Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[C:11]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:13][CH:14]=2)=[C:4]([N+:23]([O-])=O)[C:3]1=[O:26]>C(OCC)(=O)C.C(O)C.[Pt]=O>[NH2:23][C:4]1[C:3](=[O:26])[N:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:9]1[CH:10]=[C:11]([C:15]2[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Cn1ccc(Nc2cccc(-c3ccccc3C#N)c2)c([N+](=O)[O-])c1=O
Agent: O=[Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1ccc(Nc2cccc(-c3ccccc3C#N)c2)c(N)c1=O
Reaction time: 2 h

Procedure:
3′-(1-Methyl-3-nitro-2-oxo-1,2-dihydropyridin-4-ylamino)biphenyl-2-carbonitrile (0.11 g, 0.32 mmol) was suspended in ethyl acetate (10 ml) and ethanol (10 ml), platinum oxide (7.3 mg, 0.03 mmol) added and the mixture hydrogenated at 45 psi on a Parr hydrogenator for 2 h. The catalyst was filtered off through a glass fibre filter paper and the filtrate evaporated to give 3′-(3-amino-1-methyl-2-oxo-1,2-dihydropyridin-4-ylamino)biphenyl-2-carbonitrile as an orange oil. The oil was dissolved in formic acid (4 ml) and heated at 95° C. for 24 h. The mixture was allowed to cool to ambient temperature and evaporated. The residue was made basic by the addition of concentrated ammonia solution, then diluted with water (100 ml) and extracted with dichloromethane (2×100 ml). The combined organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and evaporated to give a brown oil. The oil was purified by flash column chromatography on silica eluting with dichloromethane (+1% concentrated ammonia) on a gradient of methanol (2-4%). Collecting appropriate fractions, followed by trituration with diethyl ether (5 ml), gave 3′-(5-methyl-4-oxo-4,5-dihydroimidazo[4,5-c]pyridin-1-yl)biphenyl-2-carbonitrile (64 mg, 61%) as a white solid: δH (400 MHz, CDCl3) 3.69 (3H, s), 6.66 (1H, d, J 7), 7.24 (2H, m), 7.52-7.58 (2H, m), 7.65-7.67 (2H, m), 7.69-7.74 (2H, m), 7.84 (1H, dd, J 8 and 1), 7.99 (1H, s); m/z (ES+) 327 (M++H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][C:6]([F:9])([F:8])[CH2:5][CH:4]1[NH:10][C:11](=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[N:22]=[CH:21][CH:20]=[N:19]1.Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:8][C:6]1([F:9])[CH2:5][CH:4]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[N:19]=[CH:20][CH:21]=[N:22]2)[CH:3]([NH:2][C:25]2[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)[CH2:7]1
Reactant: NC1CC(F)(F)CC1NC(=O)c1ccccc1-n1nccn1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(NC1CC(F)(F)CC1Nc1ncc(C(F)(F)F)cn1)c1ccccc1-n1nccn1
Temperature: 140 °C

Procedure:
To a solution of N-(2-amino-4,4-difluorocyclopentyl)-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 42; 120 mg, 0.39 mmol) in dry DMSO (1.2 ml) was added 2-chloro-5-(trifluoromethyl)pyrimidine (CAS number 69034-12-4; 70 mg, 0.384 mmol) and DIPEA (183 μl, 1.047 mmol). The reaction mixture was heated in a sealed vial at 140° C. for 17 hours then partitioned between ethyl acetate and water. The organics were washed with water, filtered through a hydrophobic frit and concentrated in vacuo. The crude material was purified by column chromatography (basic silica, 0-100% ethyl acetate/petrol) then was chirally separated using SFC (Waters prep30/MS system using 20% Isopropanol, Daicel AD 10 mm id×250 mm long columns at 30 ml/min, 40° C. and 100 bar) to afford the title compound as a single enantiomer.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C(O[C:34]([N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([C:48](O)=O)[CH:43]=2)[CH2:38][CH2:37]1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:48][C:44]1[CH:45]=[CH:46][CH:47]=[C:42]([CH:39]2[CH2:38][CH2:37][N:36]([CH3:34])[CH2:41][CH2:40]2)[CH:43]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)O)c2)CC1
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1cccc(C2CCN(C)CC2)c1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 38.4 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (80 mg) and 4-(3-carboxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (100 mg) according to an analogous synthetic method to Example 337 described below, the title compound (39 mg) was obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:52]=[CH:53][C:54]=1[Cl:55])[CH2:8][O:9][CH:10]1[O:15][CH:14]([CH2:16][O:17][C:18](=[O:30])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[CH:13]([O:31][CH:32]2[O:41][CH:40]3[CH:35]([O:36][CH:37]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[O:38][CH2:39]3)[CH:34]([OH:48])[CH:33]2[OH:49])[CH:12]([OH:50])[CH:11]1[OH:51])(=[O:3])[CH3:2].[K+].[Br-]>O>[C:14]([O:50][CH:12]1[CH:11]([O:51][C:18](=[O:17])[CH3:19])[CH:10]([O:9][CH2:8][C:7]2[CH:52]=[CH:53][C:54]([Cl:55])=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=2)[O:15][CH:14]([CH2:16][O:17][C:18](=[O:30])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[CH:13]1[O:31][CH:32]1[O:41][CH:40]2[CH:35]([O:36][CH:37]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:38][CH2:39]2)[CH:34]([O:48][C:8](=[O:9])[CH3:7])[CH:33]1[O:49][C:1](=[O:3])[CH3:2])(=[O:15])[CH3:13]
Reactant: COc1ccc(CC(=O)OCC2OC(OCc3ccc(Cl)c(NC(C)=O)c3)C(O)C(O)C2OC2OC3COC(c4ccccc4)OC3C(O)C2O)cc1OC
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: COc1ccc(CC(=O)OCC2OC(OCc3ccc(Cl)c(NC(C)=O)c3)C(OC(C)=O)C(OC(C)=O)C2OC2OC3COC(c4ccccc4)OC3C(OC(C)=O)C2OC(C)=O)cc1OC

Procedure:
The title compound was prepared as a white foam (0.105 g, 89%) from (3,4-dimethoxy-phenyl)-acetic acid 6-(3-acetylamino-4-chloro-benzyloxy)-3-(7,8-dihydroxy-2-phenyl-hexahydro-pyrano[3,2-d][1,3]dioxin-6-yloxy)-4,5-dihydroxy-tetrahydro-pyran-2-ylmethyl ester using a procedure similar to Example 25, mp >98° C. (decomp.); 1H NMR (DMSO-d6) δ1.92 (s, 3H), 1.94 (s, 3H), 1.97 (s, 3H), 1.99 (s, 3H), 2.07 (s, 3H), 3.62-3.77 (m, 4H), 3.66 (s, 3H), 3.67 (s, 3H), 3.89 (t, J=9.2 Hz, 2H), 3.99-4.03 (m, 1H), 4.10 (dd, J=10.5, 16.0 Hz, 1H), 4.19 (dd, J=4.4, 11.9 Hz, 1H), 4.44-4.50 (m, 2H), 4.64-4.70 (m, 2H), 4.84 (d, J=8.1 Hz, 1H), 4.87 (dd, J=4.0, 10.1 Hz, 1H), 5.21 (d, J=3.7 Hz, 1H), 5.25 (d, J=9.9 Hz, 1H), 5.30 (t, J=9.2 Hz, 1H), 5.62 (s, 1H), 6.77 (dd, J=1.8, 8.1 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 6.86 (d, J=1.8 Hz, 1H), 7.04 (dd, J=1.8, 8.3 Hz, 1H), 7.35 (s, 5H), 7.44 (d, J=8.1 Hz, 1H), 7.61 (s, 1H), 9.51 (s, 1H); IR (KBr) 3370, 2930, 2860, 1755, 1690, 1600, 1520, 1450, 1420, 1370, 1240, 1140, 1055, and 1030 cm−1; mass spectrum [(+) FAB], m/z 958/960 (M+H)+, 980/982 (M+Na)+; Anal. Calcd. for C46H52ClNO19.1.75 H2O: C, 55.81; H, 5.65; N, 1.41, Found: C, 55.60; H, 5.14; N, 1.38.
Reaction SMILES: C([O:3][C:4]([C:6](=O)[CH:7]([CH3:20])[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[O-])=[O:5])C.[Li+].Cl.[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[NH:32][NH2:33].S(=O)(=O)(O)O>C(O)C>[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[N:32]1[C:8]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=2)=[C:7]([CH3:20])[C:6]([C:4]([OH:3])=[O:5])=[N:33]1
Reactant: NNc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(=O)C(C)C([O-])c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: CCO
Product: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
A solution of 10 g of Lithium 3-ethoxycarbonyl-2-methyl-3-oxo-1-(4-trifluoromethyl-phenyl)-propan-1-olate, 6.9 g of (2,4-Dichloro-phenyl)-hydrazine hydrochloride and 74 ml of sulfuric acid (50%) in 184 ml of ethanol was heated to reflux for 7 h. After cooling to room temperature the organic solvents were removed under reduced pressure and the residue was diluted with 100 ml of water and extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was dissolved in 100 ml THF and a solution of 1.4 g of LiOH in 20 ml water was added at room temperature. The reaction mixture was heated to 60° C. for 7 h. Then, after cooling to room temperature the mixture was acidified to pH 1 by addition of half-concentrated hydrochloric acid.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[F:21])[CH:3]=1.[CH3:22][N:23]([CH3:43])[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1.[F-].[Cs+].C(=O)(O)[O-].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O:11][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:3]=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([O:27][CH2:26][CH2:25][CH2:24][N:23]([CH3:22])[CH3:43])=[N:29][CH:30]=3)[S:10][C:9]=12
Reactant: CN(C)CCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(Br)sc23)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CN(C)CCCOc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cn1
Yield: 72.4 %

Procedure:
Bromothienopyridine 50 (1.22 g, 3.30 mmol), N,N-dimethyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yloxy)propan-1-amine (1.15 g, 3.76 mmol), and tetrakis(triphenylphosphine)palladium (0.14 g, 0.12 mmol) were dissolved in dry DME (100 mL). Cesium fluoride (1.51 g, 10.0 mmol) and sodium bicarbonate (0.81 g, 9.6 mmol) were dissolved in water (5 ml each) and added to the reaction mixture, which was degassed with a stream of N2, then heated to reflux for 4 h, cooled, and concentrated. The residue was partitioned between ethyl acetate and water. The organic phase was collected, washed with brine, dried (anhydrous MgSO4), filtered, and concentrated. The resulting orange solid was triturated with ether to provide 379 (1.12 g, 75% yield). LRMS (M+H): 469.2.
Reaction SMILES: C(O)(=O)/C=C/C(O)=[O:5].[CH3:9][C:10]1[CH:41]=[CH:40][CH:39]=[CH:38][C:11]=1[CH2:12][NH:13][C:14]([C:16]1[CH:29]=[CH:28][C:27]2[S:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH:30]([CH3:37])[CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[C:18]=2[CH:17]=1)=S>C(O)(=O)C>[CH3:9][C:10]1[CH:41]=[CH:40][CH:39]=[CH:38][C:11]=1[CH2:12][NH:13][C:14]([C:16]1[CH:29]=[CH:28][C:27]2[S:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH:30]([CH3:37])[CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[C:18]=2[CH:17]=1)=[O:5]
Reactant: Cc1ccccc1CNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Reactant: O=C(O)/C=C/C(=O)O
Solvent: CC(=O)O
Product: Cc1ccccc1CNC(=O)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Temperature: 20 °C
Reaction time: 12 h

Procedure:
Fumaric acid (0.7 g) and mercuric acetate (2.5 g) are added in the course of 20 minutes to a solution of N-(2-methylbenzyl)-10[1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide, L series (3.8 g) in acetic acid (30 cc), and the mixture obtained is stirred for 12 hours at a temperature in the region of 20° C. The black suspension obtained is filtered on sintered glass plugged with Celite and the yellow filtrate is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is taken up with ethyl acetate (100 cc) and the organic phase is washed successively with normal sodium hydroxide (2×20 cc) and distilled water (2×20 cc) and with saturated aqueous sodium chloride solution (20 cc) and dried over magnesium sulphate. After filtration, the yellow filtrate is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. and N-(2-methylbenzyl)-10-[1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide, L series (3.2 g), is thereby obtained in the form of a yellow oil, which is used subsequently without further treatment.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:17](OC)=[O:18])=[C:5]([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[CH:8]=2)[N:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH3:1][C:2]1[O:3][C:4]([CH2:17][OH:18])=[C:5]([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[CH:8]=2)[N:6]=1
Reactant: COC(=O)c1oc(C)nc1-c1ccc2c(c1)CCCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: Cc1nc(-c2ccc3c(c2)CCCC3)c(CO)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of methyl [2-methyl-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-5-oxazolyl]carboxylate (4.5 g) in diethyl ether (90 mL) was added lithium aluminum hydride (0.63 g) at 0° C. After stirring the reaction mixture at room temperature for 30 min, water (3.2 mL) was added, and the precipitated solid was removed by filtration. The filtrate was concentrated and the obtained solid was washed with isopropyl ether to give [2-methyl-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-5-oxazolyl]methanol (3.63 g, yield 90%) as crystals. Recrystallization from ethanol gave colorless crystals. melting point: 132–133° C.
Reaction SMILES: [O:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([NH2:10])[C:4]=2[CH:3]=[CH:2]1.[CH3:11]C1C(=O)C2C=COC=2CC1>>[CH3:11][CH:8]1[CH:9]([NH2:10])[C:4]2[CH:3]=[CH:2][O:1][C:5]=2[CH2:6][CH2:7]1
Reactant: CC1CCc2occc2C1=O
Reactant: NC1CCCc2occc21
Product: CC1CCc2occc2C1N

Procedure:
Following the procedure for the preparation of 4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting 5-methyl-6,7-dihydro-1-benzofuran-4(5H)-one and making non-critical variations provided the title compound as a oil: MS (EI) m/z (rel. intensity) 151 (M+, 64), 151 (64), 134 (86), 110 (83), 109 (99), 108 (55), 88 (56), 86 (87), 84 (92), 80 (76), 51 (67). HRMS (FAB) calcd for C9H13NO+H 152.1075, found 152.1066.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([N:25]([CH2:27][CH2:28][O:29][CH3:30])[CH3:26])=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:15][C:14]([Cl:24])=[CH:13][CH:12]=2)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:24][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([N:25]([CH2:27][CH2:28][O:29][CH3:30])[CH3:26])[C:8]([C:6]([OH:7])=[O:5])=[C:17]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COCCN(C)c1nc2ccc(Cl)cc2c(-c2ccccc2)c1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COCCN(C)c1nc2ccc(Cl)cc2c(-c2ccccc2)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 42 step B from 6-chloro-2-[(2-methoxy-ethyl)-methyl-amino]-4-phenyl-quinoline-3-carboxylic acid tert-butyl ester and TFA. Light yellow foam. MS (ESI): 369 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:23])[CH:19]=3)[N:14]=1)[CH2:9][CH2:8]2.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31](O)=[O:32])[CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH:23][C:31]([CH:28]4[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]4)=[O:32])[CH:19]=3)[N:14]=1)[CH2:9][CH2:8]2
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Reactant: CN1CCC(C(=O)O)CC1
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)C4CCN(C)CC4)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example 172) and 1-methyl-piperidine-4-carboxylic acid; MS: m/e=414.3 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][CH:6]=1)[CH3:3].[N:14]([N:16]1[CH2:21]CNC[CH2:17]1)=[O:15]>C1(C)C=CC=CC=1>[N:14]([N:16]1[CH2:21][CH2:1][N:2]([CH2:4][C:5]2[C:9]3[C:8](=[CH:13][CH:12]=[CH:11][CH:10]=3)[NH:7][CH:6]=2)[CH2:3][CH2:17]1)=[O:15]
Reactant: O=NN1CCNCC1
Reactant: CN(C)Cc1c[nH]c2ccccc12
Solvent: Cc1ccccc1
Product: O=NN1CCN(Cc2c[nH]c3ccccc23)CC1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
A mixture of 34.8 g (0.22 mol) of gramine and 23.9 g (0.20 mol) of nitrosopiperazine in 700 ml. of toluene is refluxed while stirring under nitrogen for 48 hours. The reaction solution is then concentrated under reduced pressure until a precipitate appears and then is cooled to 0° C. and is filtered. The product is washed with cold toluene and dried to produce crystals of 3-(4-nitrosopiperazin-1-yl)methylindole. This product is recrystallized from toluene to yield pure plates, m.p. 116°-118° C. Analysis: Calculated for C13H16N4O: 63.92% C; 6.60% H; 22.93% N Found: 63.84% C; 6.64% H; 23.06% N.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH2:10][CH2:9][C:8]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][C:6]=2[CH:21]=1.B([O-])([O-])O[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][CH3:36])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(CCO)=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][O:15][CH2:14][CH2:13][CH2:12][N:11]1[C:5]2[CH:4]=[CH:3][C:2]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][CH3:36])=[CH:26][CH:25]=3)=[CH:21][C:6]=2[CH:7]=[C:8]([C:17]([O:19][CH3:20])=[O:18])[CH2:9][CH2:10]1
Reactant: COCCCN1CCC(C(=O)OC)=Cc2cc(Br)ccc21
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Solvent: O
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CCCOC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
A mixture of methyl 7-bromo-1-(3-methoxypropyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (450 mg), 4-(2-propoxyethoxy)phenyl borate (313 mg) and potassium carbonate (351 mg) in toluene-ethanol-water (15-1.5-1.5 ml) was stirred at room temperature for 1 hour under argon atmosphere. To the reaction system was added tetrakistriphenylphosphinepalladium (73 mg), and the mixture was heated to reflux for 20 hours. After cooled to room temperature, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified with column chromatography (ethyl acetate:hexane=1:4→1:2) to give methyl 1-(3-methoxypropyl)-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (376 mg) as yellow oil.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.OC1[CH:15]=[C:16]([C:20]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)([O:23][CH3:24])CC)C=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=C(C=CCO)C=1.C(O)=CC>O1CCCC1>[CH3:24][O:23][CH:20]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[CH2:16][CH3:15]
Reactant: CCC(OC)(c1cccc(O)c1)c1nccs1
Agent: CC=CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: OCC=Cc1cccnc1
Solvent: C1CCOC1
Product: CCC(OC)c1nccs1
Reaction time: 2 h
Yield: 69.4 %

Procedure:
Diethyl azodicarboxylate (0.38 ml) was added dropwise to a mixture of 2-[1-(3 hydroxyphenyl)-1-methoxypropyl]thiazole (0.37 g), triphenylphosphine (0.57 g), 3-(3-pyridyl)prop-2-en-1-ol (0.27 g) and tetrahydrofuran (7 ml) which had been cooled to 0°-5° C. in an ice-bath. The mixture was stirred at this temperature range for 2 hours and then at ambient temperature for 4 hours. Further portions of diethyl azodicarboxylate (0.1 ml), triphenylphosphine (0.14 g) and the propenol (0.045 g) were added and the mixture was stirred at ambient temperature for 18 hours. The mixture was partitioned between ethyl acetate (40 ml) and dilute aqueous hydrochloric acid (40 ml). The aqueous layer was separated and basified by adding potassium carbonate portionwise. The resulting solution was extracted with ethyl acetate (3×20 ml). The combined extracts were dried (Na2SO4) and evaporated. The residue was purified by column chromatography eluting with toluene/ethyl acetate (2/3 v/v) to give 2-[1-[3-(3-pyridyl)prop-2-en-1-yloxy)phenyl[-1-methoxypropylthiazole as a colourless oil (0.162 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([Cl:14])=[N:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[CH:4][N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[NH2:20]>CCN(CC)CC>[Cl:14][C:9]1[C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:20][C:19]3[CH:21]=[C:22]([O:26][CH3:27])[C:23]([O:24][CH3:25])=[C:17]([O:16][CH3:15])[CH:18]=3)[N:7]=2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Clc1ncnc(-c2cccnc2Cl)n1
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: CCN(CC)CC
Product: COc1cc(Nc2ncnc(-c3cccnc3Cl)n2)cc(OC)c1OC
Yield: 89.2 %

Procedure:
2-Chloro-4-(2-chloro-pyridin-3-yl)-[1,3,5]triazine (1.7 g, 7.5 mmol) was stirred overnight at RT with 3,4,5-trimethoxyaniline (1.5 g, 8.3 mmol) in IpOH (200 mL). After addition of Et3N (2 ml), stirring was continued for an additional day. The mixture was concentrated, triturated with t-BuOMe and filtered, rinsing with a small amount of IpOH. The [4-(2-chloro-pyridin-3-yl)-[1,3,5]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)amine (2.5 g) was isolated as the Et3HN+Cl− salt. Part of this material was filtered through a plug of silica and analyzed. MS m/z=374 [M+H]+; 3H). Calc'd for C17H16ClN5O3: 373.09. Remaining material was used without filtering in the next step.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:14][Si:15](Cl)([CH3:17])[CH3:16]>C1COCC1>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:13]=[CH:12][C:10]([N:11]([Si:15]([CH3:17])([CH3:16])[CH3:14])[Si:15]([CH3:17])([CH3:16])[CH3:14])=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: C[Si](C)(C)N(c1ccc(N2CCOCC2)cc1)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 73 %

Procedure:
4-Morpholinoaniline (1 g, 5.61 mmol) was dissolved in dry THF (25 ml). N-BuLi (1.41M, 8.8 ml) was added dropwise at 0° C. over 5 minutes and the solution changed from brown to yellow. After stirring for 2.5 hours while warming to room temperature, trimethylsilyl chloride (97%, 1.62 ml) was added, followed by stirring at room temperature for 12 hours. Evaporation of the solvent gave a yellow solid which was sublimed at 10-4 torr to produce pure 4-morpholino-N,N-bistrimethylsilyl aniline as white solid (1.32 g, 73%). 1H NMR (CDCl3) 6.75 (s, Ph, 4H), 3.81 (t, CH2, 4H), 3.05 (t, CH2, 4H), 0.03 (s, TMS, 18H) .
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=O)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.N1C2C(=CC(C=O)=CC=2)C=N1.[S:35]=[C:36]1[NH:40][C:39](=[O:41])[CH2:38][S:37]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:38]4[S:37][C:36](=[S:35])[NH:40][C:39]4=[O:41])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:20]([F:21])([F:23])[F:22])[CH:3]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Agent: O=Cc1ccc2[nH]ncc2c1
Product: O=C1NC(=S)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-one was prepared from 1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde was prepared from 1H-indazole-5-carbaldehyde and 2-thioxo-thiazolidin-4-one following General Procedure B.