Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](CCC2CCC(CCCO)CC2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].CCN(S(F)(F)F)CC>C(COC)OC>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:10])([F:11])[F:12]
Reactant: OCCCC1CCC(CCc2ccc(OC(F)(F)F)c(F)c2)CC1
Agent: CCN(CC)S(F)(F)F
Solvent: COCCOC
Product: Fc1ccccc1OC(F)(F)F
Yield: 7.7 %

Procedure:
Dimethoxyethane (15 ml) was added to the above 3-(4-(2-(3-fluoro-4-trifluoromethoxyphenyl)ethyl)cyclohexyl)propanol (1.52 g, 4.4 mmol), followed by-dropwise adding DAST (1.40 g, 8.7 mmol), refluxing the mixture for 5 hours, extracting the resulting product with toluene, washing the organic layer successively with a saturated aqueous solution of sodium bicarbonate and water, drying over MgSO4, distilling off the solvent, purifying the residue according to column chromatography treatment using heptane as a developing solvent, on silica gel, distilling off the solvent, and recrystallizing the residue from ethanol, to isolate 1-(3-fluoropropyl)cyclohexyl)-3-fluoro-4-trifluoromethoxybenzene (0.12 g, 0.34 mmol). Yield: 7.7%. Its clearing point measured by PERKIN-ELMER 7 series Thermal Analysis System was -5.89° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:19])([CH3:18])[CH:6]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1C=CC=CC=1>[CH3:1][NH:2][C:3]([C:5]1[C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:19])([CH3:18])[CH:6]=1)=[S:29]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CNC(=O)C1=CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Solvent: c1ccccc1
Product: CNC(=S)C1=CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Yield: 165.1 %

Procedure:
A mixture of 5.26 g of N-methyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamide prepared in accordance with Example 10-(3), 4.26 g of Lawesson's reagent, and 20 ml of benzene was heated at reflux for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromato- graphy (developing solution: methylene chloride) and then recrystallized from a mixture of ethyl acetate and n-hexane to obtain 4.84 g of N-methyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide.
Reaction SMILES: [C@H:1]12[CH2:24][C@H:4]([N:5]([C:7]3[N:12]=[C:11](S(C)(=O)=O)[N:10]=[C:9]([C:17]4[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=4)[CH:8]=3)[CH2:6]1)[CH2:3][O:2]2.C(=O)([O-])[O-].[K+].[K+].Cl.[CH:32]12[CH2:37][CH:35]([CH2:36]1)[CH2:34][NH:33]2>CS(C)=O>[CH:32]12[CH2:37][CH:35]([CH2:36]1)[CH2:34][N:33]2[C:11]1[N:10]=[C:9]([C:17]2[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=2)[CH:8]=[C:7]([N:5]2[CH2:6][C@@H:1]3[CH2:24][C@H:4]2[CH2:3][O:2]3)[N:12]=1
Reactant: CS(=O)(=O)c1nc(-c2cnc(N)nc2)cc(N2C[C@@H]3C[C@H]2CO3)n1
Reactant: C1NC2CC1C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1ncc(-c2cc(N3C[C@@H]4C[C@H]3CO4)nc(N3CC4CC3C4)n2)cn1
Temperature: 100 °C
Reaction time: 5 h
Yield: 57.4 %

Procedure:
To the mixture of 6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(methylsulfonyl)-[4,5′-bipyrimidin]-2′-amine (380 mg, 1.09 mmol) and potassium carbonate (754 mg, 5.45 mmol) in DMSO (5 mL) was added 2-azabicyclo[2.1.1]hexane hydrochloride (326 mg, 2.73 mmol). The mixture was stirred at 100° C. for 5 h. After removal of the solvent, the residue was purified by Prep-HPLC (formic acid) to afford 2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-[4,5′-bipyrimidin]-2′-amine (220 mg, 57% yield). LCMS (ESI): [MH]+=352.1; 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 2H), 7.00 (s, 2H), 6.30-6.10 (m, 1H), 5.10-4.90 (m, 1H), 4.83 (d, J=6.4 Hz, 1H), 4.70-4.64 (m, 1H), 3.78-3.76 (m, 1H), 3.66-3.64 (m, 1H), 3.45-3.38 (m, 4H), 2.89-2.87 (m, 1H), 1.93-1.86 (m, 4H), 1.32-1.31 (m, 2H).
Reaction SMILES: Br[CH2:2]/[C:3](/[F:15])=[C:4](\[CH3:14])/[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH:16]1([NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([NH:22][C:23]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:2]/[C:3](/[F:15])=[C:4](\[CH3:14])/[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:26][CH:25]=2)=[O:31])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(NC1CCCCC1)c1ccc(O)cc1
Reactant: C/C(CNC(=O)OC(C)(C)C)=C(/F)CBr
Product: C/C(CNC(=O)OC(C)(C)C)=C(/F)COc1ccc(C(=O)NC2CCCCC2)cc1

Procedure:
This compound was synthesized from tert-butyl [(2Z)-4-bromo-3-fluoro-2-methylbut-2-en-1-yl]carbamate and N-cyclohexyl-4-hydroxybenzamide following procedure F and was obtained as a colorless solid; 1H-NMR (400 MHz, CDCl3): δppm: 1.14-1.30 (3H, m), 1.35-1.49 (2H, m), 1.44 (9H, s), 1.60-1.70 (1H, m), 1.70-1.79 (2H, m), 1.76 (3H, d, J 3.2 Hz), 1.98-2.04 (2H, m), 3.90 (2H, d, J 5.3 Hz), 3.96 (1H, m), 4.59 (1H, br s), 4.63 (2H, d, J 21.2 Hz), 5.86 (1H, d, J 7.9 Hz), 6.93 (2H, d, J 8.7 Hz), 7.71 (2H, d, J 8.7 Hz).
Reaction SMILES: Cl.[NH:2]([CH2:4][C:5]([O:7]CC)=[O:6])[NH2:3].CN(C)/[CH:12]=[CH:13]/[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.C([O-])([O-])=O.[K+].[K+].Cl>CCO.CC(=O)OCC>[C:16]1([C:14]2[N:2]([CH2:4][C:5]([OH:7])=[O:6])[N:3]=[CH:12][CH:13]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)CNN
Reactant: CN(C)/C=C/C(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)Cn1nccc1-c1ccccc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 63.6 %

Procedure:
To a solution of ethyl hydrazinoacetate hydrochloride (866 mg) in EtOH (20 mL) was added (E)-3-(dimethylamino)-1-phenylprop-2-en-1-one (981 mg) and K2CO3 (774 mg). The reaction mixture was stirred at 80° C. for 20 h, cooled down and the pH was brought to 2-3 by adding 1M HCl. EA was added and the phases were separated. The org. layer was washed with brine, dried (Na2SO4) and evaporated in vacuo to afford 720 mg of white solid. LC-MS (B): tR=0.63 min; [M+H]+: 203.43.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:12][C:10]1[CH:11]=[C:2]([NH:1][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)cc(N)c1C
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Cl)cc(NC2CCCCC2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
To a stirred solution of methyl 3-amino-5-chloro-2-methylbenzoate (1 g, 5.02 mmol) and cyclohexanone (2.45 g, 25 mmol) in methanol (10 mL), acetic acid (0.3 g, 5.02 mmol) was added and reaction stirred at room temperature for 3 h. Then sodium cyanoborohydride (0.63 g, 10.05 mmol) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford methyl 5-chloro-3-(cyclohexylamino)-2-methylbenzoate (1.2 g, 89.92%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:8][CH:7]=1.O.[NH2:20][NH2:21]>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:13][CH2:14][C:15](=[O:17])[NH:20][N:21]=2)=[CH:8][CH:7]=1
Reactant: COCCOc1ccc(C(=O)CCC(=O)O)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COCCOc1ccc(C2=NNC(=O)CC2)cc1

Procedure:
6 g (0.024 mole) of 4-(4-(2-methoxy-ethoxy)-phenyl)-4-oxo-butyric acid and 1.2 g (0.024 mole) of hydrazine hydrate are stirred in 90 ml of ethanol at 50° C. for 1 hour. After the mixture has been cooled, the product is filtered off with suction, washed with ethanol and dried.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[CH:7][CH:8]=[N:9]2)=[N:4][CH:3]=1.[NH3:13].O>O1CCOCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH2:13])=[CH:7][CH:8]=[N:9]2)=[N:4][CH:3]=1
Reactant: Clc1ccnc2cc(Br)cnc12
Reactant: N
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccnc2cc(Br)cnc12
Temperature: 160 °C
Reaction time: 24 h
Yield: 76.6 %

Procedure:
In a sealed reactor, 500 mg (2.04 mmol, 1 eq) of 7-bromo-4-chloro-1,5-naphthyridine (G. B. Barlin et al. Aust. J. Chem. 1985, 38, 459-465) and 12 mL (71.3 mmol, 35 eq) of 20% aqueous ammonia solution were introduced in 12 mL of dioxane. The mixture was stirred at 160° C. for 24 h. The mixture was allowed to reach rt and water was added. Aqueous layer was extracted with ethyl acetate. Organic layers were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography using methylene chloride and then methylene chloride/ethanol: 98/2 as eluent. The solvent was evaporated to dryness to afford 350 mg of white powder with 76% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:45]=[CH:44][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:31]C(OCC3C=CC=CC=3)=O)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:18][C:17]=2[O:42][CH3:43])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CC(O)=O>CO.[Pd]>[CH2:1]([O:8][C:9]1[CH:45]=[CH:44][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH2:31])[C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])=[CH:18][C:17]=2[O:42][CH3:43])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CC(NC(=O)OCc3ccccc3)C(=O)OC(C)(C)C)cc2OC)cc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CC(N)C(=O)OC(C)(C)C)cc2OC)cc1
Yield: 92 %

Procedure:
Prepared using General Procedure 4: A solution of 4-(2-(((benzyloxy)carbonyl)amino)-3-(tert-butoxy)-3-oxopropyl)-2-methoxyphenyl 4-(heptyloxy)benzoate INT-3 (5.46 g, 8.81 mmol) and AcOH (5 mL) in MeOH (150 mL) was passed through the H-cube system with 10% Pd/C as a catalyst at 1 mL/min and 45° C. The reaction mixture was evaporated, dissolved in DCM (50 mL), and washed with saturated aqueous NaHCO3 (200 mL). The organic layer was dried over MgSO4 and concentrated to afford 3.93 g (92%) of 4-(2-amino-3-(tert-butoxy)-3-oxopropyl)-2-methoxyphenyl 4-(heptyloxy)benzoate INT-5. LCMS-ESI (m/z) calculated for C28H39NO6: 485. Found 430 [M+H-tBu]+, tR=2.15 min (Method 4). 1H NMR (400 MHz, DMSO) δ 8.06-7.99 (m, 2H), 7.12-7.05 (m, 3H), 7.02-6.98 (d, J=1.9 Hz, 1H), 6.85-6.78 (dd, J=8.1, 1.8 Hz, 1H), 4.11-4.03 (t, J=6.5 Hz, 2H), 3.71 (s, 3H), 3.51-3.45 (t, J=6.9 Hz, 1H), 2.87-2.73 (dt, J=16.9, 6.5 Hz, 2H), 1.91 (s, 2H), 1.79-1.69 (p, J=6.8 Hz, 2H), 1.47-1.23 (m, 17H), 0.90-0.83 (m, 3H).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]([F:16])([CH2:14][OH:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[F:7][C:8]([F:16])([CH2:14][O:15][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: C1=COCCC1
Reactant: CCOC(=O)C(F)(F)CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)C(F)(F)COC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dihydropyrane (2 ml, 22 mmol) was added to a solution of ethyl 2,2-difluoro-3-hydroxypropionate (3.1 g, 20 mmol) and pyridinium p-toluene sulfonate (0.25 g, 1 mmol) in anhydrous dichloromethane (50 ml). The mixture was stirred overnight at room temperature and the desired compound ethyl 2,2-difluoro-3-tetrahydropyranyloxypropionate was obtained by flash chromatography on silica gel (ethyl acetate:hexane; 15:85) (4 g, 80%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[N:5][CH:4]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([O:1][CH2:2][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[N:5][CH:4]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: OCc1cncc2ccccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCc2cncc3ccccc23)cc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of the title compound from Step A above (1.94 g, 12.2 mmoles) in anhydrous pyridine (14 mL) at 0° C. was added 4-toluenesulfonyl chloride (2.784 g, 14.6 mmoles) and the mixture was stirred at 0° C. for 2.5 h. The solution was evaporated to dryness and the product was azeotroped with toluene and then taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate, filtered and evaporated to give the title compound which was used without purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([NH2:15])[CH:3]=1.[CH3:16][O:17][C:18]1[CH:28]=[CH:27][C:21](/[CH:22]=[CH:23]/[C:24]([Cl:26])=O)=[CH:20][CH:19]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:26].[F:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[C:24](/[CH:23]=[CH:22]/[C:21]3[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:28][CH:27]=3)=[N:15][C:4]=2[CH:3]=1
Reactant: COc1ccc(/C=C/C(=O)Cl)cc1
Reactant: Nc1cc(F)ccc1Nc1ccccn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: COc1ccc(/C=C/c2nc3cc(F)ccc3n2-c2ccccn2)cc1

Procedure:
Free base of the titled compound was prepared from 4-fluoro-2-amino-N-(2-pyridyl)aniline and (E)-4-methoxycinnamoyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was treated with a 10% methanol solution of hydrogen chloride and concentrated to dryness. The residue was recrystallized from ethyl acetate/ethanol to give the titled compound. MW: 381.84; mp: 204.0-206.0° C.; 1H-NMR (CDCl3) δ: 9.01 (1H, d, J=16.1 Hz), 8.86 (1H, dd, J=4.8, 2.0 Hz), 8.18 (1H, ddd, J=7.7, 7.7, 2.0 Hz), 7.83 (1H, dd, J=7.9, 2.3 Hz), 7.76 (1H, d, J=7.9 Hz), 7.69 (1H, dd, J=7.4, 4.8 Hz), 7.59 (2H, d J=8.7 Hz), 7.40 (1H, dd, J=9.0, 4.2 Hz), 7.17 (1H, ddd, J=9.0, 9.0, 2.3 Hz), 6.85 (2H, d, J=8.7 Hz), 6.78 (1H, d, J=16.1 Hz), 3.82 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10](Br)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1B(O)O.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[CH:12]=[CH:11][C:10]([C:15]2[O:14][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH:16]=2)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: OB(O)c1cc2ccccc2o1
Reactant: Nc1ccc(Br)c2c1C(=O)NC2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc3ccccc3o2)c2c1C(=O)NC2=O
Yield: 32.6 %

Procedure:
In a similar manner to Step 2 of Example 1, 3-amino-6-bromophthalimide (80.0 mg, 0.332 mmol) was dissolved in acetonitrile (4.0 mL), and, the solution was treated with 2-benzofuraneboronic acid (161 mg, 0.996 mmol), palladium acetate (9.0 mg, 0.040 mmol), tri(o-tolyl)phosphine (24.3 mg, 0.080 mmol) and triethylamine (0.463 mL, 3.32 mmol), followed by purification by preparative thin-layer chromatography (chloroform/acetonitrile=15/1) to obtain Compound 171 (30.1 mg, yield 33%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[CH3:9].Cl[C:11](Cl)([O:13]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]=[C:11]=[O:13])[C:3]=1[CH3:9]
Reactant: Cc1c(N)cccc1Br
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1c(Br)cccc1N=C=O
Yield: 106.3 %

Procedure:
A mixture of 1-bromo-2-methyl-3-aminobenzene 25.0 g, triphosgene 60.0 g and toluene 400 mL was stirred with heating under reflux for three hours. The reaction mixtures after standing to cool were concentrated under reduced pressure to give 1-bromo-3-isocyanato-2-methylbenzene 30.3 g.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4]([N:10]2[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11]2)[N:3]=1.[CH3:16][O:17][C:18](Cl)=[O:19].[OH-].[Na+]>C(Cl)Cl.O>[NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][C:18]([O:17][CH3:16])=[O:19])[CH:5]=[C:4]([N:10]2[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]2)[N:3]=1
Reactant: Nc1cc(N2CC=CCC2)nc(N)[n+]1[O-]
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)Nc1cc(N2CC=CCC2)nc(N)[n+]1[O-]

Procedure:
20 G. of 2,4-diamino-6-[3,6-dihydro-1(2H)-pyridyl]-pyrimidine-3-oxide are suspended and stirred in 140 ml. of methylene chloride and 120 ml. of water. While cooling, there are simultaneously added dropwise 8 ml. of chloroformic acid methyl ester in 20 ml. of methylene chloride and sufficient 28% sodium hydroxide so that the pH value is held between 7.0 and 7.5. After completion of the addition, the mixture is stirred for a further 1 hour and the residue is subsequently filtered off. The two phases obtained are separated and the organic phase is treated for 1 hour while stirring at 0° C. with 150 ml. of 1-N sodium hydroxide. The mixture obtained is treated with 20 ml. of methanol and the two phases are separated. The aqueous phase is extracted twice with 200 ml. of methylene chloride and the combined organic extracts are dried over sodium sulfate. By evaporation of the solvent there is obtained pure methyl 2-amino-6-[3,6-dihydro-1(2H)-pyridyl]-4-pyrimidinecarbamate-3-oxide having a melting point of 174°-176° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:27]=1[N:26]([NH2:28])[CH:25]=[C:24]2[CH3:29].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C>[F:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:27]=1[N:26]([NH:28][C:15]([C:11]1[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=1)=[O:17])[CH:25]=[C:24]2[CH3:29]
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Reactant: Cc1cn(N)c2c(F)cccc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(C)c2cccc(F)c21
Temperature: 50 °C
Reaction time: 4 h
Yield: 47.5 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (1.34 mmol) and 7-fluoro-3-methyl-indol-1-ylamine (342 mg, 1.47 mmol) in DMF (15 mL) is stirred at 50° C. for 1 h. The mixture is treated with DMTMM (407 mg, 1.47 mmol) and stirred at 50° C. for 4 h. The mixture is concentrated in vacuo, diluted with Et2O (50 mL), and washed with saturated aqueous Na2CO3 (50 mL). The organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0%-100% DCM in EtOAc to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (7-fluoro-3-methyl-indol-1-yl)-amide (241 mg, 48%). MS: 379 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 9.05 (s, 1H), 8.32 (d, 1H), 8.18 (d, 1H), 7.64 (m, 1H), 7.45 (m, 1H), 7.40 (m, 1H), 7.31 (s, 1H), 7.05 (m, 2H), 2.74 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: CO[C:3](=[O:30])[C:4]1[CH:9]=[C:8]([CH:10]2[CH2:14][CH2:13][O:12][CH2:11]2)[C:7]([C:15]([F:18])([F:17])[F:16])=[CH:6][C:5]=1[NH:19][C:20](OC1C=CC(Cl)=CC=1)=[O:21].[CH3:31][S:32]([NH:35][NH2:36])(=[O:34])=[O:33].CCN(C(C)C)C(C)C>O1CCOCC1>[O:21]=[C:20]1[N:36]([NH:35][S:32]([CH3:31])(=[O:34])=[O:33])[C:3](=[O:30])[C:4]2[C:5](=[CH:6][C:7]([C:15]([F:18])([F:17])[F:16])=[C:8]([CH:10]3[CH2:14][CH2:13][O:12][CH2:11]3)[CH:9]=2)[NH:19]1
Reactant: CS(=O)(=O)NN
Reactant: COC(=O)c1cc(C2CCOC2)c(C(F)(F)F)cc1NC(=O)Oc1ccc(Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(C3CCOC3)cc2c1=O
Temperature: 80 °C
Reaction time: 18 h
Yield: 70.6 %

Procedure:
2-(4-Chloro-phenoxycarbonylamino)-5-(tetrahydro-furan-3-yl)-4-trifluoromethyl-benzoic acid methyl ester (80 mg, 0.18 mmol) was dissolved in dioxane (1 mL) and, after addition of CH3SO2NHNH2 (21.8 mg, 1.1 equiv) and i-Pr2NEt (61.7 μL, 2 equiv), the mixture was stirred for 18 h (TLC control) at 80° C. The crude product was purified by flash chromatography with DCM to DCM/MeOH 85:15 as eluent. The obtained product was dried, dissolved in a small quantity of DCM and precipitated with hexanes. The white solid was filtered off and dried to provide the title compound (50 mg, 70% yield) (394 [M+H]+, rt 4.58 min.).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:13])[CH3:12])(=[O:3])[CH3:2].OS(O)(=O)=O.[N+:19]([O-])([OH:21])=[O:20]>>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:19]([O-:21])=[O:20])[C:5]=1[NH:10][C:11](=[O:13])[CH3:12])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccccc1C(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1c(C(C)=O)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 7 h

Procedure:
A solution of N-(2-acetyl-phenyl)-acetamide (1 g, 5.65 mmol) in conc. H2SO4 (2.8 mL, 45.2 mmol) was cooled to −20° C. and fuming nitric acid (2 mL, 33 mmol) was slowly added. The reaction mixture was warmed to 0° C. and stirred for 7 h. After completion of the starting material, the reaction mixture was quenched with water and extracted with dichloromethane (2×25 mL). The combined organic layers were washed with brine and water, then dried over anhydrous sodium sulphate and concentrated to dryness. The resulting residue was purified by column chromatography using 1% methanol in chloroform to get the title compound as yellow solid
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH:48]1([NH:51][CH2:52][C@@H:53]2[C@@H:57]([OH:58])[CH2:56][CH2:55][NH:54]2)[CH2:50][CH2:49]1>CN(C=O)C>[CH:48]1([NH:51][CH2:52][C@@H:53]2[C@@H:57]([OH:58])[CH2:56][CH2:55][N:54]2[C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:32])[CH2:50][CH2:49]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: O[C@H]1CCN[C@@H]1CNC1CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CC[C@H](O)[C@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
A mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (250 mg, 0.5 mmol), HOBt (81 mg, 1.2 eq.), EDC (115 mg, 1.2 eq.), TEA (0.17 mL, 2.5 eq.) and (2R,3S)-2-cyclopropylaminomethyl-pyrrolidin-3-ol (312 mg, 4 eq.) in DMF (10 mL) was stirred at rt for overnight. The reaction was concentrated, washed with water, sodium bicarbonate and brine, dried and concentrated. The residue was purified on a silica gel column to give 100 mg of the titled compound as a yellow solid.