:33](Cl)([CH3:35])=[O:34]>C(Cl)Cl>[C:33]([O:25][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:19]=[CH:20][C:21]([F:24])=[CH:22][N:23]=2)[CH2:14][CH2:13]1)(=[O:34])[CH3:35]
Reactant: OC(CCCN1CCN(c2ncc(F)cn2)CC1)c1ccc(F)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC(CCCN1CCN(c2ncc(F)cn2)CC1)c1ccc(F)cc1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
A cold (5° C.) mixture of 1-(4-fluorophenyl)-4-(4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl)-1-butanol monohydrochloride1 (3.0 g, 7.8 mmol) and Et3N (2.38 mL, 17.1 mmol) in CH2Cl2 (55 mL) was treated dropwise (10 min) with AcCl (0.67 mL, 9.4 mmol). The reaction mixture was stirred at 5° C. for 0.25 h and then at 23° C. for 2 h before being diluted with CH2Cl2 (250 mL). The organic solution was washed with water (30 mL), saturated Na2CO3 solution to bring pH to 9, water (20 mL) and brine, dried (MgSO4) and concentrated in vacuo to a solid which was purified on silica gel column using a mixture of 30-40% AcOEt in CH2Cl2. The appropriate fractions were collected and concentrated in vacuo to a white solid, 2.93 g, 96%. Recrystallization from ether-hexane mixture afforded analytical sample, mp 76°-7° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[CH3:13].CNCC1C=CC2C(=CC=CC=2)C=1CCC.Cl.[NH2:31][C:32]1[N:37]=[CH:36][C:35](/[CH:38]=[CH:39]/[C:40]([OH:42])=O)=[CH:34][CH:33]=1>>[NH2:31][C:32]1[N:37]=[CH:36][C:35](/[CH:38]=[CH:39]/[C:40]([N:2]([CH3:1])[CH2:3][C:4]2[S:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[C:5]=2[CH3:13])=[O:42])=[CH:34][CH:33]=1
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Reactant: CNCc1sc2ccccc2c1C
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: Cl
Product: Cc1c(CN(C)C(=O)/C=C/c2ccc(N)nc2)sc2ccccc12
Yield: 73 %

Procedure:
According to the procedure of Example 1, except substituting methyl-(3-methyl-benzo[b]thiophen-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(6-amino-pyridin-3-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3,-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (2.2 g, 73%) was prepared as a yellow solid: 1H NMR (300 MHz, DMSO-d6) 8.21 (s, 1H), 2.81-2.75 (m, 1H), 2.71-2.59 (m, 3H), 7.41-7.25 (m, 2H), 6.85-6.65 (m, 1H), 6.50-6.41 (m, 1H), 5.01-4.81 (m, 2H), 4.78-4.61 (m, 2H), 3.12 (s, 3H), 2.41 (s, 3H); MS (ESI) m/e 338 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[S:15][C:16]4[CH:22]=[C:21]([NH:23][CH2:24]C(F)(F)F)[CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CN1CCN(C2N=CC(C3SC4C=C(NC(=O)OCC)C=CC=4N=3)=CC=2)CC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:24][NH:23][C:21]1[CH:20]=[CH:19][C:17]2[N:18]=[C:14]([C:11]3[CH:12]=[N:13][C:8]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:9][CH:10]=3)[S:15][C:16]=2[CH:22]=1
Reactant: CN1CCN(c2ccc(-c3nc4ccc(NCC(F)(F)F)cc4s3)cn2)CC1
Agent: CCOC(=O)Nc1ccc2nc(-c3ccc(N4CCN(C)CC4)nc3)sc2c1
Agent: [Al+3]
Agent: [H-]
Product: CNc1ccc2nc(-c3ccc(N4CCN(C)CC4)nc3)sc2c1

Procedure:
The title compound (11 mg, 38%) was prepared by reduction according to the method described for the preparation of 2-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-N-(2,2,2-trifluoroethyl)-1,3-benzothiazol-6-amine by the use of ethyl {2-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,3-benzothiazol-6-yl}carbamate (37 mg, 0.088 mmol) as starting material, and lithium aluminiumhydride (10 mg, 0.26 mmol) as reagent, with the following modification: The reaction mixture was stirred at reflux for 1 h then at r.t. o.n. The crude was purified by prep. HPLC, to give the title compound (11 mg) as a pale yellow solid. 1H NMR (MeOH-D4) δ 8.59 (d, 1H) 7.98 (dd, 1H) 7.56 (d, 1H) 6.93 (d, 1H) 6.82 (d, 1H) 6.73 (dd, 1H) 3.55-3.69 (m, 4H) 2.74 (s, 3H) 2.48-2.60 (m, 4H) 2.32 (s, 3H); MS m/z (M+H) 340.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)Cl>>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:9][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:7]=1[F:8]
Reactant: COc1cc(Br)c(F)cc1O
Reactant: OB(O)c1ccccc1
Solvent: ClCCl
Product: COc1cc(Br)c(F)cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-Bromo-5-fluoro-2-methoxyphenol (500 mg, 0.002 mol), phenylboronic acid (0.73 g, 0.0060 mol), TEA (2.0 mL, 0.014 mol), cupric acetate (0.70 g, 0.0038 mol) and DCM (20 mL, 0.4 mol) were added to a 100 mL oven dried flask and the reaction was stirred at rt for 48 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=3.83 (s, 3H), 6.73 (d, J=9.09 Hz, 1H), 6.94-7.00 (m, 2H), 7.07-7.15 (m, 2H), 7.34 (dd, J=8.59, 7.58 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[S:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[C:26]([C:30]1[CH:34]=[C:33]([NH:35][C:36](=O)[O:37]C2C=CC=CC=2)[N:32]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][C:46]=2[CH3:52])[N:31]=1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([C:30]1[CH:34]=[C:33]([NH:35][C:36]([NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([S:18][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:20]=2)=[O:37])[N:32]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][C:46]=2[CH3:52])[N:31]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)c(C)c1
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C)cc4C)c3)c2cc1OC
Yield: 77 %

Procedure:
The title compound was prepared from 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described in Example 230A (94 mg, 0.27 mmol) and phenyl 3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-ylcarbamate (120 mg, 0.33 mmol) using the procedure in Example 115C to give 1-(3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)urea (130 mg, 0.21 mmol, 77%). 1H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.68 (s, 1H), 8.18 (s, 1H), 7.79 (s, 1H), 7.43-7.38 (m, 2H), 7.36 (s, 1H), 7.32 (s, 1H), 7.25-7.16 (m, 4H), 6.34 (s, 1H), 4.33 (t, 2H), 3.99 (s, 3H), 3.76 (t, 2H), 3.34 (s, 3H), 2.37 (s, 3H), 1.95 (s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z 627 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][OH:13]>>[CH3:12][O:13][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[F:1]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: CO
Product: COC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 100 mL of methanol, 2,4-difluoro-benzoyl chloride (10 mL, 79.3 mmol) was added and the mixture stirred at room temperature for 2 hours. The solvent was then evaporated affording the title compound as pale yellow oil (quantitative).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:20]([F:23])([F:22])[F:21])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]3[NH:17][N:18]=[CH:19][C:12]2=3)=[O:10])[C:6]=1[CH3:7].[F:24][C:25]1[CH:26]=[CH:27][C:28](Br)=[N:29][CH:30]=1.CN[C@@H]1CCCC[C@H]1NC.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.O1CCOCC1>[Cl:1][C:2]1[C:3]([C:20]([F:23])([F:21])[F:22])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]3[N:17]([C:28]4[CH:27]=[CH:26][C:25]([F:24])=[CH:30][N:29]=4)[N:18]=[CH:19][C:12]2=3)=[O:10])[C:6]=1[CH3:7]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCCc2[nH]ncc21
Reactant: Fc1ccc(Br)nc1
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCCc2c1cnn2-c1ccc(F)cn1
Temperature: 120 °C

Procedure:
2-(4-Chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-1-(6,7-dihydro-1H-pyrazolo[4,3-b]pyridin-4(5H)-yl)ethanone (104 mg, 0.3 mmol) was combined with 5-fluoro-2-bromopyridine (106 mg, 0.6 mmol), 0.3 mL of dioxane, Cu(I)I (11.4 mg, 0.06 mmol, 20%), (±)-trans-N,N′-dimethylcyclohexane-1,2-diamine (21.3 mg, 0.15 mmol, 50%), and K2CO3 (83 mg, 0.6 mmol). The slurry was heated to 120° C. until complete (approx 3 hours). The reaction mixture was diluted in 4 mL of EtOAc and washed with 2×H2O. The organic layer was concentrated and the residue was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to provide the title compound as a white solid. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.91 (s, 0.8H), 8.33 (d, J=2.7 Hz, 0.2H), 8.28 (d, J=2.9 Hz, 0.8H), 7.87-7.94 (m, 1H), 7.68-7.77 (m, 1H), 5.42 (s, 1.6H), 5.41 (s, 0.4H), 3.93 (s, 1.6H), 3.88 (s, 0.4H), 2.88 (t, J=6.4 Hz, 2H), 2.29 (s, 0.6H), 2.28 (s, 2.4H), 2.18 (m, 2H); MS: (ES) m/z calculated for C18H16ClF4N6O [M+H]+ 443.1, found 443.0.
Reaction SMILES: CC(C)(O[C:5]([NH:7][C@@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9]1=[O:20])=[O:6])C.C(O)(C(F)(F)F)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+].[Cl:46][C:47]1[CH:56]=[C:55]2[C:50]([C:51]([N:58]3[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]3)=[CH:52][C:53]([NH2:57])=[N:54]2)=[CH:49][CH:48]=1>>[CH2:18]([O:17][C:15]([N:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@H:8]([NH:7][C:5]([N:61]2[CH2:62][CH2:63][N:58]([C:51]3[C:50]4[C:55](=[CH:56][C:47]([Cl:46])=[CH:48][CH:49]=4)[N:54]=[C:53]([NH2:57])[CH:52]=3)[CH2:59][CH2:60]2)=[O:6])[C:9]1=[O:20])=[O:16])[CH3:19]
Reactant: CCOC(=O)N1CCCC[C@@H](NC(=O)OC(C)(C)C)C1=O
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCCC[C@H](NC(=O)N2CCN(c3cc(N)nc4cc(Cl)ccc34)CC2)C1=O

Procedure:
As described for example 213, (3R)-3-[[(1,1-dimethylethoxy)carbonyl]amino]hexahydro-2-oxo-1H-azepine-1-carboxylic acid, ethyl ester, TFA, triphosgene, NaHCO3 (sat.), and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the title product as a light yellow solid. LC-MS: 489 (M++1). 1H NMR (CDCl3): δ 1.37 (t, 3H), 1.44˜2.02 (m, 5H), 2.12˜2.20 (m, 1H), 3.13 (m, 4H), 3.41 (dd, 1H), 3.67 (m, 4H), 4.35 (m, 2H), 4.42 (m, 1H), 4.74˜4.86 (m, 3H), 6.00 (d, 1H), 6.16 (s, 1H), 7.18 (dd, 1H), 7.62 (d, 1H), 7.73 (d, 1H).
Reaction SMILES: [NH:1]([C:3]([S:5][CH3:6])=[NH:4])[NH2:2].O.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]([CH:18]=O)=O>>[CH3:6][S:5][C:3]1[N:1]=[N:2][CH:18]=[C:16]([C:10]2[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=2[F:8])[N:4]=1
Reactant: CSC(=N)NN
Reactant: O=CC(=O)c1ccc(F)cc1F
Solvent: O
Product: CSc1nncc(-c2ccc(F)cc2F)n1
Yield: 69.7 %

Procedure:
3-(Methylsulfanyl)-5-(2,4-difluorophenyl)-1,2,4-triazine (1.00 g, 78%) was prepared from methyl hydrazinecarbimidothioate (0.63 g, 6.0 mmol) and 2,4-difluorophenylglyoxal monohydrate (1.00 g, 6.0 mmol) according to the general procedure of Preparation 2.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Cl)=[CH:5][C:4]=1[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1[CH3:18].[P:19]([O:26]CC)([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>>[CH2:21]([O:20][P:19]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][P:19]([O:20][CH2:21][CH3:22])([O:23][CH2:24][CH3:25])=[O:26])=[CH:5][C:4]=1[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1[CH3:18])(=[O:26])[O:23][CH2:24][CH3:25])[CH3:22]
Reactant: Cc1ccc(C)c(-c2cc(CCl)ccc2CCl)c1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc(CP(=O)(OCC)OCC)c(-c2cc(C)ccc2C)c1)OCC

Procedure:
50 g (180 mmol) of 2′,5′-bis-chloromethyl-2,5-dimethylbiphenyl are heated at 160° C. in 63 ml (366 mmol) of triethyl phosphite until the evolution of gas is complete. The residue which remains is employed in the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH:15]=[C:14]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.C(Cl)Cl.C([BH3-])#N.C([N+](CCCC)(CCCC)CCCC)CCC>C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][CH:14]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:15][CH2:16]2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(N2CC=C(N3CCCC3)CC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(N2CCC(N3CCCC3)CC2)cc1
Yield: 80 %

Procedure:
A solution of 2 g (0.0065 mol) of the compound of (C), 5 ml of 4.66M HCl (in isopropyl alcohol), 40 ml of methylene chloride and 2.68 g of tetrabutylammonium cyanoborohydride is stirred at ambient temperature overnight. The solution is diluted with sat. Na2CO3 solution and extracted with methylene chloride. The combined extracts are dried (Na2SO4) and concentrated in vacuo to give 1.6 g (80%) of the title compound. An analytical sample is prepared by recrystallization from ethyl acetate: m.p. 166°-170° C.; IR (KBr) 1595, 1295, and 880 cm-1 ; NMR (CDCl3)δ7.75 (d, 2H); 6.9 (d, 2H), 4.0-3.7 (m, 1H), 3.15-2.55 (m, 8H), 3.0 (s, 3H), and 2.05-1.55 (m, 8H)
Reaction SMILES: Br[C:2]1[C:3]([C:24]#[N:25])=[N:4][N:5]([CH2:22][CH3:23])[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].Cl.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.C(Cl)(Cl)Cl.[Pd].[Pd]>[NH2:25][C:24]1[C:3]2=[N:4][N:5]([CH2:22][CH3:23])[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][N:11]3[C:12](=[O:21])[C:13]4[C:14](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:16])=[C:2]2[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=1
Reactant: Nc1ccccc1B(O)O
Reactant: CCn1nc(C#N)c(Br)c1CCCCN1C(=O)c2ccccc2C1=O
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCn1nc2c(N)nc3ccccc3c2c1CCCCN1C(=O)c2ccccc2C1=O
Yield: 15.8 %

Procedure:
4-Bromo-1-ethyl-5-(4-phthalimidobutyl)-1H-pyrazole-3-carbonitrile (0.97 g, 2.4 mmol) was treated with 2-aminophenylboronic acid hydrochloride (839 mg, 4.84 mmol), potassium phosphate (2.56 g, 12.1 mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (124 mg, 0.12 mmol), and bis[(2-diphenylphosphino)phenyl]ether (75 mg, 0.14 mmol) according to the method described in Part F of Example 19. The reaction was heated for 24 hours. Following the purification and recrystallization, 0.157 g of 2-[4-(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]isoindole-1,3-dione was obtained as brown crystals, mp 216-217° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[C:17]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:18]([C:22]([F:25])([F:24])[F:23])[O:19]2)=[CH:14][C:13]=1[Cl:31]>CN(C=O)C>[Cl:31][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:12]=1[CH2:11][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[O:19][CH:18]([C:22]([F:25])([F:24])[F:23])[C:17]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:16]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(CBr)cc2OC1C(F)(F)F
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(COc3ccccc3)cc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of phenol (117 mg, 0.69 mmol) in 1 mL DMF was added to a mixture of NaH (30 mg, 0.75 mmol) in 1 mL DMF at 0° C. under argon. After 30 min, a solution of ethyl 7-(bromomethyl)-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (250 mg, 0.62 mmol) in 2 mL DMF described in Example 157 Step 3 was added dropwise. The reaction was warmed to 25° C. After 18 h, the reaction was filtered through a pad of Celite (1″) and washed with EtOAc (20 mL). The filtrate was concentrated to give a pale yellow solid in 230 mg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)C.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>CS(C)=O.C(OCC)(=O)C>[CH3:1][O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(-n2ccc3ccccc32)cc1
Temperature: 120 °C
Yield: 21.1 %

Procedure:
Ethyl-4-fluorobenzoate (4 mL, 27.3 mmol) and indole (3.51 g, 30 mmol) were dissolved in 50 mL of dimethylsulfoxide (DMSO). Potassium fluoride (37% on basic alumina, 12.8 g) and 18-crown-6 (720 mg, 2.73 mmol) were added and the mixture was heated to 120° C. for 24 hours. The reaction was diluted with ethyl acetate and washed with hydrochloric acid (1.0 M, aq.), sodium bicarbonate (sat'd., aq.) and sodium chloride (sat'd., aq.). The organic layer was dried over magnesium sulfate, filtered and the solvent removed. Purification by flash chromatography on silica gel eluted with 5% ethyl acetate, hexane provided 1.45 g (20%) of a white solid
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH2:18][CH:19]=[O:20])([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+].[CH2:23]([OH:25])[CH3:24]>O.[N+]([O-])([O-])=O.[Ag+]>[C:1]([N:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH2:18][C:19]([O:25][CH2:23][CH3:24])=[O:20])([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCC(CC=O)(Cc2ccc(C)cc2)C1
Reactant: CCO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC1(Cc2ccc(C)cc2)CCCN(C(C)=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Silver nitrate (1.87 g, 11.0 mmol) was dissolved in 3 ml H2O. It was added to a solution of the product from STEP 6 (1.6 g, 5.5 mmol) in 25 ml ethanol. A solution prepared from dissolving NaOH (0.88 g, 22.0 mmol) in 4.0 ml H2O was added dropwise to the silver nitrate solution. The reaction was stirred at 25° C. for 2 h. The reaction was diluted with 15 ml H2O. The ethanol was removed and the resulting residue was extracted with ethyl acetate (2×60 ml). The aqueous extracts were acidified with 1 N aqueous HCl solution to PH=5, and extracted with ethyl acetate (3×100 ml). The organic layer was washed with 15 ml brine, dried with MgSO4, filtered and concentrated to afford a 1.1 g of clean oil. The oil was dissolved in 30 ml ethanol and 15 ml 2M HCl/dioxane. The reaction was stirred at room temperature for 18 h and concentrated. The residue was purified by chromatography (on silica gel, CH2Cl2/MeOH/NH4OH=95/5/0.1) to give 0.88 g of a gummy solid. The 1H NMR spectrum of the product was consistent for the proposed structure.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([CH2:9]O)=[C:6]([CH3:8])[N:7]=1)[CH3:2].[CH2:11]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][CH2:23][CH:24]2[C:29]([NH:31][C:32]1[CH:33]=[N:34][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:36][CH:37]=1)=[O:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][CH2:23][CH:24]2[C:29]([N:31]([CH2:9][C:5]1[S:4][C:3]([CH2:1][CH3:2])=[N:7][C:6]=1[CH3:8])[C:32]1[CH:33]=[N:34][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:36][CH:37]=1)=[O:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)c1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: CCc1nc(C)c(CO)s1
Product: CCc1nc(C)c(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)s1
Yield: 60.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 142 using 2-ethyl-5-hydroxymethyl-4-methylthiazole (0.63 g) and 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.8 g) as starting materials, 5-benzyloxy-N-[(2-ethyl-4-methylthiazol-5-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.3 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH:34]=O)=[CH:4][N:3]=1.[CH3:36][NH:37][NH2:38]>O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([CH:32]2[N:37]([CH3:36])[N:38]=[CH:34][CH2:33]2)=[CH:4][N:3]=1
Reactant: CNN
Reactant: COc1cc(-c2csc3c(/C=C/C=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Solvent: O
Product: COc1cc(-c2csc3c(C4CC=NN4C)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
N-(4-{4-amino-7-[(1E)-3-oxoprop-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (0.10 g, 0.207 mmol) was stirred with methyl hydrazine (0.5 mL) at ambient temperature for 3 hours then water (8 mL) was added and the white precipitate was collected by filtration and dried to give the title compound. Rt=3.62 min (Conditions a) MS m/e: 511 (M+H)+, 509 (M−H)−.