Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2](Br)[CH2:3][C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2.C=CBr.CC(C)([O-])C.[K+]>COCCOCCOCCOC.O>[C:3]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2)#[CH:2]
Reactant: BrC(Br)CC12CC3CC(CC(C3)C1)C2
Agent: C=CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOCCOCCOC
Solvent: O
Product: C#CC12CC3CC(CC(C3)C1)C2
Temperature: 160 °C

Procedure:
A solution of 45 g (0.17 mol) of 1-bromoadamantane in 60 ml of vinyl bromide was cooled to -65° C. and 10 g of aluminum bromide was added portionwise over 2 h. The mixture was then poured on to 500 g of ice, neutralized with 10% aqueous sodium carbonate solution, and extracted with 3×100 ml of methylene chloride. The combined extracts were dried (MgSO4) and evaporated to yield 70 g of an oil containing 1-(2,2-dibromoethyl)adamantane and polyvinyl bromide (NMR). This oil was dissolved in 100 ml of triglyme, 38 g (0.34 mol) of potassium t-butoxide added, nd the mixture heated at 160° C. for 3 h. The mixture was cooled, diluted with 300 ml of water and extracted with 3×100 ml of hexane. The combined hexane extracts were dried (MgSO4) , and distilled to give 12 g (52% based on 1-bromoadamantane) of 1 -ethynyladamantane: mp 82°-83° C.; bp 95-100 (l mm); NMR δ1.9-2.6 ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[CH3:31][N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH:42]=1.CCN(C(C)C)C(C)C>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[C:14]([N:50]1[CH2:51][CH2:52][N:47]([C:43]2[CH:44]=[CH:45][CH:46]=[C:41]([C:33]3[N:32]([CH3:31])[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[N:34]=3)[CH:42]=2)[CH2:48][CH2:49]1)=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1c(-c2cccc(N3CCNCC3)c2)nc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCOCC1C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1c(-c2cccc(N3CCN(C(=O)C4COCCN4C(=O)OC(C)(C)C)CC3)c2)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
To a solution of morpholine-3,4-dicarboxylic acid-4-tert-butyl ester (0.16 g, 0.71 mmol) in acetonitrile (8 mL) was added CDI (0.16 g, 0.71 mmol) and the resulting suspension was stirred at room temperature overnight. 1-Methyl-2-(3-piperazin-1-yl-phenyl)-1H-benzoimidazole dihydrochloride (0.20 g, 0.55 mmol) (obtained as described in method C) and DIPEA (0.19 mL, 1.10 mmol) were added and the resulting solution heated at 65° C. overnight. The reaction was then cooled to room temperature, the solvent removed, the crude product was dissolved with dichloromethane (15 mL) and washed with saturated NaHCO3 solution (2×3 mL) The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (eluent: gradient from cyclohexane to cyclohexane:EtOAc 2:1) to afford 0.11 g (40%) of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH:19]([CH3:21])[CH3:20])[C:3]([NH:5][C:6]1[C:7]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:4].Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:20][CH:19]([CH3:21])[C@H:2]([NH:1][C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][NH:27]2)[C:3]([NH:5][C:6]1[C:7]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:4]
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CC(C)[C@H](N)C(=O)Nc1cccnc1Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)[C@H](Nc1ncnc2[nH]cnc12)C(=O)Nc1cccnc1Nc1ccccc1
Temperature: 100 °C
Yield: 68 %

Procedure:
A mixture of (S)-2-amino-3-methyl-N-(2-phenylaminopyridin-3-yl)butyramide (3.0 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (720 mg, 3.0 mmol) and DIPEA (2.6 mL, 15.0 mmol) in n-butanol (12 mL) was heated at 100° C. for 18 h in a sealed vial. After cooling to RT, the volatiles were removed in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford the title compound (821 mg, 68% over two steps). LCMS (Method J): RT 1.75 min [M+H]+ 403.2.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[N+:14]([O-])([O-:16])=[O:15].[K+]>OS(O)(=O)=O>[CH3:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1)=[O:8]
Reactant: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc([N+](=O)[O-])c2[nH]c(=O)oc(=O)c2c1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
6.9 g (40 mmol) of the above 5-Methylisatoic anhydride was suspended in 40 mL of conc. H2SO4 at −10° C. and cooled to −20° C. Next, 1.05 eq of potassium nitrate dissolved in 12 mL of sulfuric acid and cooled to 0° C., was then added dropwise. The reaction mixture was stirred −20° C. for 15 min then kept between −5° C. and 0° C. for 3 h. The mixture was poured into a beaker containing ice. The resulting solid was collected, washed with cold water and dried to give 3.9 g (44%) of 5-methyl-3-nitroisatoic anhydride as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]([F:35])[F:34])=[C:6]([C:8]2[N:9]=[C:10]([N:25]3[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]3)[S:11][C:12]=2[NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=23)=[O:15])[CH:7]=1.[CH3:36][NH:37][CH2:38][CH2:39][C:40]#[N:41].C(O)(=O)C.C([BH3-])#N>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]([F:35])[F:34])=[C:6]([C:8]2[N:9]=[C:10]([N:25]3[CH2:26][CH2:27][CH:28]([N:37]([CH2:38][CH2:39][C:40]#[N:41])[CH3:36])[CH2:29][CH2:30]3)[S:11][C:12]=2[NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=23)=[O:15])[CH:7]=1
Reactant: O=C1CCN(c2nc(-c3cc(Cl)ccc3OC(F)F)c(NC(=O)c3cnn4cccnc34)s2)CC1
Reactant: CNCCC#N
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CN(CCC#N)C1CCN(c2nc(-c3cc(Cl)ccc3OC(F)F)c(NC(=O)c3cnn4cccnc34)s2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.1 %

Procedure:
Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [4-(5-chloro-2-difluoromethoxy-phenyl)-2-(4-oxo-piperidin-1-yl)-thiazol-5-yl]-amide (90 mg, 0.17 mmol) was dissolved in DCM (2 ml) and N-methyl-β-alaninenitrile (20 μl, 0.21 mmol), acetic acid (200 μl) and macroporous polymer supported cyanoborohydride (166 mg, 0.36 mmol) were successively added and stirred at room temperature for 16 hours. The mixture was diluted with MeOH and loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. The resulting yellow glass was purified by MDAP (Method 1). Appropriate fractions were combined and evaporated to afford a yellow glass. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH to give the title compound as a yellow solid (46 mg, 46%). LCMS (Method 5) [M+H]+=587.2, RT=3.19 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 10.23 (s, 1H), 9.36 (dd, 1H, J=1.6, 7.0 Hz), 8.68 (s, 1H), 8.64 (dd, 1H, J=1.6, 4.3 Hz), 7.67 (d, 1H, J=2.6 Hz), 7.59 (dd, 1H, J=2.7, 8.9 Hz), 7.41 (d, 1H, J=8.6 Hz), 7.31 (dd, 1H, J=4.3, 7.1 Hz), 7.18 (t, 1H, J=73.9 Hz), 3.94 (d, 2H, J=12.8 Hz), 3.04-2.96 (m, 2H), 2.72-2.60 (m, 5H), 2.24 (s, 3H), 1.79 (d, 2H, J=10.9 Hz), 1.59-1.47 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([O:19]C)=[O:18])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C@H:11]2[CH2:12][CH2:13][C@H:14]([C:17]([OH:19])=[O:18])[CH2:15][CH2:16]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H]1CC[C@H](S(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@H]1CC[C@H](S(=O)(=O)c2ccc(Cl)cc2)CC1
Reaction time: 1 h

Procedure:
To a solution of methyl trans-4-[(4-chlorophenyl) sulfonyl]cyclohexanecarboxylate (209 mg, 0.81 mol) synthesized in (10B) in methanol (10 ml), 2 N sodium hydroxide (0.5 ml, 1 mmol) was added at room temperature, and the resulting mixture was stirred at the same temperature for 1 hour. Then, to the reaction solution, 2 N hydrochloric acid (0.5 ml, 1 mmol) was added, and extraction was performed once with ethyl acetate. The obtained organic layer was washed with water and a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:90 to 0:100 (v/v)), whereby the title compound was obtained as an oil (180 mg, yield: 73%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C@@H:7]2[CH2:12][CH2:11][NH:10][CH2:9][C@H:8]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:21](#[N:24])[CH:22]=[CH2:23].[ClH:25]>CCOCC>[ClH:25].[C:21]([CH2:22][CH2:23][N:10]1[CH2:11][CH2:12][C@@H:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:20][CH:19]=2)[C@H:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)#[N:24]
Reactant: Fc1ccc(O[C@@H]2CCNC[C@H]2c2ccccc2)cc1
Reactant: C=CC#N
Agent: Cl
Solvent: CCOCC
Product: N#CCCN1CC[C@@H](Oc2ccc(F)cc2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2.82 g of trans-4-(4-fluorophenoxy)-3-phenylpiperidine and 5 ml of acrylonitrile is stirred for two hours at room temperature under nitrogen. The mixture is diluted with ether (50 ml) and treated dropwise with 20 ml of saturated ethereal hydrogen chloride solution. After stirring for a few minutes the solid is filtered, washed with ether and dried to afford a colorless solid. Recrystallization from isopropanol (80 ml) gives of product as colorless crystals, mp 212°-214°0 C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.NC[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:10]1>C(Cl)Cl.CN(C)C=O>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH2:9][CH2:10][CH2:11]1
Reactant: NCC1CCN(CCc2ccccn2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: c1ccc(CCN2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
To a suspension of benzofurazan-5(or 6)-carboxylic acid (150 mg, 0.91 mmol) in methylene chloride (3.3 ml) was added dimethylformamide (1 drop) followed by dropwise addition of oxalyl chloride (89 μl, 1.0 mmol). The resulting solution was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The brown oil was redissolved in methylene chloride (3.3 ml) and was added to a cooled (0° C.) solution of 4-(aminomethyl)-1-(2-pyridylethyl)piperidine (0.21 g, 0.95 mmol) in methylene chloride (1.6 ml). The reaction mixture was stirred at 0° C. for 11/2 hours. Solvent evaporation, flash chromatography (silica gel, chloroform-methanol-ammonium hydroxide, 95/5/1/2) and trituration with hexane-ethyl acetate gave 4-[N-benzofurazan-5(or 6)-carbonyl)aminomethyl]-1-(2-pyridylethyl)piperidine (133 mg, 40%); mp 149°-151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:24][C:23]([O:25][C@@H:26]3[CH2:30][O:29][C@@H:28]4[C@H:31]([OH:34])[CH2:32][O:33][C@H:27]34)=[N:22][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:15][CH2:16][S:17](=[O:21])(=[O:20])[CH2:18][CH:19]=2)=[CH:10][CH:9]=1.[H][H]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:24][C:23]([O:25][C@@H:26]3[CH2:30][O:29][C@@H:28]4[C@H:31]([OH:34])[CH2:32][O:33][C@H:27]34)=[N:22][C:5]2=[N:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1
Reactant: O=S1(=O)CC=C(c2ccc(-c3nc4nc(O[C@@H]5CO[C@H]6[C@@H]5OC[C@H]6O)[nH]c4cc3Cl)cc2)CC1
Reactant: [H][H]
Solvent: CO
Solvent: ClCCl
Product: O=S1(=O)CCC(c2ccc(-c3nc4nc(O[C@@H]5CO[C@H]6[C@@H]5OC[C@H]6O)[nH]c4cc3Cl)cc2)CC1

Procedure:
Placed 4-(4-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)phenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (5 mg, 0.010 mmol) under nitrogen in methanol (1.0 ml). A few drops of DCM were added to dissolve the solid. Then 10% Pd(C) (10 mg, 9.92 μmol) was added and a slight vacuum was pulled followed by the introduction of hydrogen gas (3×). The reaction mixture was stirred under 1 atmosphere of hydrogen gas at room temperature for 1.5 hours, then filtered and concentrated under reduced pressure. The resulting residue was chromatographed using a 20 g silica gel cartridge eluted with 0-10% methanol in DCM over 10 column volumes. The desired product fractions were combined and concentrated under reduced pressure to provide the title compound as a white solid. LC-MS: calculated for C23H24ClN3O6S 505.09 observed m/e: 505.98 (M+H)+ (Rt 2.58/4 min).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][N:14]([CH3:21])[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:18]2[CH2:19][CH2:20][CH:15]([N:14]([CH3:21])[CH3:13])[CH2:16][CH2:17]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN(C)C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCC(N(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
A 100 ml flask was charged with 4-fluoro-2-methoxy-1-nitrobenzene (5.13 g, 30 mmol), N,N-dimethylpiperidin-4-amine (4.23 g, 33.0 mmol) and N,N-dimethylformamide (60 ml). To the mixture was added N-ethyl-N-isopropylpropan-2-amine (10.45 ml, 60.0 mmol) and the mixture was heated at 70° C. overnight under nitrogen. The reaction mixture was concentrated under high vacuum and the residue was partitioned between brine (100 ml) and methylene chloride (100 ml) and the pH adjusted to ca. 12-14 with sodium hydroxide. The layers were separated and the aqueous layer was extracted with methylene chloride (3×100 ml). The combined organics were dried over sodium sulfate, filtered and adsorbed directly on to silica gel (ca. 25 g). This was split in two portions each of which was purified on a silica gel cartridge (150 g) eluted with a 2.5, 4.5, 6% 7N methanolic ammonia in methylene chloride step gradient. The combined product fractions were concentrated to provide the title compound. MS (DCI(+)) m/e 280.2 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[C:8]2[CH:9]=[C:10]([O:14][CH3:15])[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][C:4]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[NH:3]1.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Cl)=[CH:35][CH:34]=1.[I-].[Cs+].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[O:30]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:14][CH3:15])[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][C:4]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[N:3]1[CH2:37][C:36]1[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCCCC1(CCCC)CN(c2ccccc2)c2cc(Br)c(OC)cc2S(=O)(=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: CCCCC1(CCCC)CN(c2ccccc2)c2cc(Br)c(OC)cc2S(=O)(=O)N1Cc1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (prepared according to WO 98/38182; 0.200 g, 0.404 mmol) in MeCN (5 ml) where added p-methoxybenzyl chloride (0.066 ml, 0.486 mmol), CsI (0.010 g, 0.038 mmol) and Cs2CO3 (0.263 g, 0.807 mmol) and the mixture was stirred at 60° C. for 4 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and 0.5M HCl (aq). The organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was filtered through silica gel (DCM:EtOAc-9:1) to give the title compound in 0.257 g (˜quant) as an off-white solid. NMR (400 MHz, CDCl3): 0.60–0.75 (m, 6H), 0.75–1.20 (m, 8H), 1.25–1.45 (m, 2H), 1.80–2.00 (m, 2H), 3.80 (s, 3H), 3.90 (s, 3H), 4.05–4.30 (m, 2H), 4.45–4.65 (m, 2H), 6.70–7.45 (m, 11H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](C(Cl)(Cl)Cl)[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.[CH2:16]([O-:18])[CH3:17].[Na+].O.Cl>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([O:18][CH2:16][CH3:17])[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1
Reactant: CC[O-]
Reactant: Nc1nc(C(F)(F)F)nc(C(Cl)(Cl)Cl)n1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1nc(N)nc(C(F)(F)F)n1
Temperature: 20 °C

Procedure:
20.0 g (71 mmol) of 2-amino-4-trichloromethyl-6-trifluoromethyl-1,3,5-triazine were added at 22° C. to a solution of 0.48 g (7.1 mmol) of sodium ethanolate in 100 ml of ethanol. The pale yellowish green solution was then refluxed for 30 minutes and, after cooling to 20° C., 20 ml of water were added and the mixture was neutralized with 2 normal hydrochloric acid. After this, most of the solvent was removed at 40° C. under reduced pressure, adding 100 ml of water a little at a time so that the solid did not agglomerate. The product was isolated in a similar manner to Example 2.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[Br:11]Br>C(O)(=O)C>[Br:11][C:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3][C:2]=1[CH3:1]
Reactant: Cc1cc2ccccc2s1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1sc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution (50 mL) of 2-methyl-1-benzothiophene (5.00 g) in acetic acid was added dropwise bromine (1.90 mL) at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give the title object compound (8.02 g, quantitative) as a brown oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:19][CH3:20])=[C:7]([CH:18]=1)[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:2].[BH4-].[Na+].Cl>CO>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([O:19][CH3:20])=[C:7]([CH:18]=1)[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: COc1ccc(C=O)cc1C(=O)OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CO)cc1C(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 100.2 %

Procedure:
Benzyl 5-formyl-2-methoxybenzoate (1.10 g, 4.07 mmol) and 30 ml of methanol were mixed and sodium borohydride (155 mg, 4.10 mmol) was added little by little under stirring and cooling with ice. After stirring for 2 hours under cooling with ice, the reaction mixture was poured into ice water and made acidic with 1 mol/l hydrochloric acid, which was extracted with ethyl acetate. The extract was washed with water and with brine, then dried over anhydrous sodium sulfate and concentrated to obtain 1.11 g (99%) of benzyl 5-hydroxymethyl-2-methoxybenzoate (without purifying further, this compound was used for the next reaction).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH:11]([CH:13]=O)=O.O>C(O)C.O>[Br:1][C:2]1[CH:7]=[N:6][C:5]2=[N:8][CH:11]=[CH:13][N:9]=[C:4]2[C:3]=1[CH3:10]
Reactant: Cc1c(Br)cnc(N)c1N
Reactant: O=CC=O
Solvent: CCO
Solvent: O
Product: Cc1c(Br)cnc2nccnc12
Temperature: 25 °C

Procedure:
5-bromo-4-methylpyridine-2,3-diamine (0.21 g, 1 mmol) was dissolved in a mixture of EtOH—H2O; to this was added aqueous glyoxal 40% (0.2 ml, 4 mmol) and the resulting mixture was refluxed for 1 h. Upon cooling to room temperature, water was then added. The product was separated, filtered and washed with excess water yielded 7-bromo-8-methylpyrido[2,3-b]pyrazine as a sufficiently enough pure material (0.21 g) for the next step.
Reaction SMILES: [CH2:1]([N:3](CC)[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][CH2:19][OH:20])[CH:16]=2)[CH:9]=[CH:8][C:7]=1[NH:21][C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:45]=[CH:44][C:36]([CH2:37][P:38](=[O:43])([OH:42])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=2OC)[N:23]=1)=[O:5])[CH3:2].C(NC(C1C=C(C2C=NN(CCCO)C=2)C=CC=1NC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(OCC)OCC)=CC=2)N=1)=O)C>>[CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][CH2:19][OH:20])[CH:16]=2)[CH:9]=[CH:8][C:7]=1[NH:21][C:22]1[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([CH2:37][P:38](=[O:42])([OH:43])[O:39][CH2:40][CH3:41])=[CH:44][CH:45]=2)[N:23]=1)=[O:5])[CH3:2]
Reactant: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Agent: CCNC(=O)c1cc(-c2cnn(CCCO)c2)ccc1Nc1nc(Nc2ccc(CP(=O)(OCC)OCC)cc2)ncc1C(F)(F)F
Product: CCNC(=O)c1cc(-c2cnn(CCCO)c2)ccc1Nc1nc(Nc2ccc(CP(=O)(O)OCC)cc2)ncc1C(F)(F)F
Yield: 53 %

Procedure:
Prepared analogously to Compound 3A using diethyl (4-{[4-({2-(ethylcarbamoyl)-4-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Compound 10B, 589 mg, 872 μmol) to afford 296 mg of the title compound (53%). 1H NMR (400 MHz, CD3OD) δ 8.41 (br. s., 1H), 8.27 (s, 1H), 8.16 (s, 1H), 7.93 (s, 1H), 7.82 (d, J=1.5 Hz, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.46 (d, J=8.1 Hz, 2H), 7.24 (d, J=7.6 Hz, 2H), 4.31 (t, J=6.8 Hz, 2H), 3.84 (t, J=6.9 Hz, 2H), 3.58 (t, J=6.1 Hz, 2H), 3.40 (q, J=7.1 Hz, 2H), 2.90-3.03 (m, 2H), 2.10 (t, J=6.3 Hz, 2H), 1.22 (t, J=7.2 Hz, 3H), 1.14 (t, J=6.9 Hz, 3H). MS (ESI): m/z 648.70 [M+H]+. UPLC: tR=1.04 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].[CH:7]1([CH2:13][NH2:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>C1C=CC=CC=1>[CH:7]1([CH2:13][NH:14][C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:6])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCCN=C=O
Reactant: NCC1CCCCC1
Solvent: c1ccccc1
Product: CCCNC(=O)NCC1CCCCC1
Reaction time: 0.25 h
Yield: 95.7 %

Procedure:
Propyl isocyanate (Aldrich, 42 mL, 0.442 mol) was added dropwise to a solution of cyclohexanemethylamine (Aldrich, 50.1 g, 0.442 mol) in anhydrous benzene (800 mL) at 0° C. under nitrogen. The solution was then stirred for 15 min before being concentrated in vacuo to a volume of 250 mL. The colorless crystals which formed upon standing at 0° C. were filtered off, washed with hexanes (2×70 mL), and dried (0.5 Torr) to give 1-(cyclohexylmethyl)-3-propylurea (83.90 g, 96%), m.p. 60°-61° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]#[N:18])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:17]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:16]2)#[N:18]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C#N)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CNC2
Temperature: 40 °C
Yield: 94.5 %

Procedure:
A mixture of 2-(tert-butyloxycarbonyl)-5-cyano-2,3-dihydro-1H-isoindole (7.6 g) and trifluoroacetic acid (20 ml) in dichloromethane (200 ml) was heated at 40° C. for 0.5 h, then cooled and evaporated in vacuo and the residue partitioned between dichloromethane and 2M sodium hydroxide. The aqueous phase was re-extracted with dichloromethane and the combined organics dried and evaporated to give the title compound as a pink solid (4.24 g, 94%).