Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]([NH:9][C:10]([NH:12][C:13]1[N:28]=[C:16]2[N:17]=[CH:18][CH:19]=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[N:15]2[N:14]=1)=[O:11])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[N:29]1([CH2:35][CH2:36]O)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[ClH:69]>C(Cl)Cl.CO>[ClH:69].[CH3:1][C@H:2]([NH:9][C:10]([NH:12][C:13]1[N:28]=[C:16]2[N:17]=[CH:18][CH:19]=[C:20]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:36][CH2:35][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:25][CH:26]=3)[N:15]2[N:14]=1)=[O:11])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: OCCN1CCOCC1
Reactant: CC(C)CCC[C@H](C)NC(=O)Nc1nc2nccc(-c3ccc(O)cc3)n2n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: CC(C)CCC[C@H](C)NC(=O)Nc1nc2nccc(-c3ccc(OCCN4CCOCC4)cc3)n2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-1-(1,5-dimethylhexyl)-3-[7-(4-hydroxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]urea (the compound obtained in Example 255; 20 mg) was dissolved in methylene chloride (1 ml) in an argon atmosphere. Thereafter, 2-morpholin-4-ylethanol (21 mg) and triphenylphosphine (41 mg) were added to the obtained solution, and the obtained mixture was stirred at a room temperature for 30 minutes. Thereafter, the reaction solution was cooled on ice, and diethyl azodicarboxylate (27 mg) was then added thereto, followed by stirring the mixture at the same temperature for 30 minutes. The reaction solution was further stirred at a room temperature overnight. Thereafter, the reaction solution was concentrated under a reduced pressure. Thereafter, ethyl acetate (3 ml) and 1 M hydrochloric acid (3 ml) were added thereto, and the obtained mixture was separated. After the obtained water layer was washed with ethyl acetate (3 ml), an aqueous 6 M sodium hydroxide solution was added thereto to convert the solution to be alkaline. After extraction with methylene chloride (5 ml), the organic layer was washed with distilled water (5 ml×2), and the solvent was then distilled off under a reduced pressure. The residue was washed by suspension in a mixed solvent (2 ml) consisting of 50% ethyl acetate and hexane to obtain the captioned compound in the form of a free body (18 mg). Thereafter, methanol (1 ml) and 1 M hydrochloric acid (0.2 ml) were added to the obtained compound and dissolved therein, and the obtained mixture was then concentrated under a reduced pressure. The obtained residue was washed by suspension in acetone (0.5 ml) to obtained the captioned compound (17 mg).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]([N:11]2C(=O)C3=CC=CC=C3C2=O)[CH2:4][CH2:3]1.Cl>C(O)C>[O:1]=[C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]([NH2:11])[CH2:4][CH2:3]1
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)c2sccc21
Agent: Cl
Solvent: CCO
Product: NC1CCC(=O)c2ccsc21

Procedure:
A 0.55 g. sample of N-(4,5,6,7-tetrahydro-4-oxobenzo[b]thien-7-yl)phthalimide is stirred and heated at reflux with 5 ml. of 6N HCl and one ml. of ethanol for 16 hours. Subsequently, the ethanol is distilled off and refluxing is continued for another 4 hours with the addition of 2 ml. of concentrated HCl. The mixture is cooled in ice, the white crystals of phthalic acid are filtered and washed with 5 ml. of water. The filtrate is washed with 15 ml. of CHCl3 and the aqueous solution of 4,5,6,7-tetrahydro-4-oxobenzo[b]thiophen-7-amine hydrochloride is neutralized until the solution is at pH 10-11 with 50% aqueous NaOH. The amine is then extracted from the aqueous mixture with chloroform (3×25 ml.). The combined extracts are dried over MgSO4 and evaporated to afford 0.17 g. of light yellow syrup. This gives the title compound with infrared absorption bands at 1660, 1620 and 1520 cm-1.
Reaction SMILES: [CH:1]1([C:16]([OH:18])=[O:17])[CH2:6][CH:5]([C:7]([OH:9])=O)[CH:4]([C:10]([OH:12])=[O:11])[CH2:3][CH:2]1[C:13]([OH:15])=O.C(OC(=O)C)(=O)C>>[CH2:6]1[CH:1]2[C:16]([O:18][C:13](=[O:15])[CH:2]2[CH2:3][CH:4]2[C:10]([O:11][C:7](=[O:9])[CH:5]12)=[O:12])=[O:17]
Reactant: O=C(O)C1CC(C(=O)O)C(C(=O)O)CC1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)C2CC3C(=O)OC(=O)C3CC12
Yield: 96.7 %

Procedure:
Successively, 450 g of the obtained 1,2,4,5-cyclohexanetetracarboxylic acid and 4000 g of acetic anhydride were charged into a 5-L glass separable flask equipped with a Dimroth condenser. The inner atmosphere of the reactor was replaced with nitrogen gas under stirring. The temperature was raised to the refluxing temperature of the solvent to allow the solvent to reflux for 10 min. Thereafter, the temperature was lowered to room temperature under stirring to precipitate crystals. The precipitated crystals were separated by solid-liquid separation and dried to obtain primary crystals. The mother liquor after separation was concentrated under reduced pressure using a rotary evaporator to precipitate crystals. The precipitated crystals were separated by solid-liquid separation and dried to obtain secondary crystals. In total of the primary and secondary crystals, 375 g of 1,2,4,5-cyclohexanetetracarboxylic dianhydride was obtained (yield of anhydration: 96.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[N+:10]([O-])([OH:12])=[O:11].[OH-].[Na+]>S(=O)(=O)(O)O>[NH2:1][C:2]1[C:7]([N+:10]([O-:12])=[O:11])=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C)c([N+](=O)[O-])c(N)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
6.0 g(0.04911 mole) of 2-amino-4,6-dimethyl pyridine was dissolved in 20 ml of conc. sulfuric acid. The reaction solution was cooled to 0° C. in an ice bath and thereto was added dropwise 2.3 ml(0.04911 mole) of conc. nitric acid diluted with 5 ml of conc. sulfuric acid over 10 minutes. The resultant was stirred for 30 minutes at 0° C. and then added into ice water slowly to terminate the reaction. The reaction solution was neutralized to pH 7-8 with 20% aqueous sodium hydroxide solution and extracted with ethyl acetate(100 ml×3). The organic layer was dried over sodium sulfate anhydride and concentrated under reduced pressure. The residue was recrystallized from methanol-ethyl acetate to obtain 4.26 g of the title compound as a yellow solid(yield 52%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][CH:7]([F:39])[C:8]1[N:12]([C:13]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:16]=[C:15]([N:25]3[CH2:31][CH:30]4[O:32][CH:27]([CH2:28][CH2:29]4)[CH2:26]3)[N:14]=2)[C:11]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:10]=2[N:9]=1.C([O-])([O-])=O.[K+].[K+].O>C(Cl)Cl>[F:39][CH:7]([F:6])[C:8]1[N:12]([C:13]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][N:22]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:21][CH2:20]3)[N:16]=[C:15]([N:25]3[CH2:31][CH:30]4[O:32][CH:27]([CH2:28][CH2:29]4)[CH2:26]3)[N:14]=2)[C:11]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:10]=2[N:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCNCC2)nc(N2CC3CCC(C2)O3)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCN(S(C)(=O)=O)CC2)nc(N2CC3CCC(C2)O3)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.5 %

Procedure:
Methanesulfonyl chloride (0.12 mL, 1.55 mmol) was added dropwise to a stirred suspension of 3-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-8-oxa-3-azabicyclo[3.2.1]octane (165 mg, 0.349 mmol) and powdered K2CO3 (434 mg, 3.15 mmol) in CH2Cl2 (5 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 3 days. Water was added, the phases were separated and the aqueous phase was extracted with CH2Cl2. The combined organic phases were dried (Na2SO4) and the solvent removed under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (99:1), followed by recrystallization from CH2Cl2/MeOH gave 170 mg (89% yield) of 3-{4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-[4-(methylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-8-oxa-3-azabicyclo[3.2.1]octane: mp (CH2Cl2/MeOH) 312-314° C.; 1H NMR (CDCl3) δ7.86 (dd, J=8.4, 0.6 Hz, 1H), 7.45 (t, JHF=53.6 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 4.49 (br s, 2H), 4.32 (d, J=13.2 Hz, 2H), 4.05 (s, 3H), 4.02 (br s, 4H), 3.30 (m, 6H), 2.81 (s, 3H), 1.99 (m, 2H), 1.79 (m, 2H); Anal. Calcd. for C23H28F2N8O4S: C, 50.2; H, 5.1; N, 20.35. Found: C, 50.3; H, 5.1; N, 20.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[C:21]([C@H:23]2[CH2:27][S:26][C@H:25]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=3)[S:24]2)[CH:20]=[C:19]([O:40][CH3:41])[C:4]=1[O:5][CH2:6][CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[O:10].[C:42](Cl)(=[O:44])[CH3:43].C(N(CC)CC)C>ClCCl>[C:42]([N:11]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:9]([O:8][CH2:7][CH2:6][O:5][C:4]1[C:19]([O:40][CH3:41])=[CH:20][C:21]([C@H:23]2[CH2:27][S:26][C@H:25]([C:28]3[CH:29]=[C:30]([O:38][CH3:39])[C:31]([O:36][CH3:37])=[C:32]([O:34][CH3:35])[CH:33]=3)[S:24]2)=[CH:22][C:3]=1[O:2][CH3:1])=[O:10])(=[O:44])[CH3:43]
Reactant: COc1cc([C@H]2SC[C@H](c3cc(OC)c(OCCOC(=O)NCc4ccccn4)c(OC)c3)S2)cc(OC)c1OC
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc([C@H]2SC[C@H](c3cc(OC)c(OCCOC(=O)N(Cc4ccccn4)C(C)=O)c(OC)c3)S2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Trans-2-[{2,6-dimethoxy-4-(3-(3,4,5-trimethoxyphenyl)-2,4-dithiolanyl)phenoxy}ethoxycarbonylaminomethyl]pyridine (31) (FIG. 26) (0.313 g,0.520 mmole) was dissolved in 20 ml dry dichloromethane. The reaction was cooled to 0° C. under an argon atmosphere and 44 μl of acetyl chloride was added. The reaction was allowed to warm to room temperature and was stirred overnight. The reaction was recooled to 0° C. and 87 μl triethyl amine and 44 μl acetyl chloride was added. The reaction was then allowed to warm to room temperature and was stirred for an additional 12 hours. The reaction was then quenched with 10% NaHCO3 and extracted with dichloromethane. The organic layer was dried over MgSO4 and concentrated to a brown oil which was purified by flash column chromatography using 1:1 hexane/ethyl acetate--1:2 hexane/ethyl acetate as eluent. The column yields 293 mg (88%) as a white foam.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=O)[NH:11]3)[CH2:4][CH2:3][CH2:2]1.Cl.Cl.Cl.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][C@H:34]([OH:37])[C@@H:33]([CH3:38])[CH2:32]2)[CH2:25][CH2:24]1>>[OH:37][C@H:34]1[CH2:35][CH2:36][N:31]([CH2:30][CH2:29][N:26]2[CH2:25][CH2:24][CH:23]([NH:22][C:16]([C:10]3[NH:11][C:12]4[C:8]([CH:9]=3)=[C:7]([O:6][CH2:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)[CH:15]=[CH:14][CH:13]=4)=[O:18])[CH2:28][CH2:27]2)[CH2:32][C@@H:33]1[CH3:38]
Reactant: C[C@H]1CN(CCN2CCC(N)CC2)CC[C@@H]1O
Reactant: O=C(O)c1cc2c(OCC3CCC3)cccc2[nH]1
Agent: Cl
Product: C[C@H]1CN(CCN2CCC(NC(=O)c3cc4c(OCC5CCC5)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid, 82 (see example 22) and amine 14.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Br[C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=[O:14].C(OC(C)C)(C)C.C1(NC2CCCCC2)CCCCC1>CN(C=O)C.CCOC(C)=O>[C:1]([S:3][C@@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=[O:14])(=[O:4])[CH3:2]
Reactant: CC(O)=S
Reactant: CC(C)C[C@@H](Br)C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)S[C@@H](CC(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
Thioacetic acid (4.2 g, 54.4 mmol) and DMF (100 mL, 1.0 mol) were combined, and the mixture cooled in an ice bath. Sodium carbonate (5.8 g, 54.4 mmol) was added. After 30 minutes, (R)-2-bromo-4-methylpentanoic acid (10.1 g, 51.8 mmol) in DMF (20 mL) was added dropwise and the mixture was stirred at 0° C. to room temperature over 6 hours. The mixture was diluted with 100 mL EtOAc and extracted with 100 mL of a 1:1 1N HCl:saturated aqueous NaCl solution. The layers were separated and the aqueous phase was extracted with additional EtOAc (100 mL). The organics were combined, washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The recovered oil was dissolved into diisopropyl ether (45 mL, 320 mmol) and chilled at 0° C. Dicyclohexylamine (10.1 mL, 50.7 mmol) was added dropwise and the solid was allowed to crash out of solution. After stirring for an additional 30 minutes the material was filtered and washed with 75 mL cold diisopropyl ether. The recovered solid (14 g) was suspended in 100 mL EtOAc. 150 mL of 5% KHSO4 was added and the layers were separated. The organic was washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The recovered oil was then azeotroped (3×25 mL toluene) to yield the title compound (6.1 g) as a dicyclohexylamine salt.
Reaction SMILES: [Li+].[Cl-].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][CH3:23])[CH:18]=3)[CH:13]([C:24]3[CH:29]=[CH:28][C:27]4[O:30][CH2:31][O:32][C:26]=4[CH:25]=3)[CH:12]2[C:33]([O-:35])=[O:34])=[C:7](OS(C(F)(F)F)(=O)=O)[CH:6]=1.C([Sn]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)(CCCC)CCCC)CCC>O1CCOCC1.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][CH3:23])[CH:18]=3)[CH:13]([C:24]3[CH:29]=[CH:28][C:27]4[O:30][CH2:31][O:32][C:26]=4[CH:25]=3)[CH:12]2[C:33]([OH:35])=[O:34])=[C:9]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[CH:10]=1
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OS(=O)(=O)C(F)(F)F)C(C(=O)[O-])C2c1ccc2c(c1)OCO2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1-c1ccccc1)C(C(=O)O)C2c1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
To a slurry of anhydrous LiCl (46 mg, 1.1 mmol) and tetrakis(triphenylphosphine)-palladium(0) (24 mg, 0.02 mmol) in dry dioxane (3 mL) was added a solution of Methyl (1RS, 2RS, 3RS)-3-(4-Methoxy-2-trifluoromethanesulfonyloxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (95 mg, 0.16 mmol) and tri(but-1-yl)stannylbenzene (319 mg, 0.87 mmol) in dioxane (1 mL). The mixture was refluxed under Argon for 17 h, cooled to room temperature, diluted with ethyl acetate (5 ml) and the resulting solution washed sequentially with brine and water. The organic layer was dried (MgSO4 anhydrous), filtered through a short pad of silica gel and concentrated in vacuo to yield an oil. The product was purified by flash column chromatography (silica gel, gradient elution from hexanes to 10% ethyl acetate/hexanes) to afford the title compound as a white solid. (92 mg, 86%).
Reaction SMILES: [CH2:1]([C:3]1[O:8][C:7](C)(C)O[C:5](=[O:11])[C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].C=[N:19][C:20]([CH3:28])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21]>C1(C)C(C)=CC=CC=1>[CH2:1]([C:3]1[O:8][CH2:7][N:19]([C:20]([CH3:28])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])[C:5](=[O:11])[C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCC1=C(c2ccccc2)C(=O)OC(C)(C)O1
Reactant: C=NC(C)(C)c1ccccc1
Solvent: Cc1ccccc1C
Product: CCC1=C(c2ccccc2)C(=O)N(C(C)(C)c2ccccc2)CO1
Yield: 75 %

Procedure:
Xylene (2 ml) was added to a mixture of 6-ethyl-5-phenyl-2,2-dimethyl-2H,4H-1,3-dioxin-4-one (0.70 g) and N-methylene-1-methyl-1-phenylethylamine (0.44 g), and the resulting mixture was heated at reflux for 20 minutes for reaction. The reaction mixture was purified by silica gel chromatography to obtain the captioned compound (0.72 g).
Reaction SMILES: [ClH:1].Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH:5]([NH:11][NH2:12])[CH2:4]2.[CH3:13][N:14](C=NC=[N+](C)C)[CH3:15].[Cl-].CCN(CC)CC.C(=O)([O-])[O-].[K+].[K+].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.CO.CC(C)=O.C(OCC)C>C(Cl)(Cl)Cl>[ClH:1].[ClH:1].[N:11]1([CH:5]2[CH:6]3[CH2:9][CH2:10][N:3]([CH2:8][CH2:7]3)[CH2:4]2)[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CN(C)C=NC=[N+](C)C
Reactant: NNC1CN2CCC1CC2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: c1ncn(C2CN3CCC2CC3)n1

Procedure:
3-Quinuclidyl-hydrazine dihydrochloride salt (D5) (200 mg, 1.0 mmol) and Gold's reagent ([3-(dimethylamino)-2-azaprop-2-en-1-ylidene]-dimethylammonium chloride) (153 mg, 1.0 mmol) were dissolved in dry CHCl3 (20 ml) under N2 and dry Et3N (0.28 ml, 2.0 mmol) was added. The solution was heated at reflux under nitrogen for 2.5 h. The solution was cooled, saturated aqueous potassium carbonate was added and the organic layer separated. The aqueous layer was extracted with CHCl3 (2×100 ml), the organic extracts were dried (Na2SO4), filtered and were evaporated to dryness under reduced pressure. The resulting orange/yellow oil was purified by column chromatography (basic alumina eluting with 2% MeOH/EtOAc). The resulting clear oil was recrystallised as the dihydrochloride salt from methanol/acetone/diethyl ether (45 mg, 0.18 mmol, 18%), m.p. 187-190° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2.[BH3-]C#N.[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH2:12][CH2:11]2
Reactant: COc1cc(CCc2ccc3[nH]ccc3c2)cc(OC)c1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2ccc3c(c2)CCN3)cc(OC)c1OC
Reaction time: 1 h
Yield: 100.8 %

Procedure:
To a solution of the product of Step B (0.12 g; 0.38 mmol) in tetrahydrofuran (THF)/acetic acid 1:1 mixture (6 ml) NaBH3CN (0.1 g; 1.16 mmol) was added at room temperature. After stirring for 1 h the solvents were removed in vacuo and the residue was diluted to 15 ml with Et2O and washed with 1 N NaOH (5 ml), H2O (2×5 ml), brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.12 g; 100%), which was used in next step without further purification. 1H-NMR (CDCl3) 2.85 (s, 4H); 2.99 (tr, 2H, J=8.3 Hz); 3.52 (tr, 2H, J=8.3 Hz); 3.66 (broad s, 1H); 3.8 (s, 9H); 6.39 (s, 2H); 6.57 (d, 1H, J=7.9 Hz); 6.84 (d, 1H, J=7.9 Hz); 6.96 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][C:6]1[NH:7][C:8](=O)[C:9]2[C:14]([CH3:15])=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:12][C:10]=2[N:11]=1.P(Cl)(Cl)([Cl:28])=O.CN(C)C1C=CC=CC=1>>[Cl:28][C:8]1[C:9]2[C:14]([CH3:15])=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:12][C:10]=2[N:11]=[C:6]([CH2:5][C:4]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:2]([Cl:1])[CH:3]=2)[N:7]=1
Reactant: CCOC(=O)c1sc2nc(Cc3ccc(Cl)c(Cl)c3)[nH]c(=O)c2c1C
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)c1sc2nc(Cc3ccc(Cl)c(Cl)c3)nc(Cl)c2c1C
Reaction time: 4 h

Procedure:
Three (3.00) g of ethyl 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate and 37 mL of phosphorus oxychloride were mixed, and to which 1.4 mL of N,N-dimethylaniline was added, followed by stirring at 90° for 4 hours. The reaction liquid was poured on ice and stirred for 3 hours, and the precipitated crystals were recovered by filtration and washed with water. Drying the crystals under aeration, 3.05 g of the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:21]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:10]([Cl:21])=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(N)ncnc21
Solvent: CN(C)C=O
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc(Cl)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a pre-cooled solution (0° C.) of the compound from Step F of Example 62 (140 mg, 0.50 mmol) in DMF (2.5 mL) was added N-chlorosuccinimide (0.075 g, 0.55 mmol) in DMF (0.5 mL) dropwise. The solution was stirred at rt for 1 h and the reaction quenched by addition of methanol (4 mL) and evaporated in vacuo. The crude product was purified on silica gel using methanol/dichloromethane (1:9) as eluent. Fractions containing the product were pooled and evaporated in vacuo to give the desired product (55 mg) as a colorless solid.
Reaction SMILES: Br[CH:2]([C:4]1[C:5]([F:27])=[CH:6][C:7]2[O:16][CH2:15][CH2:14][N:13]3[C:9](=[N:10][C:11]([C:17]4[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=4)=[CH:12]3)[C:8]=2[CH:26]=1)[CH3:3].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C>O1CCOCC1>[F:27][C:5]1[C:4]([CH:2]([N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)[CH3:3])=[CH:26][C:8]2[C:9]3[N:13]([CH:12]=[C:11]([C:17]4[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=4)[N:10]=3)[CH2:14][CH2:15][O:16][C:7]=2[CH:6]=1
Reactant: CN1CCNCC1
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(C(C)Br)c(F)cc2OCC3)n(C(C)C)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1nc(-c2cn3c(n2)-c2cc(C(C)N4CCN(C)CC4)c(F)cc2OCC3)n(C(C)C)n1
Yield: 63.3 %

Procedure:
A solution of 9-(1-bromoethyl)-8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 374 (99 mg, 0.23 mmol), N-methylpiperazine (28 μL, 0.25 mmol) and DIPEA (60 μL, 0.35 mmol) in dioxane (1 mL) was stirred at RT for 72 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (Si-PPC, gradient 0-8% 2 M NH3/MeOH in DCM) to give 66 mg of a pale yellow oil. The compound was further purified by reverse phase column chromatography (C18, gradient 2-50% MeOH in 1% TFA/H2O) and then loaded in MeOH onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 2 M NH3 in MeOH. The basic fraction was concentrated in vacuo to afford 373 (47 mg, 40% over 2 steps) as a white solid. LCMS (Method K): RT 2.70 min [M+H]+ 454.2. 1H NMR (CD3OD, 400 MHz): δ 8.54 (1H, d, J=8.6 Hz), 7.68 (1H, s), 6.76 (1H, d, J=11.0 Hz), 5.83 (1H, sept., J=6.7 Hz), 4.49 (4H, br s), 3.84 (1H, q, J=6.8 Hz), 2.47 (8H, br s), 2.33 (3H, s), 2.22 (3H, s), 1.53 (3H, d, J=6.7 Hz), 1.52 (3H, d, J=6.7 Hz), 1.40 (3H, d, J=6.8 Hz)
Reaction SMILES: Cl[C:2]1[C:3]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])(=[O:11])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1.[OH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[F:19][C:18]([F:21])([F:20])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:3]1[C:2]([C:27]2[CH:28]=[CH:29][C:24]([CH2:23][OH:22])=[CH:25][CH:26]=2)=[N:7][CH:6]=[CH:5][N:4]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Nc1nccnc1Cl)c1ccccc1C(F)(F)F
Reactant: OCc1ccc(B(O)O)cc1
Product: O=S(=O)(Nc1nccnc1-c1ccc(CO)cc1)c1ccccc1C(F)(F)F
Yield: 85 %

Procedure:
Following the general method as outlined for Intermediate 4, starting from N-(3-chloropyrazin-2-yl)-2-(trifluoromethyl)benzenesulfonamide and 4-hydroxymethyl benzene boronic acid, the title compound was isolated, after evaporation and recrystallization, as a yellowish solid in 85% yield (97% purity by HPLC).