Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[N+:6]([C:9]1[CH:10]=[CH:11][C:12]2[NH:17][CH2:16][CH2:15][S:14][C:13]=2[CH:18]=1)([O-:8])=[O:7]>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:17]1[CH2:16][CH2:15][S:14][C:13]2[CH:18]=[C:9]([N+:6]([O-:8])=[O:7])[CH:10]=[CH:11][C:12]1=2)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: O=[N+]([O-])c1ccc2c(c1)SCCN2
Solvent: Cc1ccccc1
Product: O=C(CCl)N1CCSc2cc([N+](=O)[O-])ccc21
Temperature: 110 °C

Procedure:
2-Chloroacetyl chloride (4.08 mL, 50.9 mmol) was added dropwise to a solution containing 7-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine (5 g, 25.5 mmol) in toluene (30 mL). The mixture was refluxed at 110° C. for 20 minutes. The mixture was quenched with saturated sodium bicarbonate solution (100 mL). The mixture was transferred to a separatory funnel and extracted with EtOAc (4×100 mL). The crude material was filtered through a pad of silica gel and washed with EtOAc. The filtrate was concentrated to give a yellow-brown solid. 1H-NMR (DMSO-d6) δ 8.12 (d, J=2.7 Hz, 1H), 7.94 (dd, J=2.7, 9.0 Hz, 1H), 7.72 (d, J=9.0 Hz, 1H), 4.63 (s, 2H), 3.96 (t, J=5.1 Hz, 2H), 3.32 (t, J=5.4 Hz, 2H, overlap with solvent peak); ESI-MS (m/z, %): 273 (MH+, 100), 295 (40).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1>CN(C=O)C.O>[F:27][C:26]([F:28])([F:29])[O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a dried flask charged with tert-butyl 4-hydroxypiperidine-1-carboxylate (3.60 g, 17887 μmol) was added dry DMF (40 mL) and the resulting solution cooled in an ice water bath prior to the addition of NaH (60% in mineral oil) (748 mg, 18781 μmol) in two portions 5 min apart. The reaction mixture was stirred for 1 hr and allowed to warm to RT over that time. The resulting suspension was cooled in an ice water bath prior to the addition of a solution of 1-(bromomethyl)-4-(trifluoromethoxy)benzene (5018 mg, 19676 μmol) in DMF (5 mL) via syringe. The resulting reaction mixture was allowed to slowly warm to RT while stirring for 15 h. The resulting pale yellow suspension was carefully diluted with water (about 150 mL) and extracted 2× with EtOAc. The combined organics were dried with Na2SO4, filtered and concentrated under reduced pressure. The material was purified through silica gel column chromatography ramping ethyl acetate in hexanes from 0% to 10% over 5 mins, then remaining at 10% for 10 min, then ramping to 50% over 5 min providing tert-butyl 4-(4-(trifluoromethoxy)benzyloxy)-piperidine-1-carboxylate (5 g) as a white crystalline solid upon drying.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=2)[N:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:6]=1[C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:3])[CH3:2]>[Pd].C(OCC)(=O)C>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[N:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:6]=1[C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2cc(N)ccc21

Procedure:
3-Acetylamino-2-benzoyl-1-(ethoxycarbonyl)-5-nitroindole (Example 96, step 3; 200 mg, 0.51 mmol) was hydrogenolyzed in the presence of palladium on activated carbon (5%, 50 mg) in ethyl acetate (40 ml) at atmospheric pressure for 4 h. Catalyst was removed by filtration and the filtrate was concentrated to afford the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:5]=[C:4]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[N:3]=1.[C:31]([SiH2:35][O:36][C:37]([CH3:48])([CH3:47])[C:38]1[CH:39]=[C:40]([CH2:44][C:45]#[N:46])[CH:41]=[CH:42][CH:43]=1)([CH3:34])([CH3:33])[CH3:32].[H-].[Na+]>CN(C=O)C>[C:31]([SiH2:35][O:36][C:37]([CH3:48])([CH3:47])[C:38]1[CH:39]=[C:40]([CH:44]([C:2]2[C:7]([CH:8]([CH3:10])[CH3:9])=[C:6]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:5]=[C:4]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[N:3]=2)[C:45]#[N:46])[CH:41]=[CH:42][CH:43]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cccc(CC#N)c1
Reactant: COc1ccc(COc2nc(Cl)c(C(C)C)c(OCc3ccc(OC)cc3)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2nc(OCc3ccc(OC)cc3)c(C(C)C)c(C(C#N)c3cccc(C(C)(C)O[SiH2]C(C)(C)C)c3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
To a stirred mixture of 4-chloro-5-isopropyl-2,6-bis-(4-methoxy-benzyloxy)-pyrimidine (5.65 g, 13.17 mmol) and [3-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-acetonitrile (3.27 g, 12.54 mmol) in anhydrous DMF (25 ml) in a water bath under a nitrogen atmosphere, was added 60% sodium hydride (1.0 g, 25.09 mmol). After 30 min., water bath was removed and the mixture was stirred for overnight at room temperature. The reaction mixture was neutralized with aqueous saturated ammonium chloride solution. The mixture was then partitioned between ether and water. The ether layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a crude product as a yellow oil. The crude product was purified by silica gel column chromatography (eluent, EA:hexanes (1:15)) to afford 5.34 g (65%) of a pale yellow syrup. 1H NMR (200 MHz, CDCl3) δ 0.06 (6H, s), 0.90 (9H, s), 1.06 (6H, d, J=7.0 Hz), 3.01 (1H, m), 3.81 (6H, s), 4.71 (2H, s), 5.32 (2H, s), 5.35 (2H, s), 5.41 (3H, s), 6.86-6.91 (4H, m), 7.20-7.35 (6H, m), 7.41-7.49 (2H, m).
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[F:15][C:16]([F:37])([F:36])[C:17]([OH:35])([CH3:34])[C:18]#[C:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.C(OCC)C>[F:37][C:16]([F:15])([F:36])[C:17]([OH:35])([CH3:34])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)(=[O:27])=[O:28])=[CH:22][CH:21]=1
Reactant: CC(O)(C#Cc1ccc(S(=O)(=O)N2CCCC2)cc1)C(F)(F)F
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(O)(/C=C/c1ccc(S(=O)(=O)N2CCCC2)cc1)C(F)(F)F
Yield: 88.9 %

Procedure:
To a solution of sodium bis(methoxyethoxy) aluminum hydride (720 mL of a 3.4M solution in toluene, 2.45 mmol) in anhydrous diethyl ether (6 mL) cooled to -2° C. under a nitrogen atmosphere was added dropwise an ethereal solution (25 mL) of 4,4,4-trifluoro-3-hydroxy-3-methyl-1-[4-(1-pyrrolidinylsulfonyl)phenyl]but-1-yne (500 mg). The rate of addition was adjusted such that the reaction temperature (internal) did not exceed 10° C. Upon complete addiron the reaction was kept near 0° C. After 30 minutes the reaction was quenched by the addition of 3M sulfuric acid (20 mL). The product was extracted into diethyl ether. The combined organic extracts were dried, filtered, and evaporated. The crude product was adsorbed onto silica gel and purified by chromatography (1:8 diethyl ether: chloroform) to yield a white compound (447 mg). This material was further purified by recrystalization employing diethyi ether:hexanes (1:5) to provide the title compound (251 mg); mp 119°-121° C.; MS: m/z=350(M+1); NMR: (CDCl3): 1.59 (s,3), 1.73-1.78 (m,4), 2.45 (s,1), 3.22-3.27 (m,4), 6.41 (d,1, J=16.0), 6.93 (d,1,J=16.0), 7.52-7.55 (m,2), 7.77-7.81 (m,2). Analysis for C15H18F3NO3S: Calculated: C, 51.57; H, 5.19; N, 4.01; Found: C, 51.45; H, 5.19; N, 3.90.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[N:22]1([CH2:27][CH2:28][NH2:29])[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH2:18][NH:29][CH2:28][CH2:27][N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: NCCN1CCCC1
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccc(Cl)cc21
Product: Cn1c(-c2cncc(CNCCN3CCCC3)c2)c(C#N)c2ccc(Cl)cc21

Procedure:
6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 126) and 2-pyrrolidin-1-yl-ethylamine are processed according to the method described in Example 170 to give 6-chloro-1-methyl-2-{5-[(2-pyrrolidin-1-yl-ethylamino)-methyl]-pyridin-3-yl}-1H-indole-3-carbonitrile. The free base is taken up in 4M HCl in dioxane, concentrated in vacuo, dissolved in water and lyophilized to give the HCl salt. 1H NMR (400 MHz, DMSO-d6) δ ppm (HCl salt) 1.83-1.93 (m, 2H), 2.04 (br. s., 2H), 3.06 (br. s., 2H), 3.50 (br. s., 2H), 3.54-3.60 (m, 2H), 3.66 (br. s., 2H), 3.84 (s, 3H), 4.43 (br. s., 2H), 7.39 (dd, J=8.6, 1.8 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 8.01 (d, J=1.5 Hz, 1H), 8.43 (t, J=2.0 Hz, 1H), 8.94 (d, J=2.0 Hz, 1H), 8.99 (d, J=2.0 Hz, 1H), 9.97 (br. s., 2H), 10.89 (br. s., 1H). HRMS (ESI) m/z 394.1803 [(M+H)+ Calcd for C22H25ClN5: 394.1798].
Reaction SMILES: ClC(OCC(C)C)=O.C[N:10]1[CH2:15][CH2:14]O[CH2:12][CH2:11]1.[C:16]([O:20][C:21]([NH:23][CH2:24][C:25]([C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33]([OH:35])=O)=[CH:29][CH:28]=1)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C(NCC)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:16]([O:20][C:21](=[O:22])[NH:23][CH2:24][C:25]([C:27]1[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33](=[O:35])[N:10]([CH2:15][CH3:14])[CH2:11][CH3:12])=[CH:36][CH:37]=1)=[O:26])([CH3:17])([CH3:18])[CH3:19]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)c1ccc(OCC(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCN(CC)C(=O)COc1ccc(C(=O)CNC(=O)OC(C)(C)C)cc1
Reaction time: 0.25 h

Procedure:
Isobutyl chloroformate (0.84 ml; 6.5 mmol) was added to a stirred solution of 4-methylmorpholine (0.72 ml; 6.5 mmol) and the compound of example 1f (2.0 g; 6.5 mmol) in DMF (10 ml) at −25° C., followed by the addition of diethyl amine (0.88 ml; 8.45 mmol). The reaction mixture was stirred for 15 min., poured into a 10% aqueous NaHCO3 solution and extracted with EtOAc. The EtOAc layer was washed with brine, concentrated and crystallized using EtOAc-PE60-80° C. to obtain the title compound. Yield, 1.95 g (82%); mp, 100-01° C.; MS (EI): 364 (M+), 291, 234 (100%); analysis: C19H28N2O5 requires C, 62.62; H, 7.74; N, 7.69; found: C, 62.43; H, 7.60; N, 7.25%.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[C:4]([C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[F:20])=[CH:9][CH:10]=1)[C:5]([OH:7])=O.S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[O:11][C:12]3[C:17](=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[F:20])[C:5](=[O:7])[C:4]=2[C:3]=1[F:21]
Reactant: COc1ccc(Oc2ccc(Br)c(F)c2C(=O)O)c(F)c1
Agent: O=S(=O)(O)O
Product: COc1cc(F)c2oc3ccc(Br)c(F)c3c(=O)c2c1
Temperature: 60 °C
Yield: 56.5 %

Procedure:
To a 500 mL flask was added 3-bromo-2-fluoro-6-(2-fluoro-4-methoxyphenoxy)benzoic acid (43.45 g, 121 mmol) in conc. sulfuric acid (127 mL, 1815 mmol). The sticky mixture was heated at 60° C. for 2.5 h. The reaction was then poured into ice water very slowly with stirring. The yellow precipitate was filtered through Buchner funnel and washed excess water. Then the filter cake was put in a beaker and carefully neutralized with mixture of 2N aqoueous NaOH solution and saturated aqueous NaHCO3. The mixture was stirred for half an hour and filtered by Buchner funnel again. The light yellow solid was washed by excess water and finally little amount of acetone to yield 2-bromo-1,5-difluoro-7-methoxy-9H-xanthen-9-one (23.34 g, 68.4 mmol, 56.6% yield) as light yellow solid. It was used for next step without further purification.
Reaction SMILES: [I:1][C:2]1[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]([OH:13])=[CH:4][CH:3]=1.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][CH:16]=[C:15]2[O:13][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CCOC(=O)c1cc(I)ccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1cc(I)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 4.2 %

Procedure:
Ethyl 5-iodosalicylate (457 mg), 4-chloro-6,7-dimethoxyquinoline (348 mg), and 4-dimethylaminopyridine (573 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (31 mg, yield 4%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[N:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[F-].[K+].[CH3:38][OH:39]>C1(C)C=CC=CC=1.[Cu](I)I>[CH3:38][O:39][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[N:3]=1
Reactant: CO
Reactant: Cc1ccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)cn1
Agent: I[Cu]I
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1nn(Cc2ccc(C)nc2)c2cccc([N+](=O)[O-])c12
Yield: 66 %

Procedure:
A mixture of 3-iodo-1-((6-methylpyridin-3-yl)methyl)-4-nitro-1H-indazole (0.520 g, 1.32 mmol), 1,10-phenanthroline (0.238 g, 1.32 mmol), copper iodide (0.251 g, 1.32 mmol) and potassium fluoride (40% on alumina) (1.05 g, 7.26 mmol) in methanol (2.7 mL) and toluene (13 mL) was purged with argon and heated at reflux for 14 hours. After cooling, the mixture was filtered through glass fiber filter paper, concentrated under reduced pressure and purified by silica gel chromatography (5-25% EtOAc in hexanes) to give 3-methoxy-1-((6-methylpyridin-3-yl)methyl)-4-nitro-1H-indazole (0.260 g, 66% yield) as a brown gum.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[NH:14][NH2:15].C(O)C>C(OCC)(=O)C>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:15][NH:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCOC(=O)NN
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)NNC(=O)c1ccccc1N
Yield: 66.8 %

Procedure:
A mixture of 16.3 g of isatoic anhydride, 10.4 g of ethyl carbazate and 50 ml of ethanol was heated to reflux for 3 hours. After the reaction mixture was allowed to cool to around room temperature, ethyl acetate was added thereto and the mixture was washed with water two times. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was washed with methyl tert-butyl ether to obtain 14.9 g of N-(2-aminobenzoyl)-N′-ethoxycarbonylhydrazine of the formula:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[C:22]=2[N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([O:28][C:24]3[C:22]4[N:23]=[C:19]([NH2:18])[S:20][C:21]=4[CH:27]=[CH:26][CH:25]=3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: Nc1nc2c(O)cccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Temperature: 80 °C

Procedure:
To a solution of 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), ((0.13 g, 0.5 mmol) and 2-amino-4-hydroxybenzothiazole (83 mg, 0.5 mmol, Astatech) in DMF (1 mL) was added potassium carbonate (0.14 g, 1 mmol) and the mixture was heated at 80° C. for 16 h with sirring. The reaction mixture was allowed to cool to room temperature and partitioned between EtOAc and brine. The layers were separated and the aq. layer was extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum. Purification of the residue by silica gel chromatography (2:1 hexanes:EtOAc) provided the title compound as a white solid. MS (ESI, pos. ion) m/z: 389 (M+1). Mp: 232.0–233.5° C. Anal. Calcd for C18H11F3N4OS: C, 55.67; H, 2.85; N, 14.43; S, 8.26. Found: C, 55.52; H, 3.08; N, 14.23; S, 8.36.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=[O:13])=[CH:6][CH:5]=1.O>CO>[CH3:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH:10]2[OH:13])=[CH:6][CH:5]=1
Reactant: Cc1ccc2c(c1)C(=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc2c(c1)C(O)CC2
Reaction time: 1 h
Yield: 108.5 %

Procedure:
Sodium borohydride (1.3 g) was added to a solution of 6-methyl-indane-1-one (5.0 g) in methanol (50 ml) at 0° C., and the mixture was stirred for one hour. The reaction mixture was poured into ice-cooled water, and extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain 6-methylindane-1-ol (5.5 g). To a solution of 6-methylindane-1-ol in toluene (50 ml) was added p-toluene sulfonic acid monohydrate (0.2 g), and the mixture was stirred for 20 minutes. The temperature of the reaction mixture was returned to room temperature, and the reaction mixture was washed with water, 5% sodium hydrogencarbonate aqueous solution, and saturated saline solution in order and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain 5-methyl-1H-indene (5.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([C:8]([O:10][CH2:17][CH3:18])=[O:9])=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ncc(Br)cc1C
Temperature: 95 °C
Reaction time: 20 h

Procedure:
To a stirring solution of 5-bromo-3-methylpicolinic acid (10000 g, 1 equiv, 46.29 moles) in ethanol (50 L) at 0° C. was added sulfuric acid (2.52 L, 1 equiv, 46.29 moles) over 1 h. Following addition of sulfuric acid, the mixture was heated at 95° C. for 20 h. Reaction progress was monitored by using TLC and LCMS. After 20 hours, LCMS showed 12.61% unreacted SM, at RT-0.67 ((M−1)−215.92) and 86.95% product at RT-2.04 ((M+1)−244.2). The reaction mass heated for additional 6 h and LCMS analysis following the additional heating showed 10.07% unreacted SM, at RT-0.7 and 89.93% product at RT-2.08 ((M+1)−244.2. The reaction was stopped by concentrating the reaction mixture under reduced pressure to remove as much solvent as possible. To the residue was added dichloromethane (DCM), (25 L) and the reaction mixture was poured into ice cold water (20 L). The organic (DCM) layer was separated from the aqueous layer and the latter was further extracted twice with DCM (10 L). The combined organic layers were washed with saturated sodium bicarbonate solution (30 L), dried over sodium sulfate, and concentrated under reduced pressure to obtain a brown oil. This brown oil was used in the next step without further purification. Yield: 10.1 Kg, (89.4%); MS (ESI) m/z 244.2 [M+1]+; LCMS purity: 99.11%; 1H NMR (400 MHz, DMSO-d6) δ: 8.61 (s, 1H), 8.13 (s, 1H), 4.29 (q, 2H), 2.44 (s, 1H), 1.28 (t, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:13][C:12]3=[O:25])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][CH2:29][C:3]1=2.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:49].Cl>>[ClH:49].[ClH:49].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:13][C:12]3=[O:25])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:26][NH:27][CH2:28][CH2:29][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccn5)cc4=O)cc31)CNCC2
Yield: 77 %

Procedure:
tert-Butyl 5-methyl-7-(2-oxo-4-(pyridin-2-ylmethoxy)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (113 mg, 0.23 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (81 mg, 77%) as a white solid: mp 206-211° C.; 1H NMR (300 MHz, CDCl3) δ 8.88 (d, J=5.2 Hz, 1H), 8.59 (dd, J=7.9, 1.5 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H), 8.01 (overlapping dd, J=6.6 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.48 (d, J=1.6 Hz, 1H), 7.06 (dd, J=8.4, 1.8 Hz, 1H), 6.44 (dd, J=7.6, 2.7 Hz, 1H), 6.21 (d, J=2.7 Hz, 1H), 5.57 (s, 2H), 4.48 (s, 2H), 3.74 (s, 3H), 3.68 (t, J=6.2 Hz, 2H), 3.21 (t, J=6.2 Hz, 2H); ESI MS m/z 387 [M+H]+; HPLC (Method B) 98% (AUC), tR=9.3 min.
Reaction SMILES: BrCCBr.[Mg].Br[C:7]1[CH:11]=[CH:10][S:9][CH:8]=1.[CH3:12][C@H:13]1[CH2:18][C:17](=[O:19])[CH2:16][CH2:15][O:14]1>C(OCC)C>[OH:19][C@:17]1([C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)[CH2:16][CH2:15][O:14][C@@H:13]([CH3:12])[CH2:18]1
Reactant: C[C@H]1CC(=O)CCO1
Reactant: Brc1ccsc1
Agent: [Mg]
Solvent: BrCCBr
Solvent: CCOCC
Product: C[C@H]1C[C@@](O)(c2ccsc2)CCO1
Yield: 19.7 %

Procedure:
A solution of 1,2-dibromoethane (5 g) in diethyl ether (10 ml) was added to a stirred suspension of magnesium (3 g) in diethyl ether (10 ml) to initiate the formation of a Grignard reagent. A mixture of 1,2-dibromoethane (16.7 g) and 3-bromothiophene (4 g) in diethyl ether (30 ml) was added dropwise. The mixture was stirred and heated to reflux for 2 hours. A solution of (2S)-2-methyltetrahydropyran-4-one (2 g) in diethyl ether (5 ml) was added and the mixture was heated to reflux for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 7:3 mixture of petroleum ether and ethyl acetate as eluent. There were thus obtained in turn (2S,4R)-4-hydroxy-2-methyl-4-(3-thienyl)tetrahydropyran (0.685 g, 18.5%) and the corresponding (2S,4S)-isomer (1 g, 32%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH:11]=[O:12])[S:10][C:3]=12.[F:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[OH:23].C([O-])([O-])=O.[K+].[K+].O(C1C=CC=CC=1)C1C=CC=CC=1>O.CCOC(C)=O>[F:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[O:23][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH:11]=[O:12])[S:10][C:3]=12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: O=Cc1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: O
Product: O=Cc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 170 °C
Reaction time: 12 h
Yield: 46.2 %

Procedure:
A mixture of aldehyde 232 (500 mg, 2.53 mmol), 2-fluoro-4-nitrophenol (595 mg, 3.79 mmol), K2CO3 (700 mg, 5.06 mmol) and Ph2O (3.4 mL) was stirred in a sealed tube for 12 h at 170° C. The mixture was suspended in a water/EtOAc mixture, sonicated a few minutes and filtered, the solid residue was washed successively with water, EtOAc and ether, giving crude 233 (500 mg, 1.17 mmol, 46% yield) that was used in the next step without further purification. MS (m/z): (M+1) 319.0 (14%), (M+MeOH+1) 351.0 (100%).