Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.Cl[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH:1]1([N:7]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClCCN1CCCCC1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SC#N)s2)C2CCCCC2)CC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCN3CCCCC3)s2)C2CCCCC2)CC1

Procedure:
Prepared as described in general procedure (H) using 1-cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and N-(2-chloroethyl)piperidine
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[I:13])[C:7]([OH:9])=O)[CH3:2].C(Cl)(=O)C(Cl)=O.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl.CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:9])[CH:10]=[CH:11][C:12]=1[I:13])[CH3:2]
Reactant: C1CCNCC1
Reactant: CCOc1cc(C(=O)O)ccc1I
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1cc(C(=O)N2CCCCC2)ccc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
3-Ethoxy-4-iodo-benzoic acid (2.73 grams, 9.36 mmol) was suspended in methylene chloride (25 mL), and oxalyl chloride (5.15 mL, 2.0 M in methylene chloride, 10.3 mmol) was added by pipette. Three drops of dimethylformamide was added and this mixture was stirred overnight at room temperature. The volatiles from the now homogeneous reaction were removed under vacuum and the residue reconstituted in methylene chloride. One half of this was treated with piperidine (2.0 mL, 20 mmol). The mixture was stirred at room temperature for 2 h. The reaction was diluted with methylene chloride, washed with 1.0 M hydrochloric acid, water, saturated sodium bicarbonate solution and brine. The organic layers was dried (magnesium sulfate), filtered and concentrated to give (3-ethoxy-4-iodo-phenyl)-piperidin-1-yl-methanone (1.69 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20]Cl)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: ClCCCOc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1
Product: Brc1cnc2[nH]c(-c3ccc(OCCCN4CCCCC4)cc3)nc2c1

Procedure:
The title compound was prepared from 6-bromo-2-[4-(3-chloropropoxy)phenyl]-3H-imidazo[4,5-b]pyridine and piperidine using the method described in Example 46.
Reaction SMILES: [C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:29]([Mg]Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(OCC)C>[C:23]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C:13]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([OH:16])[CH2:12][CH2:11]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1CCN(CCC(c2ccccc2)(c2ccccc2)c2ccccn2)CC1
Reactant: Br[Mg]Cc1ccccc1
Solvent: CCOCC
Product: OC1(Cc2ccccc2)CCN(CCC(c2ccccc2)(c2ccccc2)c2ccccn2)CC1

Procedure:
A solution of 1 part of this ketal in 5 parts of glacial acetic acid is added 0.1 part of sulfuric acid and the mixture is heated on a steam bath for 1 hour. The reaction mixture is poured into 50 parts of cold water to provide 1-[3,3-diphenyl-3-(2-pyridyl)propyl]-4-oxopiperidine. 3 Parts of this ketone in 20 parts by volume of ethyl ether and 5 parts by volume of 3 molar solution of benzylmagnesium bromide in ethyl ether are reacted under reflux for 4 hours. The mixture is cooled, quenched with water, and the ethereal layer is dried over anhydrous sodium sulfate. Removal of the ether provides 1-[3,3-diphenyl-3-(2-pyridyl)propyl]-4-benzyl-4-hydroxypiperidine, having the following structural formula ##STR22##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])[CH:9]=[CH2:10].[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[C:2]1([NH:1][CH2:10][CH2:9][C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)CCNc1ccccc1
Yield: 33.9 %

Procedure:
To a solution of aniline (27.9 g, 0.30 mol) and tert-butyl acrylate (38.4 g, 0.30 mol) in dry benzene (500 ml) was added tin tetrachloride (2 ml) and the resulting solution was heated under reflux for 18 h. The resulting suspension was filtered and the filtrate was concentrated in vacuo giving a residue which was chromatographed on silica gel eluting with 25/75 ethyl acetate/hexane to give the title compound (22.53 g, 34%) as an oil. 1H NMR (300 MHz, CDCl3) δ7.12 (2H, t), 6.71 (1H, m), 6.62 (2H, d), 3.40 (2H, t), 2 54 (2H, t), 1.44 (9H, s).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:7][NH:6][CH2:5][CH:4]1[OH:8].[Br:9][C:10]1[CH:11]=[CH:12][C:13](F)=[N:14][CH:15]=1.C(N(C(C)C)CC)(C)C>C(#N)C.C(=O)(O)[O-].[Na+]>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([N:6]2[CH2:7][C@@H:3]([NH:2][CH3:1])[C@H:4]([OH:8])[CH2:5]2)=[N:14][CH:15]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CNC1CNCC1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN[C@@H]1CN(c2ccc(Br)cn2)C[C@H]1O
Yield: 39.3 %

Procedure:
Dissolve 4-methylamino-pyrrolidin-3-ol (430 mg, 3.29 mmol) in acetonitrile (10 mL) and add 5-bromo-2-fluoro-pyridine (868 mg, 4.93 mmol) and diisopropylethylamine (0.688 mL, 3.95 mmol). Reflux the mixture for 3 days. Dilute the mixture with saturated sodium bicarbonate and extract with dichloromethane (3×). Combine the organic fractions, dry over sodium sulfate, filter, and evaporate. Purify by silica gel chromatography, eluting with 0-7.5% methanol in dichloromethane with 2N ammonia to give 352 mg (37%) of the title compound as a yellow foam. MS/ES m/z (79Br) 272.0 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14](Cl)[N:13]=1>C1COCC1>[CH2:3]([O:10][C:14]1[CH:15]=[N:16][CH:17]=[C:12]([Cl:11])[N:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cncc(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
To a cooled mixture of sodium hydride (60%, 300 mg, 7.5 mmol) in THF (20 mL) at 0° C. was added dropwise benzyl alcohol (0.75 mL, 7.24 mmol). After 30 minutes, 2,6-dichloropyrazine (999 mg, 6.71 mmol) was added and mixture was warmed to room temperature and stirred overnight. After quenching with sat. NH4Cl(aq), mixture was extracted with ethyl acetate and combined organics were washed with water then brine. Organics were dried, filtered, and concentrated under reduce pressure to yield 2-(benzyloxy)-6-chloropyrazine 5.33 (1.45 g), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[S:12]1[C:16]2[C:17](O)=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[CH:13]1>C1COCC1>[Cl:1][CH2:2][CH2:3][C@H:4]([O:5][C:17]1[C:16]2[S:12][CH:13]=[CH:14][C:15]=2[CH:20]=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Oc1cccc2ccsc12
Reactant: O[C@H](CCCl)c1ccccc1
Solvent: C1CCOC1
Product: ClCC[C@H](Oc1cccc2ccsc12)c1ccccc1
Reaction time: 18 h
Yield: 37.4 %

Procedure:
4,4-(Dimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-triphenyl phosphonium (327 mg, 0.80 mmol) was added in one portion to a stirred solution of (R)-(+)-3-chloro-1-phenyl-1-propanol (90 mg, 0.53 mmol) and 1-benzothiophen-7-ol (80 mg, 0.53 mmol) in dry THF (5 mL) under an inert atmosphere on nitrogen. The resulting suspension was allowed to stir for a further 18 hrs before the solvent was removed in vacuo. The residue was triturated with hexane (ca. 15 mL) and the solid filtered, the filtrate was concentrated in vacuo and the resulting pale yellow oil was purified by flash chromatography eluting silica gel with hexane:ether [95:5] to yield the title compound as a colourless oil (60 mg, 37%); Rf=0.8 in hexane:ether [10:1]; δH (300 MHz, CDCl3) 7.66–7.00 (9H, m, Ar); 6.55 (1H, d, Ar), 5.80–5.72 (1H, m, CHO), 3.91–3.60 (2H, m, CH2), 2.62–2.50 (1H, m, CHH), 2.38–2.22 (1H, m, CHH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.C(NC(C)C)(C)C.C([Li])CCC.[C:23](O)(=O)[C:24](O)=[O:25]>CCCCCC.C(N=CC)(C)(C)C.ClP(=O)(OCC)OCC.O1CCCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[CH:23]/[CH:24]=[O:25])=[CH:5][CH:4]=1
Reactant: O=C(O)C(=O)O
Reactant: COc1ccc(C=O)cc1
Agent: CC=NC(C)(C)C
Agent: CCOP(=O)(Cl)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: COc1ccc(/C=C/C=O)cc1
Reaction time: 72 h

Procedure:
The compound was prepared according to the procedure described in Example 84 except that the reaction was worked up after 3 days. The following reagents were used: 4-methoxybenzaldehyde (13.5 g), diisopropylamine (32.2 mL). 1.6M n-butyl lithium in hexane (143 mL), acetaldehyde N-tert-butylimine (14.75 mL), diethyl chlorophosphonate (16.6 mL) and tetrahydrofuran (200 mL). The work up, varied only in that the oxalic acid catalyzed hydrolysis was done overnight at room temperature and then at 85° C. for 2 hours, furnished 12.5 g of crude product which was crystallized from ether-hexane to yield 10 g of (E)-3-(4-methoxyphenyl)-2-propenal, mp 58.5°-60° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH2:24]I)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.Cl.[F:27][C:28]1([F:33])[CH2:32][CH2:31][NH:30][CH2:29]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH2:24][N:30]3[CH2:31][CH2:32][C:28]([F:33])([F:27])[CH2:29]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2CCI
Reactant: FC1(F)CCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: FC1(F)CCN(CCn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)C1
Reaction time: 120 h
Yield: 27.8 %

Procedure:
A solution of 4-chloro-1-(2-iodoethyl)-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine (91 mg, 0.2 mmol) in dry CH2Cl2 (2 mL) was added to 3,3-difluoropyrrolidine hydrochloride (143 mg, 1 mmol), DIPEA (0.2 mL, 1.1 mmol) was added and the reaction stirred for 5 days. The resultant residue was purified using chromatography (silica gel, gradient 20 to 50% ethyl acetate/isohexane, followed by preparative HPLC to provide Compound IIv as a white solid (24.5 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3]/[CH:4]=[CH:5]/[C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=[N:11][C:10]=2[NH2:20].[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=[N:11][C:10]=2[NH2:20]
Reactant: [H][H]
Reactant: COC/C=C/c1cnc2c(N)nc3ccccc3c2c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COCCCc1cnc2c(N)nc3ccccc3c2c1
Reaction time: 3 h

Procedure:
To a solution of (E)-2-(3-methoxyprop-1-enyl)benzo[f][1,7]naphthyridin-5-amine (Example 34) in ethyl acetate/methanol (1:4, 0.05 M) was added 10% wt palladium on carbon (0.2 eq.). Hydrogen gas was introduced via a balloon, and the reaction was stirred for 3 hours. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated en vacuo and the crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 2-(3-methoxypropyl)benzo[f][1,7]naphthyridin-5-amine as a white solid. 1H NMR (CDCl3): δ 8.64 (d, 1H), 8.46 (d, 1H), 8.19 (d, 1H), 7.66 (d, 1H), 7.53 (m, 1H), 7.31 (m, 1H), 6.56 (bs, 2H), 3.37 (t, 2H), 3.31 (s, 3H), 2.91 (t, 2H), 1.93-2.00 (m, 2H). LRMS [M+H]=268.1.
Reaction SMILES: [CH:1]1([C:6]([OH:31])([CH2:21][C:22]2[O:23]C(C)(C)[O:25][C:26](=O)[CH:27]=2)[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:18]#[N:19])[CH2:17][CH2:16]3)=[C:11]([F:20])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>>[CH:1]1([C:6]2([CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4([C:18]#[N:19])[CH2:16][CH2:17]4)=[C:11]([F:20])[CH:10]=3)[CH2:21][C:22](=[O:23])[CH2:27][C:26](=[O:25])[O:31]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)C=C(CC(O)(CCc2ccc(C3(C#N)CC3)c(F)c2)C2CCCC2)O1
Agent: [Na+]
Agent: [OH-]
Product: N#CC1(c2ccc(CCC3(C4CCCC4)CC(=O)CC(=O)O3)cc2F)CC1
Yield: 47.3 %

Procedure:
A solution of 1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-butyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile (0.9 g, 2.1 mmol) from Step 6 below in NaOH (0.3 M in MeOH, 21 mL, 6.3 mmol) was stirred at room temperature for 3 hours. The reaction was then quenched with 100 mL saturated NH4Cl and 5 mL 1 N HCl. To this solution was added 100 mL CH2Cl2 and the layers were separated. The aqueous layer was extracted with 2×100 mL CH2Cl2 and the organic layers were combined. After drying the organic with MgSO4, and filtering to remove the solids, the solvent was removed by rotary evaporation. The remaining oil was purified by flash chromatography to yield the desired product (0.367 g, 47%). 1H NMR (CDCl3) δ: 1.27-1.30 (m, 2H), 1.51-1.73 (m, 10H), 1.84-1.89 (m, 2H), 2.19 (p, J=8.08 Hz, 1H), 2.58-2.71 (m, 4H), 3.36 (d, J=4.04 Hz, 2H), 6.81-6.86 (m, 2H), 7.16-7.18 (m, 1H). MS (ESI): 368 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10](Cl)[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:7]([CH3:18])[C:6]=2[CH:19]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C.O1CCCC1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=3)[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:7]([CH3:18])[C:6]=2[CH:19]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: Cc1c(C(Cl)C2CCCCC2)oc2ccc(Cl)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)oc2ccc(Cl)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
A mixture of 5-chloro-2-[chloro(cyclohexyl)methyl]-3-methyl-1-benzofuran (270 mg) synthesized above, ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (215 mg) synthesized in Example 1(2), sodium iodide (204 mg), sodium carbonate (144 mg) and N,N-dimethylformamide (10 mL) was stirred overnight at 80° C. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give a pale-yellow oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) 1N aqueous sodium hydroxide solution (1.00 mL) was added, and the mixture was stirred at room temperature for 2 hr, and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (132 mg, 31%) as a yellow solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:14][CH2:13][N:12]([CH3:15])[C:11]2=[O:16])=[N:8][CH:9]=1.[CH3:17]I.O>CN(C)C=O.C(OCC)(=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([CH3:17])[CH2:14][CH2:13][N:12]([CH3:15])[C:11]2=[O:16])=[N:8][CH:9]=1
Reactant: CN1CCC(c2ccc(Br)cn2)C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CCC(C)(c2ccc(Br)cn2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (55% in mineral oil, 0.17 g) was added to a solution of 3-(5-bromo-pyridin-2-yl)-1-methyl-pyrrolidin-2-one (0.77 g) and methyl iodide (0.44 mL) in N,N-dimethylformamide (15 mL) in argon atmosphere at room temperature. The resulting mixture was stirred at room temperature overnight. Water and ethyl acetate were then added and the organic phase of the resulting mixture was separated. The organic phase was washed with brine, dried (MgSO4), and concentrated. The residue was chromatographed on silica gel (dichloro-methane/ethyl acetate 1:1) to give the title compound as a colorless oil. Yield: 0.50 g (61% of theory); LC (method 1): tR=1.60 min; Mass spectrum (ESI+): m/z=269/271 (Br) [M+H]+.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][N:6]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=3[Cl:16])[CH2:5]2)[CH2:3][O:2]1.CS(O[CH:22]1[CH2:25][N:24]([C:26]([C:28]2[O:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:31][N:32]=2)=[O:27])[CH2:23]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:3]1[C:4]2([CH2:5][N:6]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH:22]4[CH2:23][N:24]([C:26]([C:28]5[O:29][C:30]([C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)=[N:31][N:32]=5)=[O:27])[CH2:25]4)=[CH:11][C:10]=3[Cl:16])[CH2:7]2)[CH2:1][O:2]1
Reactant: Oc1ccc(CN2CC3(COC3)C2)c(Cl)c1
Reactant: CS(=O)(=O)OC1CN(C(=O)c2nnc(-c3ccccc3)o2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(c1nnc(-c2ccccc2)o1)N1CC(Oc2ccc(CN3CC4(COC4)C3)c(Cl)c2)C1
Temperature: 90 °C
Reaction time: 24 h
Yield: 44.5 %

Procedure:
1A (0.30 g, 1.25 mmol) was dissolved in dry DMF (10 mL) and 1C (0.61 g, 1.88 mmol) was added followed by Cs2CO3 (0.82 g, 2.50 mmol). The reaction mixture was stirred at 90° C. for 24 h. The mixture was filtered and approximately half the volume of solvent was evaporated. The product was purified by preparative RP HPLC (gradient: 15-55% acetonitrile over 30 min, 0.2% ammonia buffer). The pure fractions were combined and concentrated. Dichloromethane was added and the solution was dried (phase separator) and concentrated in vacuo. There was obtained 0.26 g (44.5%) of 1 as a solid. 1H NMR (500 MHz, CDCl3): δ 3.57 (s, 4H), 3.73 (s, 2H), 4.33 (d, 1H), 4.65 (dd, 1H), 4.73 (m, 1H), 4.77 (s, 4H), 5.06 (m, 1H), 5.14 (dd, 1H), 6.70 (d, 1H), 6.80 (s, 1H), 7.37 (m, 1H), 7.54 (m, 2H), 7.59 (m, 1H), 8.16 (d, 2H), MS (APCI+) m/z 467 [M+H]+. LC purity: 96%. A slurry experiment was performed by weighing 2.5 mg of Example 1 into a vial and adding ethanol (100 μL). The slurry was shaken for 7 days at ambient temperature and then crystals were collected using a small spatula. The crystals were dried in a hood for one hour and then analyzed using DSC (differential scanning calorimetry). A sample was weighed into an aluminium pan with a pierced lid and heated from 0° C. to 300° C. with a ramp of 5° C./min and modulated with the amplitude of ±0.6° C. every 45 seconds. The instrument was purged with nitrogen at 50 mL/minute; melting point 119±5° C.
Reaction SMILES: B.O1CCCC1.[CH2:7]([CH:9]1[O:14][CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH2:12][N:11]([CH2:23][CH2:24][CH3:25])[C:10]1=O)[CH3:8]>C1COCC1>[CH2:7]([CH:9]1[O:14][CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH2:12][N:11]([CH2:23][CH2:24][CH3:25])[CH2:10]1)[CH3:8]
Reactant: CCCN1CC(c2cccc(OC)c2)OC(CC)C1=O
Agent: B
Solvent: C1CCOC1
Product: CCCN1CC(CC)OC(c2cccc(OC)c2)C1
Temperature: 85 °C

Procedure:
Borane-tetrahydrofuran complex (1 M in THF) (3 mL, 3 mmol) was added dropwise to the product from example 45 (0.33 g, 1.18 mmol) in dry THF (4 mL) under an atmosphere of nitrogen. The reaction mixture was heated at 85° C. for 3 hours then cooled and quenched by the addition of methanol (1 mL). The reaction mixture was then concentrated in vacuo and the residue suspended in 6N HCl (aq) (10 mL) and heated to 60° C. for 1.5 hours. The reaction mixture was cooled and extracted with diethyl ether (2×10 mL). The aqueous layer was rendered basic (pH 9-10) by addition of solid potassium carbonate before re-extracting with dichloromethane (2×15 mL). The dichloromethane extracts were dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the crude products as a clear oil. Purification by column chromatography on silica eluting with ethyl acetate:pentane (1:10) yielded the two title compounds as single diastereomers. Example 46A: clear oil (0.10 g, 0.38 mmol, 32%): 1H NMR (CDCl3, 400 MHz) δ: 1.00 (m 6H), 1.60 (bm, 3H), 1.85 (m, 1H), 2.25 (bt, 2H), 2.35 (s, 1H), 2.45 (m, 1H), 2.60 (m, 1H), 2.65 (m, 1H), 3.70 (s, 1H), 3.80 (s, 3H), 4.80 (s, 1H), 6.80 (d, 1H), 7.00 (m, 2H), 7.25 (m, 1H). LRMS (APCl): m/z 264 (M−H+). Example 46B: clear oil (0.10 g, 0.38 mmol, 32%): 1H NMR (CDCl3, 400 MHz) δ: 0.90 (t, 3H), 1.00 (t, 3H), 1.60 (bm, 4H), 1.80 (bs, 1H), 2.00 (bs, 1H), 2.35 (bs, 2H), 2.85 (bd, 1H), 2.95 (bd, 1H), 3.60 (s, 1H), 3.80 (s, 3H), 4.60 (s, 1H), 6.80 (d, 1H), 6.95 (s, 2H), 7.25 (t, 1H). LRMS (APCl): m/z 264 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([O:21]C)=[CH:16][N:15]=2)=[N:6]1>CN1CCCC1=O>[NH2:20][C:18]1[C:17]([OH:21])=[CH:16][N:15]=[C:14]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]([CH2:4][C:3]3[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=3[F:1])[N:6]=2)[N:19]=1
Reactant: COc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1N
Solvent: CN1CCCC1=O
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ccccc23)ncc1O
Temperature: 140 °C

Procedure:
558 mg of 2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methoxypyrimidin-4-amine (1-4-2, 1.60 mmol, 1 eq.) was suspended in 10 ml of 1-methyl-2-pyrrolidon. 623 mg of sodium sulfidosodium (7.99 mmol, 5 eq.) were added and stirred for an hour at 140° C. The reaction mixture was extracted with half-saturated aq. ammonium chloride-solution and ethyl acetate. The aqueous layer was reextracted twice by ethyl acetate. The aqueous layer gave a precipitate, which was filtered off and first purified by flash chromatography (hexane/dichloro methane/methanol), followed by a HPLC purification. This provided 23.4 mg (0.07 mmol, 4.37%) of the analytically pure target compound.
Reaction SMILES: C([N:8]1[C:12]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=2[NH:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[N:11][N:10]=[N:9]1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:19][C:18]1[C:13]([C:12]2[NH:8][N:9]=[N:10][N:11]=2)=[C:14]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cccc(NS(=O)(=O)c2ccccc2)c1-c1nnnn1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cccc(NS(=O)(=O)c2ccccc2)c1-c1nnn[nH]1
Reaction time: 168 h
Yield: 205.7 %

Procedure:
N-[2-(1-Benzyl-1H-tetrazol-5-yl)-3-methylphenyl]-benzenesulfonamide (Intermediate 15, 0.05 g) was dissolved in ethyl acetate (10 mL) under a nitrogen atmosphere. Palladium on carbon (10%, 0.02 g) was added and the nitrogen atmosphere was replaced by hydrogen. The mixture was stirred for 7 days and then filtered through celite and the solvent was removed by evaporation under vacuum. The residue was purified by preparative HPLC (C18). The fractions containing the desired product were combined, and the solvent was removed by evaporation to give the title compound as a white solid (0.08 g).