Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([OH:26])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:28]1[C:32](=[O:33])[CH2:31][CH2:30][C:29]1=[O:34].C1(N=C=NC2CCCCC2)CCCCC1>COCCOC>[O:34]=[C:29]1[CH2:30][CH2:31][C:32](=[O:33])[N:28]1[O:25][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]2)[CH2:19]1)=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)O)C2)CC1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)ON3C(=O)CCC3=O)C2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 108.2 %

Procedure:
To (3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidine-3-carboxylic acid (1.91 g, 5.18 mmol) in 1,2-dimethoxyethane (13.5 mL) was added N-hydroxysuccinimide (0.60 g, 5.18 mmol) and 1,3-dicyclohexyl carbodiimide (1.18 g, 5.7 mmol). The solution was stirred for 4 hours at room temperature while a precipitate formed. The mixture was then cooled to 0° C. filtrated and the solid washed with diethyl ether. The filtrate and the diethyl ether wash were combined and concentrated to yield 2.61 g of raw tert-butyl 4-{3-[(3R)-3-{[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][O:31][CH3:32])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:32][O:31][CH2:30][C:10]1[CH:11]=[C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])[CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][C:6]([OH:33])=[O:5]
Reactant: COCc1cc(OCCc2nc(-c3ccccc3)oc2C)ccc1CCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCc1cc(OCCc2nc(-c3ccccc3)oc2C)ccc1CCC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
A 15 mL round bottomed flask was charged 3-{2-methoxymethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}propionic acid tert-butyl ester (0.060 g, 0.13 mmol), CH2Cl2 (1.2 mL), and then trifluoroacetic acid (0.6 mL). The solution was stirred at ambient temperature under a nitrogen atmosphere for 16 h and was concentrated. The residue was diluted with CH2Cl2 (30 mL) and washed with brine. The organic layer was dried (Na2SO4), filtered, and concentrated to give a white solid (0.046 g, 89%). MS (ES) m/e 648 (M+1).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][N:4]1[CH:8]=[C:7]([NH2:9])[CH:6]=[N:5]1.Cl[C:13]1[N:18]=[C:17]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]2)[C:16]([Cl:33])=[CH:15][N:14]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>O1CCOCC1>[Cl:33][C:16]1[C:17]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]2)=[N:18][C:13]([NH:9][C:7]2[CH:6]=[N:5][N:4]([CH2:3][C:2]([F:1])([F:10])[F:11])[CH:8]=2)=[N:14][CH:15]=1
Reactant: Nc1cnn(CC(F)(F)F)c1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3cnn(CC(F)(F)F)c3)ncc2Cl)CC1
Temperature: 120 °C
Yield: 26 %

Procedure:
A mixture of 1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-amine (0.160 g, 0.967 mmol), 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.101 g, 0.300 mmol) and TsOH.H2O (0.010 g, 0.051 mmol) in 1,4-dioxane (2.0 mL) was heated to 120° C. for 3 hours in the microwave. The mixture was concentrated under reduced pressure and purified using silica gel column chromatography (0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound 29 (0.036 g, 26%). LCMS-D: rt 3.402 min; m/z 465.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH3:5])[CH3:3].[N:6]1([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:10]=[N:9][CH:8]=[N:7]1.C(#N)C>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:3])[CH:4]([CH3:5])[O:13][C:12]1([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1
Reactant: CC=C(C)C
Reactant: O=C(Cn1cncn1)c1ccccc1
Solvent: c1ccccc1
Solvent: CC#N
Product: CC1OC(Cn2cncn2)(c2ccccc2)C1(C)C
Yield: 27.1 %

Procedure:
4.0 ml (37.64 mmole) of 2-methyl-2-butene were added to a solution of 1.1 g (5.88 mmole) of 2-(1H-1,2,4-triazol-1-yl)acetophenone in 15 ml of a 2:1 by volume mixture of acetonitrile and benzene. The mixture was then irradiated with a 450 watt medium pressure mercury-arc lamp (Hannovea Co., Inc.) for 15 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was subjected to column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to afford 409.7 mg (yield 27%) of the title compound, melting at 102° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=2)[C:10]#N)=[CH:5][C:4]=1[CH3:23].O=[CH:25][C:26](=C)[CH3:27]>>[CH3:27][C:26]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:23])[CH:5]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=2)[CH:25]=1
Reactant: COc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1C
Reactant: C=C(C)C=O
Product: COc1ccc(-c2cc(C)cn2-c2ccc(S(N)(=O)=O)cc2)cc1C

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(4-methoxy-3-methylphenyl)-α-(4-sulfamoylanilino)acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as a pale yellow powder (yield 39%), melting at 149-151° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:14])=[C:6]([O:12][CH3:13])[CH:7]=[C:8]([CH:11]=1)[CH:9]=[O:10])([O-:3])=[O:2].[CH2:15](Cl)[CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:15]([O:14][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:12][CH3:13])[CH2:16][CH2:17][CH3:18]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: CCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1c(OC)cc(C=O)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of 5-nitrovanillin (2.2 g), butyl chloride (10 ml), potassium carbonate (8 g) and N,N-dimethylformamide (50 ml) is stirred at 100° C. for 24 hours. After cooling, water (300 ml) is added to the reaction mixture, followed by extraction with ethyl acetate (200 ml). The extract solution is washed with water, dried, and concentrated under reduced pressure. The residue is purified by means of a silica gel column chromatography (hexane: ethyl acetate=1:1) to afford 4-butoxy-3-methoxy-5-nitrobenzaldehye (2 g) as a pale yellow oily product. This product is dissolved in acetone (100 ml), potassium permanganate (6 g) is added to the mixture, and the mixture is stirred at room temperature overnight. To the reaction mixture are added ethanol (20 ml), water (20 ml) and acetone (200 ml). The whole mixture is left standing for two hours, then insolubles are filtered off. The filtrate is concentrated under reduced pressure. The concentrate is dissolved in water (100 ml) and the mixture is acidified with concentrated hydrochloric acid. Precipitating crystals are collected by filtration to afford 4-butoxy-3-methoxy-5-nitrobenzoic acid (1.6 g) as colorless crystals. This product is recrystallized from a mixture of ethanol and water to give colorless prisms, m.p. 114°-115° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[C:5]([N+:14]([O-])=O)[CH:4]=1.CCO>[Fe].O>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([NH2:14])=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=1
Reactant: COc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1OC
Agent: [Fe]
Solvent: O
Solvent: CCO
Product: COc1cc(N)c([N+](=O)[O-])cc1OC
Temperature: 70 °C
Yield: 119.3 %

Procedure:
4.50 g (20.0 mmol) 4,5-dimethoxy-1,2-dinitrobenzene was taken into 50.0 mL EtOH/8.4 mL AcOH mixture. To this was added 4.00 g powdered iron (O). The reaction was heated to an oil bath temperature of 70° C. overnight. The reaction was allowed to cool to room temperature and was poured into 400 mL H2O. Aqueous layer was extracted several times with diethyl ether. Organic layers were dried over magnesium sulfate and evaporated under reduced pressure to give 4.73 g orange solid as a mixture of starting material and product. This solid was purified over silica gel (30% DCM in hexanes) to give the title compound 86A as an orange solid (1.15 g, 5.80 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[Li]CCCC.[C:14]([O:18][C:19]([N:21]1[CH2:24][CH:23]([C:25]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[N:33]=[C:32]([O:37][CH3:38])[C:31]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=2)=[C:30]3[Cl:50])=[O:26])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH:23]([C:25]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[N:33]=[C:32]([O:37][CH3:38])[C:31]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:44][CH:45]=2)=[C:30]3[Cl:50])([C:7]2[C:2]([CH3:1])=[N:3][C:4]([CH3:8])=[CH:5][CH:6]=2)[OH:26])[CH2:24]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: Cc1cccc(C)n1
Reactant: COc1nc2ccc(C(=O)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C)nc3C)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.05 h

Procedure:
A flask containing 2,6-dimethylpyridine (277 mg, 1.49 mmol) and THF (5 mL) was cooled to −78° C. and then n-BuLi (2.5 M in hexanes, 0.610 mL, 1.52 mmol) was added dropwise producing a homogeneous orange solution. After 3 minutes, tert-butyl 3-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline-6-carbonyl)azetidine-1-carboxylate (505 mg, 0.94 mmol, Intermediate 61: step b) in 3 mL THF was introduced. After 5 minutes, the −78° C. bath was replaced with an ice-water bath. After 30 minutes, the reaction mixture was quenched with aqueous NH4Cl solution and extracted with EtOAc (3×30 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. This material was combined with a batch from a duplicate experiment for chromatography on silica gel (5% acetone-DCM increasing to 30% acetone with 1% MeOH) which provided the title compound as an off white amorphous solid. 1H NMR (500 MHz, CDCl3) δ 8.10 (d, J=1.8 Hz, 1H), 7.73 (dd, J=8.7, 1.5 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.51 (d, J=7.9 Hz, 2H), 7.37 (dd, J=25.7, 8.4 Hz, 4H), 7.05 (d, J=8.0 Hz, 1H), 4.34 (s, 2H), 4.12-4.02 (m, 5H), 3.93-3.84 (m, 1H), 3.78-3.71 (m, 1H), 3.59-3.49 (m, 1H), 2.70 (s, 1H), 2.51 (s, 3H), 2.14 (s, 3H), 1.41 (s, 9H); MS (ESI): mass calcd. Chemical Formula: C34H35ClF3N3O4, Exact Mass: 641.2. m/z found 641.9 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:38][N:39](C1CC1)[CH2:40][CH2:41][CH2:42][CH:43]=[CH2:44])[C:10]([N:12]1[CH2:16][C@H:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:14][C@H:13]1[C:25]([NH:27][C@:28]1([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:30][C@H:29]1C=C)=[O:26])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:10](=[O:11])[N:12]2[C@@H:13]([CH2:14][C@@H:15]([O:17][Si:18]([C:21]([CH3:23])([CH3:22])[CH3:24])([CH3:19])[CH3:20])[CH2:16]2)[C:25](=[O:26])[NH:27][C@@:28]2([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C@@H:30]([CH2:29]2)[CH:44]=[CH:43][CH2:42][CH2:41][CH2:40][NH:39][CH2:38]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C=CCCCN(C[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C)C1CC1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2)c(C)c1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCNC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)N2
Solvent: ClCCl
Product: CCOC(=O)[C@@]12C[C@H]1C=CCCCNC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 1(R)-[1-[2(S)-(tert-butoxycarbonylamino)-3-[N-cyclopropyl-N-(pent-4-enyl)amino]propanoyl]-4(R)-(tert-butyldimethylsilyloxy)pyrrolidine-2(S)-carboxamido]-2(S)-vinylcyclopropanecarboxylate (1.45 g, 2.14 mmoL) in 1 L of methylene chloride was added 181 mg (0.21 mmoL) of Grubb's 2nd generation catalyst [(1,3-Bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium]. The mixture was heated at reflux for 1 h. A second fraction of the catalyst (50 mg, 0.058 mmol) was added, and the mixture was stirred at rt overnight. The residue was concentrated in vacuo, and then purified by flash chromatography eluting with 50% ether/hexane to give 0.84 g (62%) of (1S,4R,6S,14S,18R)-7-cis-14-tert-Butoxycarbonylamino-18-(tert-butyldimethylsilyloxy)-2,15-dioxo-3,12,16-triazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid, ethyl ester as a white solid: LC-MS (Phenomenex 10 μm C18 HPLC column: 3.0×50 mm length. Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B. Gradient time: 2 min. Hold time: 1 min. Flow rate: 5 mL/min. Detector Wavelength: 220 nM. Solvent A: 10% MeOH/90% H2O/0.1% TFA. Solvent B: 10% H2O/90% MeOH/0.1% TFA.) (Retention time: 2.43 min), MS m/z 649 (M++1).
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:23]S(C3C=CC(C)=CC=3)(=O)=O)=[N:8][N:9]3[C:14]=2[C:13]([CH3:15])=[N:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][N:35]1[C:39]([CH2:40]O)=[N:38][CH:37]=[N:36]1.[H-].[Na+].O>CN(C=O)C>[CH:1]1([C:6]2[C:7]([O:23][CH2:40][C:39]3[N:35]([CH3:34])[N:36]=[CH:37][N:38]=3)=[N:8][N:9]3[C:14]=2[C:13]([CH3:15])=[N:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cn1ncnc1CO
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4ccccc4F)nnc(C)c3c2C2CCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nnc(-c2ccccc2F)n2nc(OCc3ncnn3C)c(C3CCCC3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To toluene-4-sulfonic acid 3-cyclopentyl-7-(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester (Example 3, step c; 230 mg, 0.494 mmol) and (2-methyl-2H-[1,2,4]triazol-3-yl)methanol (67 mg, 1.2 molar eq; prepared as described in EP-A-170073) in DMF (10 ml) was added sodium hydride (22 mg of a 60% dispersion in mineral oil; 1.2 molar eq) and the mixture was stirred at room temperature for 1 h. Water (90 ml) was added then the solution was extracted with diethyl ether (4×50 ml). The combined ether layers were washed with brine (1×100 ml), dried (Na2SO4), the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate in dichloromethane. 3-Cyclopentyl-7-(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine was isolated as a gum, which solidified upon trituration under diethyl ether/isohexane (77 mg, mp=123° C.). 1H NMR (360 MHz, CDCl3) δ 1.60-1.98 (8H, m), 2.88 (3H, s), 3.42 (1H, m), 3.73 (3H, s), 5.44 (2H, s), 7.22-7.37 (2H, m), 7.56-7.71 (2H, m), 7.85 (1H, s); MS (ES+) m/e 408 [MH]+. Anal. Found C, 61.64; H, 5.31; N, 23.77%. C21H22FN7O requires C, 61.90; H, 5.44; N, 24.06%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:8])=[N:4][O:5][C:6]=1[CH3:7].[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH:8][C:3]1[C:2]([CH3:1])=[C:6]([CH3:7])[O:5][N:4]=1)(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: Cc1onc(N)c1C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1onc(NS(=O)(=O)c2ccccc2Br)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4,5-dimethyl-3-isoxazolamine (1.62 g, 13.00 mmol, prepared as described in T. Konoike et al., Tetrahedron Letters, 37, 3339 (1996)) and 4-dimethylaminopyridine (159 mg, 1.3 mmol) in 6.5 ml pyridine at 0° C., 2-bromobenzenesulphonyl chloride (3.65 g, 14.3 mmol) was added in portions over 10 minutes. After stirring at room temperature overnight, the mixture was added dropwise to 40 ml 6N HCl at 0° C. The mixture was extracted with 3×50 ml EtOAc. The combined organic extracts were washed with 30 ml each of 1N HCl and brine and dried and concentrated. The residue was dissolved in 160 ml MeOH and 160 ml 3% aqueous NaHCO3 solution was added and the mixture was concentrated in vacuo to remove most of the MeOH. The solid was filtered off and the aqueous filtrate was acidified to pH 2 with solid NaHSO4, and extracted with 3×100 ml of EtOAc. The extracts were washed with brine, dried and concentrated to give the title compound of this step (3.0 g, 70%). Rf=0.57, silica gel, 1:1 hexane/EtOAc.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:6]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:16]=[CH:15][C:7]=2[N:8]=[C:9]([NH:11]C(=O)C)[N:10]=1>C1COCC1>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:17]2[CH:16]=[CH:15][C:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:5]([O:2][CH3:1])[C:6]=3[N:18]=2)=[CH:24][CH:23]=1
Reactant: C[O-]
Reactant: CC(=O)Nc1nc(Cl)c2nc(-c3ccc(F)cc3)ccc2n1
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc(N)nc2ccc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.2 %

Procedure:
Sodium methoxide (0.32 mL, 0.158 mmol; 0.5 N in MeOH) was added to a solution of N-[4-chloro-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidin-2-yl]-acetamide (20 mg, 0.063 mmol) in THF (1.5 mL). After stirring at room temperature for 20 minutes, solvents were concentrated in vacuo and the residue was purified by RP HPLC using a C18 column with a gradient of H2O and 0.1% TFA-acetonitrile, to provide the pure title compound as a white solid (14 mg, yield 50%) which was characterised as follows: MS (m/z) 271.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:30])[CH2:9][NH:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[C:12]=2[C:18]2[NH:19][C:20]3[CH:26]=[C:25]([C:27]#N)[CH:24]=[C:23]([CH3:29])[C:21]=3[N:22]=2)[CH:5]=[CH:6][CH:7]=1.C([Al]CC(C)C)C(C)C.C(OCC)(=[O:42])C.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:30])[CH2:9][NH:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[C:12]=2[C:18]2[NH:19][C:20]3[CH:26]=[C:25]([CH:27]=[O:42])[CH:24]=[C:23]([CH3:29])[C:21]=3[N:22]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C#N)cc2[nH]c(-c3c(NCC(O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Reactant: CCOC(C)=O
Agent: CC(C)C[Al]CC(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C=O)cc2[nH]c(-c3c(NCC(O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Temperature: -78 °C
Reaction time: 6 h
Yield: 2.5 %

Procedure:
To a suspension of (±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-7-methyl-3H-benzimidazole-5-carbonitrile (76 mg, 0.18 mmol) in toluene (anhydrous, 20 mL) was added diisobutylaluminium (1.4 M toluene solution) (0.65 mL, 0.97 mmol) at −78° C. under nitrogen. The mixture was stirred at −78° C. for 6 h. Ethyl acetate (1 mL) was then added followed by water (0.5 mL). The mixture was stirred at room temperature for 20 min. The mixture was then passed through a pad of celite and the filtrate was concentrated. The crude product was purified by prep. HPLC to yield the title compound (4 mg, 2.5%) as a brown solid. 1H NMR (300 MHz, CD3OD) δ 7.65 (1H, s), 7.57 (1H, s), 7.24–7.50 (5H, m), 6.26 (1H, d, J=7.6 Hz), 5.49 (1H, s), 4.96 (1H, m), 3.53–3.79 (2H, m), 2.62 (3H, s). LCMS (M+H)+ m/z 423 (t=1.79 min.).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.OC(C(F)(F)F)=O.Br[CH2:18][C:19]([NH2:21])=[O:20].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[N:1]1([CH2:18][C:19]([NH2:21])=[O:20])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCNCCN1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: NC(=O)CN1CCNCCNCC1
Yield: 141.8 %

Procedure:
Bis-TFA 1,4,7-triazacyclononane (261.4 mg, 0.81 mmol) was dissolved in acetonitrile (5.0 mL), bromoacetamide (168.1 mg, 1.22 mmol) and K2CO3 (225.0 mg, 1.62 mmol) were added sequentially. The mixture was refluxed for 15 hours. Filtration and chromatography of the residue after removal of all volatiles gave the desired product as an oil (214.0 mg, 70%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[C:5](=[CH:9][CH:10]=[C:11]([F:13])[CH:12]=1)[C:6]([NH2:8])=[O:7].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH3:1][O:2][C:3](=[O:14])[C:4]1[C:5](=[CH:9][CH:10]=[C:11]([F:13])[CH:12]=1)[C:6](/[N:8]=[CH:17]/[N:18]([CH3:20])[CH3:19])=[O:7]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1cc(F)ccc1C(N)=O
Product: COC(=O)c1cc(F)ccc1C(=O)/N=C/N(C)C
Temperature: 25 °C

Procedure:
A solution of 5-fluoro-phthalamic acid methyl ester plus regioisomer (2.24 g, 11.36 mmol) in N,N-dimethylformamide dimethyl acetal (10 mL) is heated at 110° C. for 3 hours. The reaction mixture is allowed to cool to room temperature and is concentrated under reduced pressure to afford crude N-[1-dimethylamino-meth-(E)-ylidene]-5-fluoro-phthalamic acid methyl ester plus regioisomer (2.9 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8](=[O:22])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][CH2:2]1.[O:23]1CCO[CH:24]1[C:28]1[C:33]([CH3:34])=[CH:32][C:31]([NH:35][C:36](=[O:39])[CH:37]=[CH2:38])=[C:30]([CH3:40])[CH:29]=1.C(O)C.[ClH:44]>ClCCl>[ClH:44].[CH:24]([C:28]1[C:33]([CH3:34])=[CH:32][C:31]([NH:35][C:36]([CH2:37][CH2:38][N:1]2[CH2:2][CH2:3][CH:4]([O:7][C:8](=[O:22])[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:5][CH2:6]2)=[O:39])=[C:30]([CH3:40])[CH:29]=1)=[O:23]
Reactant: C=CC(=O)Nc1cc(C)c(C2OCCO2)cc1C
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1C=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 50 mL round-bottom flask was added biphenyl-2-ylcarbamic acid piperidin-4-yl ester (1.2 g, 4.04 mmol) and N-(4-[1,3]dioxolan-2-yl-2,5-dimethylphenyl)acrylamide (1.0 g, 4.04 mmol). Ethanol (10 mL) and dichloromethane (10 mL) were added to form a slurry. The reaction mixture was heated at 45° C. to 50° C. for about 18 hours and then cooled to room temperature. Aqueous 1M hydrochloric acid (10 mL) was added and the resulting mixture was stirred vigorously for about 3 hours. Dichloromethane (10 mL) was added and the resulting mixture was stirred for about 5 minutes. The layers were then separated and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to provide crude biphenyl-2-ylcarbamic acid 1-[2-(4-formyl-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester hydrochloride (1.9 g). 1H NMR (300 MHz, DMSO-d6) δ 1.2-1.4 (m, 2H), 1.58-1.75 (m, 2H), 2.0-2.17 (m, 2H), 2.19 (s, 3H), 2.38 (s, 3H), 2.41-2.50 (m, 4H), 2.5-2.75 (m, 2H), 4.31-4.42 (m, 1H), 7.10-7.35 (m, 9H), 7.55 (s, 1H), 7.75 (s, 1H), 8.59 (s, 1H), 9.82 (s, 1H), 9.98 (s, 1H); MS [M+H+] found 500.2.