Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16]C)=[C:8]2[C:4]=1[CH2:5][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[C:30](=[O:31])[C:29]3=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]3[C:27]1=[O:36])[CH2:7]2.N1C(C(O)=O)=CC=CC=1C(O)=O.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O.C(OCC)(=O)C>[CH3:15][O:14][C:10]1[C:9](=[O:16])[C:8]2[CH2:7][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]3[C:30](=[O:31])[C:29]4=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]4[C:27]3=[O:36])[CH2:5][C:4]=2[C:3](=[O:2])[C:11]=1[O:12][CH3:13]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCN1C(=O)c3ccccc3C1=O)C2
Agent: O=C(O)c1cccc(C(=O)O)n1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C2=C(CC(CCCCCCCCN3C(=O)c4ccccc4C3=O)C2)C1=O
Reaction time: 0.25 h
Yield: 76.1 %

Procedure:
To a mixture of N-[8-(4,5,6,7-tetramethoxyindan-2-yl)octyl]phthalimide (470 mg), 2,6-pyridinedicarboxylic acid (475 mg), acetonitrile (10 ml), and water (5 ml) was dropwise added a solution of CAN (1.56 g) in acetonitrile (1.5 ml) and water (1.5 ml) with cooling with ice. After the reaction mixture was stirred for 15 min, a solution of CAN (520 mg) in water (2.0 ml) was dropwise added with cooling with ice and stirring was continued for additional 15 min. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=5:1) and then with recrystallization from hexane-ethyl acetate to yield the entitled compound (336 mg) as crystals.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([C:10](=[O:15])[C:11](Br)([CH3:13])[CH3:12])[CH:4]=1>C(O)C.C1C=CC=CC=1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]2[O:9][C:11]([CH3:13])([CH3:12])[C:10](=[O:15])[C:5]=2[CH:4]=1
Reactant: CC(C)(Br)C(=O)c1cc(Cl)ccc1O
Agent: [Na]
Solvent: CCO
Solvent: c1ccccc1
Product: CC1(C)Oc2ccc(Cl)cc2C1=O
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 82.5 %

Procedure:
With stirring under ice-cooling, 3 g of metallic sodium were added in 100 ml of absolute ethanol to dissolve the metal. Then, 12.5 g (0.045 mol) of 4-chloro-2-(2-bromoisobutyryl)phenol dissolved in 60 ml of benzene was added to the said solution dropwise for about 15 minutes under heating to reflux (internal temperature: 80° C.). After the completion of the dropping, the stirring was continued for additional 30-60 minutes with heating and the solution was vacuum-concentrated to one third in volume. The solution concentrated was diluted with large amount of water, and the solution was extracted with ether. The ether layer was washed with water, then vacuum-concentrated to dryness to produce 10 g of crude crystallized subject compound, 5-chloro-2,2-dimethyl-4-benzofuran. Then, the crude product was recrystallized from methanol, to obtain 7.3 g (yield: 82.5%) of the subject compound in colorless pillow crystal.
Reaction SMILES: [CH3:1][N:2]([C@@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1)[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([F:13])([F:12])[F:11].Cl[C:21]1[C:22]2[CH:29]=[CH:28][NH:27][C:23]=2[N:24]=[CH:25][N:26]=1.CCN(C(C)C)C(C)C>CCO>[N:24]1[C:23]2[NH:27][CH:28]=[CH:29][C:22]=2[C:21]([N:17]2[CH2:18][CH2:19][C@@H:15]([N:2]([CH3:1])[C:3](=[O:14])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[C:10]([F:13])([F:11])[F:12])[CH2:16]2)=[N:26][CH:25]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CN(C(=O)c1ccccc1C(F)(F)F)[C@@H]1CCNC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ccccc1C(F)(F)F)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Temperature: 25 °C

Procedure:
To a solution of (R)—N-methyl-N-(pyrrolidin-3-yl)-2-(trifluoromethyl)benzamide (1 mmol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.8 mmol) in the EtOH (3 mL) was added DIPEA (2 mmol) with stirring at room temperature. The reaction mixture was refluxed overnight. The mixture was then concentrated, and purified by flash chromatography to give the title compound. MS (m/z): 390 (M+H)+.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH:17]([C:21]([NH:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[O:22])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=CC=1>FC(F)(F)C(O)=O>[C:24]1([NH:23][C:21]([CH:17]2[CH2:16][C:15]3[CH:14]=[N:13][C:12]4[NH:8][N:9]=[CH:10][C:11]=4[C:20]=3[CH2:19][CH2:18]2)=[O:22])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CC(C(=O)Nc2ccccc2)CC4)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1)C1CCc2c(cnc3[nH]ncc23)C1

Procedure:
A solution of 3-(4-Methoxybenzyl)-N-phenyl-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinoline-7-carboxamide in trifluoroacetic acid (5 mL) was heated at 65° C. for 8 hours. The mixture was evaporated to dryness and partitioned between ethyl acetate (100 mL) and saturated sodium hydrogen carbonate (100 mL). The organic layer was dried with anhydrous magnesium sulfate and evaporated under reduced pressure the residue obtained was triturated with dichloromethane (2 mL) to give N-phenyl-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinoline-7-carboxamide as a white powder (10 mg). M.p.=>300° C. 1H NMR (DMSO-d6) 400 MHz δ 13.30 (s, 1H), 10.05 (s, 1H), 8.0 (s, 1H), 7.95 (s, 1H), 7.63 (d, J=7.6 Hz, 2H), 7.31 (t, J=7.6 Hz, 2H), 7.04 (t, J=7.6 Hz, 1H), 3.09-3.00 (m, 4H), 2.96-2.81 (m, 1H), 2.19-2.17 (m, 1H), 2.03-1.93 (m, 1H). LCMS [M+H]: 293.
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9][C@@H:10]([C:12]2[CH:13]=[CH:14][C:15]([OH:21])=[C:16]([NH:18][CH:19]=[O:20])[CH:17]=2)[OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:31][Si:32]([CH3:39])([CH3:38])[CH2:33][CH2:34][O:35][CH2:36]Cl.P([O-])([O-])([O-])=O>CN(C=O)C.O>[C:1]1([CH2:7][N:8]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9][C@@H:10]([C:12]2[CH:13]=[CH:14][C:15]([O:21][CH2:36][O:35][CH2:34][CH2:33][Si:32]([CH3:39])([CH3:38])[CH3:31])=[C:16]([NH:18][CH:19]=[O:20])[CH:17]=2)[OH:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=CNc1cc([C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)ccc1O
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCOc1ccc([C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)cc1NC=O
Reaction time: 0.17 h

Procedure:
A solution of (5-{(1R)2-[bis(phenylmethyl)amino]-1-hydroxyethyl}-2-hydroxyphenyl)formamide (354 mg) in DMF (10 ml) under nitrogen was treated with sodium hydride (60% dispersion in mineral oil, 38 mg) and the mixture stirred at 20° for 10 min. 2-(Trimethylsilyl)ethoxymethyl chloride (0.17 ml) was added and the mixture was stirred at 20° for 3 h. Phosphate buffer solution (pH 6.5) and water were added and the mixture was extracted with EtOAc. The extract was washed with water and dried (Na2SO4). Solvent evaporation in vacuo gave a residue which was purified on a silica SPE bond elut cartridge (20 g) using a gradient of 0% to 2% MeOH in DCM (Gradmaster™). The appropriate fractions were evaporated in vacuo to give the title compound (286 mg). LCMS RT=3.08 min.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:14])[CH2:12][NH2:13].[Cl:15][C:16]1[CH:34]=[CH:33][C:19]([C:20]([C:22]2[N:26]([CH3:27])[C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24][C:23]=2[CH3:32])=[O:21])=[CH:18][CH:17]=1>C(Cl)(Cl)Cl>[Cl:15][C:16]1[CH:34]=[CH:33][C:19]([C:20]([C:22]2[N:26]([CH3:27])[C:25]([CH2:28][C:29]([NH:13][CH2:12][C:11]([O:10][CH3:9])=[O:14])=[O:30])=[CH:24][C:23]=2[CH3:32])=[O:21])=[CH:18][CH:17]=1
Reactant: COC(=O)CN
Reactant: Cc1cc(CC(=O)Cl)n(C)c1C(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)CNC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
A 22.6 ml (0.16 mole) sample of triethylamine was added to a suspension of 6.78 g (0.054 mole) of glycine methyl ester hydrochloride in 200 ml of spectral grade chloroform. The mixture was cooled to 0° C. and a solution of 16.8 g (0.54 mole) of [5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl]-acetyl chloride in 80 ml of chloroform was added slowly. The mixture was stirred at room temperature overnight. The solution was washed successively with dilute hydrochloric acid and water and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo. The residue was recrystallized successively from methanol and acetonitrile to give 9.2 g (47% yield) of crystalline methyl N-{[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl]-acetyl}-glycinate, m.p. 198°-201° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C([C@@]23C(C)(C)[C@@](C)(CC2)C(=O)O3)=O)=[C:4]([C@@:22]([OH:32])([C:27]#[C:28][CH:29]2[CH2:31][CH2:30]2)[C:23]([F:26])([F:25])[F:24])[CH:3]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C@@:22]([OH:32])([C:27]#[C:28][CH:29]2[CH2:31][CH2:30]2)[C:23]([F:25])([F:26])[F:24])[CH:3]=1
Reactant: CC1(C)[C@@]2(C)CC[C@]1(C(=O)Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F)OC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F
Temperature: 92.5 °C
Reaction time: 20 h

Procedure:
A suspension of (1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide (10, 1 g, 2.13 mmol) and 40% NaOH aqueous solution (20 mL) was stirred at 90-95° C. for 20 hours. Toluene (20 mL) was added and the layers were separated. The organic layer was washed with water (20 mL) and evaporated to dryness to give (S)-4-chloro-2-(4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl) aniline (8).
Reaction SMILES: Br[CH:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([C:13]#[N:14])=[CH:8][CH:9]=2)[O:4][CH2:3]1.C(O)(=O)C.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.O>[N:19]([CH:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([C:13]#[N:14])=[CH:8][CH:9]=2)[O:4][CH2:3]1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)OCC(Br)C2=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)OCC(N=[N+]=[N-])C2=O
Temperature: -15 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
3-Bromo-4-oxochroman-7-carbonitrile Int-2-A (140 mg, 0.55 mmol) was dissolved in DMF (3627 μL) and glacial acetic acid (91.0 μL) was added. The solution was cooled to −15° C. To this solution was added sodium azide (54.2 mg, 0.83 mmol) in water (725 μL) dropwise. After stirring for 2 h at −15° C., the reaction mixture was warmed to room temperature and stirred until all the starting material was consumed. The color of the solution turned dark red. The reaction mixture was diluted by the addition of 50 mL water and extracted by EtOAc twice. The combined organic layers were washed with saturated NaHCO3 solution then brine, dried (MgSO4), and filtered before it was concentrated to give racemic 3-azido-4-oxochroman-7-carbonitrile (110 mg, 0.51 mmol, 92.5% yield): LCMS=237.02 [M+Na]+.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]([N:15]=[N:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([N:29]=[N:30][CH:31]([C:35]([NH:37][C:38]4[CH:43]=[CH:42][C:41](C)=[CH:40][C:39]=4C)=[O:36])[C:32]([CH3:34])=[O:33])=[C:25]([Cl:46])[CH:24]=3)=[CH:19][C:18]=2[Cl:47])[C:12]([CH3:14])=[O:13])=[O:10])=[C:4](C)[CH:3]=1.C(NC1C=CC=CC=1)(=O)CC(C)=O>>[CH3:34][C:32]([CH:31]([N:30]=[N:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[CH:21]=[CH:22][C:17]([N:16]=[N:15][CH:11]([C:9]([NH:8][C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)=[O:10])[C:12]([CH3:14])=[O:13])=[C:18]([Cl:47])[CH:19]=2)=[CH:24][C:25]=1[Cl:46])[C:35]([NH:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:36])=[O:33]
Reactant: CC(=O)C(N=Nc1ccc(-c2ccc(N=NC(C(C)=O)C(=O)Nc3ccc(C)cc3C)c(Cl)c2)cc1Cl)C(=O)Nc1ccc(C)cc1C
Agent: CC(=O)CC(=O)Nc1ccccc1
Product: CC(=O)C(N=Nc1ccc(-c2ccc(N=NC(C(C)=O)C(=O)Nc3ccccc3)c(Cl)c2)cc1Cl)C(=O)Nc1ccccc1

Procedure:
The pigment suspension was prepared similarly to C.I. Pigment Yellow 13 by coupling of 28 g of tetrazotized 3,3'-dichlorobenzidene with 41.1 g of acetoacetanilide.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH2:19][OH:20])[CH:16]=3)[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:28][S:29]([O:20][CH2:19][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][N:10]([CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:18]2)(=[O:31])=[O:30]
Reactant: OCc1ccc2c(c1)CN(CCCc1ccccc1)C2
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc2c(c1)CN(CCCc1ccccc1)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.835 g (6.863 mM) of 2-(3-phenylpropan-1-yl)-2,3-dihydro-1H-isoindol-5-ylmethanol and 1.43 ml (10.3 mM) of triethylamine in 50 ml of tetrahydrofuran was added 0.64 ml (8.24 mM) of methanesulfonyl chloride dropwise with ice-cooling and the mixture was stirred at 0° C. for 0.5 hour. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of diethyl ether. The pooled organic layer was dried over MgSO4 and the solvent was distilled off under reduced pressure. The crude 2-(3-phenylpropan-1-yl)-2,3-dihydro-1H-isoindol-5-ylmethyl methanesulfonate thus obtained was dissolved in 60 ml of N,N-dimethylformamide, followed by addition of 1.40 g (7.55 mM) of potassium phthalimide, and the mixture was stirred at 100° C. for 4 hours. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The pooled organic solution was dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane/ethyl acetate=3/1 to 2/1) to provide a mixture of the objective compound and phthalimide. This product was dissolved in ethyl acetate and the solution was washed serially with aqueous solution of sodium hydroxide and saturated aqueous solution of sodium chloride. It was then dried over anhydrous sodium sulfate (Na2SO4) and the solvent was distilled off under reduced pressure to provide the title compound.
Reaction SMILES: [S-:1][CH2:2][CH3:3].[Na+].Cl[C:6]1[CH:11]=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[CH:9]=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17]>C(COC)OC>[CH2:2]([S:1][C:6]1[CH:11]=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[CH:9]=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])[CH3:3]
Reactant: CC[S-]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])c(Cl)c1
Agent: [Na+]
Solvent: COCCOC
Product: CCSc1cc(NC(C)=O)ccc1[N+](=O)[O-]

Procedure:
To a suspension of 25.2 g (0.3 mol) of sodium thioethoxide in 220 ml of dimethoxyethane at room temperature are added, portionwise over 30 minutes with stirring, 46.2 g (0.216 mol) of 2-chloro-4-acetylaminonitrobenzene.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)=[CH:6][C:5]([CH:17]2[C@H:22]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@@H:21]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@H:20]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:19]([CH2:47][O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[O:18]2)=[C:4]([CH:56]=[CH2:57])[C:3]=1[OH:58].[CH2:59](Br)[CH:60]=[CH2:61].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:61]([O:58][C:3]1[C:4]([CH:56]=[CH2:57])=[C:5]([CH:17]2[C@H:22]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@@H:21]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@H:20]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C@@H:19]([CH2:47][O:48][CH2:49][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[O:18]2)[CH:6]=[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=2)[C:2]=1[Cl:1])[CH:60]=[CH2:59]
Reactant: C=CCBr
Reactant: C=Cc1c(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc(Cc2ccc(CC)cc2)c(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1c(Cl)c(Cc2ccc(CC)cc2)cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1C=C
Reaction time: 18 h
Yield: 38.9 %

Procedure:
A mixture of compound 82 (320 mg, 0.4 mmol) and allyl bromide (0.05 mL, 0.6 mmol) and K2CO3 (110 mg, 0.8 mmol) in acetone (2.0 mL) was stirred for 18 hours under reflux. The mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 83 (130 mg, 37%) as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH:12]1([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([C:18]2[CH:19]=[CH:20][C:21]([C:22]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)=[O:23])=[CH:25][CH:26]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: Nc1ccc2cccnc2c1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(C2CCCCC2)cc1

Procedure:
Using the procedure outlined in Example 45, the title compound was prepared from 7-aminoquinoline (D55) (30 mg, 21 mmol) and 4-cyclohexylbenzoic acid (51 mg, 0.25 mmol) as a yellow solid. MS(ES): MH+ 331, M-H+ 329
Reaction SMILES: N[C:2]1[C:10]2[C:5](=[N:6][C:7]([N:14]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]3)=[CH:8][C:9]=2[CH2:11][CH2:12][CH3:13])[S:4][C:3]=1[C:21]#[N:22].C(=O)(O)O.[NH2:27][C:28]([NH2:30])=[NH:29]>>[NH2:29][C:28]1[N:30]=[C:21]([NH2:22])[C:3]2[S:4][C:5]3[N:6]=[C:7]([N:14]4[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]4)[CH:8]=[C:9]([CH2:11][CH2:12][CH3:13])[C:10]=3[C:2]=2[N:27]=1
Reactant: CCCc1cc(N2CCC(O)CC2)nc2sc(C#N)c(N)c12
Reactant: N=C(N)N
Agent: O=C(O)O
Product: CCCc1cc(N2CCC(O)CC2)nc2sc3c(N)nc(N)nc3c12
Temperature: 25 °C
Yield: 16.7 %

Procedure:
3-Amino-6-(4-hydroxy-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carbonitrile (316 mg, 1.00 mol) (see Example 2) and guanidine carbonate (360 mg, 2 mmol) was mixed in a test tube. The mixture was heated to a melt for 15 min until the gas evolution stopped. After cooling to room temperature, the mixture purified by flash chromatography (35 g silica gel cartridge, 10% MeOH in dichloromethane, 30 mL/min for 15 min, Rf=0.25) to give the title compound as a yellow solid (120 mg, 33%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([O:8][CH3:9])[CH:7]=1.[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CC([O-])(C)C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([O:8][CH3:9])[CH:7]=2)[CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(Br)ccc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Cl
Temperature: 80 °C

Procedure:
An oven dried glass vial was charged with 5-Bromo-2-chloroanisole (1.0 mmol), N-Bocpiperazine (1.2 mmol), NaOtBu (1.4 mmol), tris(dibenzylideneacetone)-dipalladium(0) {Pd2dba3} (0.0025 mmol, 0.5 mol %) and BINAP (0.0075 mmol), and the vial was then flushed with nitrogen and capped tightly. The mixture was heated to 80° C. overnight and then cooled to room temperature, taken up in ether, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel with ethyl acetate to yield 4-(4-Chloro-3-methoxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: O=[C:2]([CH:8]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[CH3:9])[C:3](OCC)=[O:4].C(=O)(O)O.[NH2:27][NH:28][C:29]([NH2:31])=[NH:30]>CCO>[NH2:30][C:29]1[NH:31][C:3](=[O:4])[C:2]([CH:8]([NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH3:9])=[N:27][N:28]=1
Reactant: N=C(N)NN
Reactant: CCOC(=O)C(=O)C(C)NC(=O)c1cccc(C(F)(F)F)c1
Agent: O=C(O)O
Solvent: CCO
Product: CC(NC(=O)c1cccc(C(F)(F)F)c1)c1nnc(N)[nH]c1=O
Yield: 92.3 %

Procedure:
A solution of ethyl 2-oxo-3-{[3-(trifluoromethyl)benzoyl]amino}butanoate (8.75 g, 27.6 mmol) and aminoguanidine bicarbonate (3.75 g, 27.6 mmol) in EtOH(aq) (80%, 200 mL) was heated at reflux for 3h. Concentration gave crude N-[1-(3-amino-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)ethyl]-3-(trifluoromethyl)benzamide (8.34 g) as a colourless solid which was used without further purification. 1H NMR (DMSO-d6): δ8.87 (d, J=7.5 Hz, 1H), 8.23 (s, 1H), 8.20-8.15 (m, 2H), 7.93-7.89 (m, 1H), 7.75-7.69 (m, 1H), 7.00 (bs, 1H), 5.16 (p, J=7.1 Hz, 1H), 1.40 (d, J=7.1 Hz, 3H). MS m/z 326 (M−1).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([O:13][CH3:14])=[O:12])(=[O:5])=[O:4].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CN(C=O)C>[CH3:1][N:2]([CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[S:3]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([O:13][CH3:14])=[O:12])(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccsc1C(=O)OC
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sccc1S(=O)(=O)N(C)CCN1CCOCC1
Reaction time: 5 h

Procedure:
To a solution of methyl 3-(N-methylsulfamoyl)thiophene-2-carboxylate (prepared in an analogous manner as described in Example 10, Scheme 10, Step 1, 530 mg, 2.253 mmol) in dry DMF (20 ml) under nitrogen atmosphere, K2CO3 (623 mg, 4.51 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (838 mg, 4.51 mmol) were added, and the mixture was reacted at 60° C. overnight and then at 80° C. for 5 hours. The insoluble inorganic salts were filtered off, the filtrate was evaporated and the residue was purified by flash chromatography on silica gel (DCM/MeOH=9/1) to afford methyl 3-(N-methyl-N-(2-morpholinoethyl)sulfamoyl)thiophene-2-carboxylate (Int. 47) (510 mg, 1.464 mmol, MS/ESI+348.8 [MH]+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.ClC1C=C(C(=[N:35][OH:36])C(C2C=CC(F)=CC=2)=O)C=CN=1>>[Br:1][C:2]1[CH:7]=[C:6]([C:8](=[N:35][OH:36])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cc1ccnc(Br)c1)c1ccc(F)cc1
Reactant: O=C(C(=NO)c1ccnc(Cl)c1)c1ccc(F)cc1
Product: O=C(C(=NO)c1ccnc(Br)c1)c1ccc(F)cc1

Procedure:
22d was prepared from 21c (5.0 g; 17 mmol) using the method described in the synthesis of 22a.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16]([S:18](Cl)(=[O:20])=[O:19])[S:17][C:11]=2[N:10]=[C:9]1[CH3:22].O.[NH3:24]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16]([S:18](=[O:20])(=[O:19])[NH2:24])[S:17][C:11]=2[N:10]=[C:9]1[CH3:22]
Reactant: Cc1nc2sc(S(=O)(=O)Cl)cc2c(=O)n1-c1ccccc1Cl
Reactant: N
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2sc(S(N)(=O)=O)cc2c(=O)n1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
In 200 ml of tetrahydrofuran was suspended 23 g of 3,4-dihydro-3-(2-chlorophenyl)-6-chlorosulfonyl-2-methyl-4-oxothieno[2,3-d]pyrimidine, and this suspension was poured onto 200 ml of ammonia water at one time. The mixture was stirred at room temperature for 40 minutes. The reaction mixture was concentrated, and water was added to the residue. The crystals were collected by suction-filtration to afford 15.8 g of the title compound, m.p. 251° C.