Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][C:4](=[O:8])[C:5]([OH:7])=O.O.ON1C2C=CC=CC=2N=N1.C(Cl)CCl.[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][CH:38]([CH:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[CH2:37][CH2:36]2)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:9][CH:2]([CH3:1])[CH2:3][C:4](=[O:8])[C:5]([N:44]1[CH2:43][CH2:42][CH:41]([CH:38]2[CH2:37][CH2:36][N:35]([C:32]3[CH:31]=[CH:30][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:34][CH:33]=3)[CH2:40][CH2:39]2)[CH2:46][CH2:45]1)=[O:7]
Reactant: CS(=O)(=O)c1ccc(N2CCC(C3CCNCC3)CC2)cc1
Reactant: CC(C)CC(=O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O
Product: CC(C)CC(=O)C(=O)N1CCC(C2CCN(c3ccc(S(C)(=O)=O)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-methyl-2-oxovaleric acid (8.07 mg; 0.062 mmol) was treated sequentially with 1-hydroxybenzotriazole hydrate (11.4 mg; 0.0741 mmol), EDC (14.3 mg; 0.074 mmol) and 1 1-[4-(methylsulfonyl)phenyl]-4,4′-bipiperidine (20.0.0 mg; 0.062 mmol) and stirred at ambient temperature for 18 h. The reaction was diluted with CH2Cl2(10 mL) and washed with water (15 mL). The organic phase was then dried over Na2SO4, filtered and concentrated in. vac to a residue. The crude product was purified by preparative HPLC reserve phase and eluted with acetonitrile/water+0.1% TFA. The title compound was isolated.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=2[CH3:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26].C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[C:16]([NH:18][C:25]([C:21]3[S:20][CH:24]=[CH:23][CH:22]=3)=[O:26])[CH:15]=[CH:14][C:13]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1cccs1
Reactant: CCOC(=O)c1ccc(-c2cc(N)ccc2C)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)c3cccs3)ccc2C)cc1
Reaction time: 18 h
Yield: 106 %

Procedure:
A mixture of 5′-amino-2′-methyl-biphenyl-4-carboxylic acid ethyl ester (280 mg) and thiophene-2-carbonyl chloride (161 mg) in dichloromethane (5 ml) containing triethylamine (222 mg) was stirred at 20 C for 18 h. The mixture was then partitioned between water and dichloromethane. The dried extracts were then evaporated giving the title compound as a colourless solid (425 mg)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:47]1(=[O:57])[NH:51][C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]12>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:51]2[C:47](=[O:57])[C:48]3[C:49](=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:50]2=[O:52])=[N:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1ccc(Br)cn1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(Br)cn1
Yield: 63.9 %

Procedure:
A mixture of (5-bromopyridin-2-yl)methanol (1.2 g, 6.38 mmol), 1,1′-(azodicarbonyl)-dipiperidine (2.093 g, 8.30 mmol), triphenylphosphine (2.176 g, 8.30 mmol) and phthalimide (1.221 g, 8.30 mmol) in THF (60 mL) at rt was stirred over the weekend. The reaction mixture was filtered and the filtrate was concentrated to a yellow solid that was triturated with methanol. Filtration and drying afforded 2-((5-bromopyridin-2-yl)methyl)isoindoline-1,3-dione (1.295 g, 4.08 mmol, 64.0% yield) as a colorless crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J=2.0 Hz, 1H), 8.03 (dd, J=8.4, 2.2 Hz, 1H), 7.90 (d, J=9.0 Hz, 4H), 7.44 (d, J=8.4 Hz, 1H), 4.89 (s, 2H). MS (ES+) m/z: 316.95, 318.96 (M+H); LC retention time: 2.297 min (analytical HPLC Method O).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16](=[O:33])[CH2:17][CH2:18][N:19]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[CH2:20][CH2:21][OH:22])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.P([O-])(O)(O)=O.[K+]>ClCCl>[C:11]([O:15][C:16](=[O:33])[CH2:17][CH2:18][N:19]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[CH2:20][CH:21]=[O:22])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)CCN(CCO)C(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)CCN(CC=O)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
To a solution of 4.53 ml (35.65 mmol) of oxalyl chloride in 76 ml dichloromethane at −50 to −60° C. was added a solution of 5.81 ml (74.40 mmol) dimethylsulfoxide in 16 ml of dichloromethane within 20 min. The solution was stirred for 5 min and a solution of 10.03 g (31.0 mmol) 3-[benzyloxycarbonyl-(2-hydroxy-ethyl)-amino]-propionic acid tert-butyl ester in 67 ml dichloromethane was added within 20 min. The mixture was stirred for 15 min and 21.6 ml (155 mmol) of triethylamine were added within 25 min. The suspension was stirred for 2 h and slowly warmed to 0° C. The reaction was neutralized with cold 10% aq. potassium dihydrogenphosphate solution (adjusted with solid potassium dihydrogenphosphate to pH 4-5) and extracted with diethyl ether (3×). The organic phases were washed with 10% aq. potassium dihydrogenphosphate solution, sat. aq. sodium hydrogencarbonate solution, 10% aq. sodium chloride solution, dried over Na2SO4 evaporated to yield 9.94 g (99.8%) of the title compound as yellow oil. MS: 322.1 (MH+).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[C:10]([C:12]1[CH:33]=[CH:32][C:15]([C:16]([N:18]([CH3:31])[C:19]2[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][C:20]=2[N+:28]([O-:30])=[O:29])=[O:17])=[CH:14][CH:13]=1)#[N:11].Cl.[NH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40]>C(Cl)Cl>[CH3:42][O:41][C:39]([CH2:38][CH2:37][CH2:36][NH:35][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([N:18]([CH3:31])[C:16](=[O:17])[C:15]2[CH:32]=[CH:33][C:12]([C:10]#[N:11])=[CH:13][CH:14]=2)=[C:20]([N+:28]([O-:30])=[O:29])[CH:21]=1)=[O:40]
Reactant: COC(=O)CCCN
Reactant: CN(C(=O)c1ccc(C#N)cc1)c1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CCCNC(=O)c1ccc(N(C)C(=O)c2ccc(C#N)cc2)c([N+](=O)[O-])c1
Reaction time: 64 h

Procedure:
2.84 g of N-ethyl-diisopropylamine are added, with cooling to 0° C., to a mixture of 3.2 g of 4-[N-(4-cyano-benzoyl)-methylamino]-3-nitro-benzoylchloride, 1.68 g of methyl 4-aminobutyrate-hydrochloride and 50 ml of methylene chloride. The mixture is stirred for 64 hours and allowed to return to ambient temperature. The methylene chloride is evaporated off and the residue is purified over silica gel (eluant:ethyl acetate/ethanol=200:1). Yield: 3.9 g (100% of theory), Rf value: 0.62 (silica gel; ethyl acetate/ethanol=9:1)
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([OH:9])=O)[N:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[C:32]([C:36]1[CH:45]=[CH:44][C:39]([C:40](=[NH:43])[NH:41]O)=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>CN(C=O)C.O.CCOC(C)=O>[C:32]([C:36]1[CH:45]=[CH:44][C:39]([C:40]2[N:41]=[C:7]([C:4]3[N:3]=[C:2]([CH3:1])[NH:6][N:5]=3)[O:9][N:43]=2)=[CH:38][CH:37]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: Cc1nc(C(=O)O)n[nH]1
Reactant: CC(C)(C)c1ccc(C(=N)NO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(-c2nc(-c3ccc(C(C)(C)C)cc3)no2)n[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
5-Methyl-1H-1,2,4-triazole-3-carboxylic acid (200 mg, 1.57 mmol), EDC.HCl (360 mg, 1.89 mmol), and HOBT (255 mg, 1.89 mmol) were dissolved in DMF (15 mL) and the solution was stirred at RT for 30 min. 4-(tert-Butyl)-N-hydroxybenzimidamide (363 mg, 1.89 mmol) was added and the reaction was stirred at RT for 1 h and then at 140° C. for an additional 2 h. The reaction mixture was cooled to RT, and diluted with H2O (100 mL) and EtOAc (100 mL). The organic layer was separated, washed with H2O (2×50 mL) and brine (25 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product which was purified by silica gel chromatography (EtOAc/Hexane 12%-100% EtOAc) to afford 3-(4-(tert-butyl)phenyl)-5-(5-methyl-1H-1,2,4-triazol-3-yl)-1,2,4-oxadiazole as a yellow solid (210 mg, 47%). MS (ES+) C15H17N5O requires: 283. found 284 [M+H]+; 1H NMR (600 MHz, CDCl3) δ 8.02 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 2.50 (s, 3H), 1.34 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH:4]=[CH2:5].[CH2:7](OC(=O)C=C)[CH2:8][CH2:9][CH3:10].[CH2:16](OC(=O)C=C)C>>[C:3]([O:2][CH2:1][C:9]([CH3:10])([CH3:16])[CH2:8][CH3:7])(=[O:6])[CH:4]=[CH2:5]
Reactant: C=CC(=O)OCCCC
Reactant: C=CC(=O)OC
Reactant: C=CC(=O)OCC
Product: C=CC(=O)OCC(C)(C)CC

Procedure:
Especially suited (meth)acrylic acid esters are 2-propenoic acid methyl ester, 2-propenoic acid n-butyl ester and 2-propenoic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:9]([I:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4](Cl)[CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[NH2:1][C:2]1[C:9]([I:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: N#Cc1cc(I)c(N)cc1Cl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc(I)c(N)cc1N1CCOCC1
Temperature: 100 °C
Reaction time: 40 h

Procedure:
To a flask containing 4-amino-2-chloro-5-iodobenzonitrile (1 g, 3.6 mmol) in DMSO (5.0 mL) was added morpholine (1.0 mL, 11.5 mmol) dropwise. Upon complete addition, the mixture was warmed to 100° C. After 40 h, the reaction mixture was cooled to rt, then an additional 2 mL of morpholine was added to the mixture. The reaction was re-heated to 100° C. and monitored with LC-MS. After 17 h, the reaction was cooled to rt, then 1 g of potassium carbonate was added in portions. The reaction was re-heated to 100° C. and monitored with LC-MS. After 13 days, the reaction was diluted with water then subsequently extracted five times with EtOAc. The organic extractions were then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-35% EtOAc in hexanes) to afford a pale brown solid as 4-amino-5-iodo-2-morpholinobenzonitrile. 1H NMR (500 MHz, CDCl3) δ ppm 7.80 (1H, m), 6.27 (1H, s), 4.57 (2H, br. s.), 3.92 (4H, m), 3.20 (4H, m). Mass Spectrum (pos.) m/e: 330.0 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21]C1C=CC=CC=1B(O)O>>[Cl:21][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[C:7]1[NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=1[C:14]=23
Reactant: OB(O)c1ccccc1Cl
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: O=C1NCCc2c(-c3ccccc3Cl)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (210 mg, 0.79 mmol) and 2-chlorophenylboronic acid (136 mg, 0.87 mmol) were coupled to yield 2-(2-chlorophenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 78 mg (33%), as a shiny white solid. mp 275° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ2.76 (m, 2H), 3.38 (m, 2H), 7.23 (app t, 1H, J=7.8 Hz), 7.56 (m, 5H), 7.71 (dd, 1H, J=7.5, 0.9 Hz), 8.07 (br t, 1H), 11.53 (br s, 1H); MS (FAB, MH+) 297; Anal. (C17H13N2OCl.0.15 H2O) C, H, N.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:20]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:33][C:34]1[CH:49]=[CH:48][C:37]([C:38]([NH:40][CH:41]2[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]2)=[O:39])=[CH:36][CH:35]=1>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([C:38]([NH:40][CH:41]5[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]5)=[O:39])=[CH:48][CH:49]=4)=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17]1
Reactant: CN1CCC(NC(=O)c2ccc(N)cc2)CC1
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCC3)CC(F)(F)C(=O)N4C)cc2)CC1
Yield: 63.8 %

Procedure:
A mixture of 0.0605 g (0.20 mmole) 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1), 0.0571 g (0.30 mmole) of toluenesulfonic acid monohydrate, 0.0467 g (0.20 mmole) of 4-amino-N-(1-methyl-piperidin-4-yl)-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 19.5 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from acetonitrile-methanol to give 0.0637 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide (I-16) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:12][CH3:13])[CH2:7]2.[Cl:14][C:15]1[C:16]([O:26][CH3:27])=[CH:17][C:18]([O:24][CH3:25])=[C:19]([CH:23]=1)[C:20](Cl)=[O:21]>>[ClH:14].[CH2:12]([N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:20](=[O:21])[C:19]2[CH:23]=[C:15]([Cl:14])[C:16]([O:26][CH3:27])=[CH:17][C:18]=2[O:24][CH3:25])[CH2:7]1)[CH3:13]
Reactant: CCN1CCc2c(N)cccc2C1
Reactant: COc1cc(OC)c(C(=O)Cl)cc1Cl
Product: CCN1CCc2c(cccc2NC(=O)c2cc(Cl)c(OC)cc2OC)C1
Product: Cl

Procedure:
The title compound was prepared in an analogous manner to Example 2 from 5-amino-2-ethyl-1,2,3,4-tetrahydroisoquinoline and 5-chloro-2,4-dimethoxybenzoyl chloride.
Reaction SMILES: C(OP([CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[CH:20][CH:19]=2)[CH:11]=1)[F:9])OCC)C.[Li+].CC([N-]C(C)C)C.[CH:36]1([CH:39]=O)[CH2:38][CH2:37]1.Cl>O.C1COCC1>[CH:36]1([CH:39]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[C:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH:25]([F:26])[F:27])=[CH:22][CH:23]=3)[CH:11]=2)[F:9])[CH2:38][CH2:37]1
Reactant: O=CC1CC1
Reactant: CCOP(OCC)C(F)c1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: FC(=CC1CC1)c1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Reaction time: 0.5 h

Procedure:
Into a cold solution of diethyl[(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)(fluoro)methyl]phosphonite (2.0 g, 4.08 mmol) and THF (20 mL) was added dropwise LDA (14.64 mL, 1.0M). The mixture was stirred for 30 minutes and then cyclopropanecarbaldehyde (410 mg, 5.8 mmol) was added and the mixture was allowed to come to room temperature and stirred for 24 hours. Then, HCl (5 mL, 2N) was added and the mixture was stirred for 30 minutes, poured into water and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by ICSO (hexane/EtOAc 20/1) gavel-(2-cyclopropyl-1-fluorovinyl)-3-{[4-(difluoromethoxy)phenyl]ethynyl}benzene 1:1 Z/E isomers as a yellow oil (0.72 g); MS m/e (M)+ 328.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([OH:20])=O)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:21]([N:23](CC)[CH2:24][CH3:25])[CH3:22].ClC(OCC)=O.C(NCC)C>C(Cl)(Cl)Cl>[CH2:21]([N:23]([CH2:24][CH3:25])[C:18]([C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:17]2[C:12]([CH:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:20])[CH3:22]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc2ccccc2c(-c2cccc(Cl)c2)n1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCNCC
Product: CCN(CC)C(=O)c1cc2ccccc2c(-c2cccc(Cl)c2)n1
Yield: 71.4 %

Procedure:
Operations are carried out as for Example 7, starting with 1.7 g of 1-(3-chlorophenyl) isoquinoline 3-carboxylic acid, 0.69 g of triethylamine, 0.74 g of ethyl chloroformate and 0.56 g of diethylamine in 60 ml of chloroform. 1.45 g of N,N-diethyl 1-(3-chlorophenyl) isoquinoline 3-carboxamide melting at 116° C., are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([NH2:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[Ca+2].Cl[CH2:19][CH:20]([OH:23])[CH2:21][OH:22]>O>[CH3:1][C:2]1[CH:8]=[C:7]([NH2:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH:4][CH:21]([OH:22])[CH:20]([OH:23])[CH3:19]
Reactant: Cc1cc(N)c([N+](=O)[O-])cc1N
Reactant: OCC(O)CCl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: Cc1cc(N)c([N+](=O)[O-])cc1NC(O)C(C)O
Temperature: 0 °C

Procedure:
0.2 mol (33.4 g) of 2-methyl-4-amino-5-nitroaniline and 0.1 mol (10 g) of calcium carbonate, suspended in 100 ml of water, are heated beforehand on a boiling water-bath, whilst stirring. 0.216 mol (24 g) of 1-chloropropane-2,3-diol is added. The reaction mixture is heated for 24 hours on the boiling water-bath, seven portions each containing 0.035 mol (3.5 g) of calcium carbonate and 0.066 mol (7.3 g) of 1-chloropropane-2,3-diol being added, one every three hours. The hot reaction mixture is filtered and the filtrate is diluted with 60 ml of water. After cooling for 24 hours at 0° C., the expected product, which has crystallised, is filtered off. The product is washed with water and recrystallised three times from ethanol. It melts at 150° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C:18]([OH:20])=O)=[C:6]2[O:21][CH:22]([CH3:24])[CH3:23].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[OH:32].C(N(CC)CC)C.O>O1CCCC1>[OH:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:25][C:18]([C:7]1[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:5]([C:6]=1[O:21][CH:22]([CH3:24])[CH3:23])=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)=[O:20]
Reactant: Nc1ccccc1O
Reactant: COc1ccc2c(c1)c(OC(C)C)c(C(=O)O)n2-c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)c(OC(C)C)c(C(=O)Nc1ccccc1O)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
The procedure described in Example 16 is used to prepare the acyl chloride of 5-methoxy-3-(1-methylethoxy)-1-phenyl-1H-indole-2-carboxylic acid (4.0 g, 12 mmol). A solution of the crude acyl chloride in 45 mL of tetrahydrofuran is cooled in ice and treated dropwise with a solution of 2-aminophenol (1.3 g, 12 mmol) in 20 mL of tetrahydrofuran, followed by dropwise addition of triethylamine (1.7 mL, 1.2 g, 12 mmol). The mixture is stirred at room temperature for 2 hours and added to 300 mL of water. The mixture is extracted with dichloromethane, and the combined organic layers are washed with brine, dried (anhydrous sodium sulfate), and evaporated. Trituration of the residue with tert-butyl methyl ether yields 3.5 g (69%) of product; mp 168°-170° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH2:8][CH2:9][CH2:10]O)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:32][CH2:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCc1cccc(Cl)c1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: Fc1c(Cl)cccc1CCCBr
Yield: 87.1 %

Procedure:
Compound 63-2 (2.48 g) was dissolved in methylene chloride (45 ml), triphenylphosphine (3.80 g) and N-bromosuccinimide (2.57 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.88 g) as a colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[C:42]2[N:43]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[C:44](=[O:48])[CH2:45][CH2:46][CH2:47][C:41]=2[CH:40]=[CH:39][CH:38]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[C:42]3[N:43]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:54])([CH3:56])[CH3:55])[C:44](=[O:48])[CH2:45][CH2:46][CH2:47][C:41]=3[CH:40]=[CH:39][CH:38]=2)=[CH:9][CH:10]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)CCCc2cccc(CCl)c21
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc3c2N(COCC[Si](C)(C)C)C(=O)CCC3)cc1

Procedure:
Analogously to Method D, 0.400 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.303 g of 9-chloromethyl-1-(2-trimethylsilanylethoxymethyl)-1,3,4,5-tetrahydrobenz[b]azepin-2-one are reacted. The title compound is obtained as a yellowish oil. Rf=0.20 (1:1 EtOAc-heptane); Rt=6.58.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][O:11][C:12]1[C:13]([CH3:18])=[N:14][CH:15]=[CH:16][CH:17]=1>>[CH3:10][O:11][C:12]1[C:13]([CH3:18])=[N:14][C:15]([N+:6]([O-:9])=[O:7])=[CH:16][CH:17]=1
Reactant: COc1cccnc1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COc1ccc([N+](=O)[O-])nc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cold mixture of 3 ml. of concentrated sulfuric acid and 3 ml. of fuming nitric acid, was added 0.5 g. of 3-methoxy-2-methylpyridine over 5 minutes. After warming spontaneously to room temperature the mixture was heated at 55°-60° C. for 6 hours. The mixture was cooled and added to 35 ml. of ice-water. After stirring 2 hours, the precipitate was collected and dried to give 3-methoxy-2-methyl-6-nitropyridine, m.p. 99°-100.5° C.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:28][C:15]3[N:16]=[C:17](SC)[N:18]=[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].C([Sn](CCCC)(CCCC)[C:34]1[CH:35]=[N:36][C:37]2[N:42]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[CH:41]=[N:40][C:38]=2[CH:39]=1)CCC>COCCOC.C(OCC)(=O)C.[Cu]Br.CSC.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>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:28][C:15]3[N:16]=[C:17]([C:34]4[CH:39]=[C:38]5[N:40]=[CH:41][N:42]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:37]5=[N:36][CH:35]=4)[N:18]=[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:3])=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2c(c1)ncn2COCC[Si](C)(C)C
Reactant: CSc1nc(N2CCOCC2)c2cc(CN3CCN(S(C)(=O)=O)CC3)sc2n1
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CSC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cnc2cc(-c3nc(N4CCOCC4)c4cc(CN5CCN(S(C)(=O)=O)CC5)sc4n3)cnc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-yl-thieno[2,3-d]pyrimidine (90 mg) in 1,2-dimethoxyethane (10 mL) was added 6-tributylstannanyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-]pyridine (219 mg) and copper(I)bromide-dimethylsulfide (84 mg) and the reaction stirred at room temperature for 10 min. Then, tetrakis(triphenylphosphine)palladium (0) (12 mg) was added and the reaction heated at reflux for 16 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (2×30 mL), aqueous brine solution (2×20 mL), dried (MgSO4), reduced in vacuo and purified by column chromatography to give 6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-2-[3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]-thieno[2,3-d]pyrimidine as a white solid.