Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:19][C@H:20]1[CH2:25][NH:24][CH2:23][CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH3:19][C@H:20]1[CH2:25][N:24]([CH2:11][C:10]2[CH:13]=[CH:14][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:8][C:9]=2[C:15]([F:18])([F:17])[F:16])[CH2:23][CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27]
Reactant: O=Cc1ccc(N2CCOCC2)cc1C(F)(F)F
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: C[C@H]1CN(Cc2ccc(N3CCOCC3)cc2C(F)(F)F)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
A 100 mL round-bottom flask was charged with 4-(morpholin-4-yl)-2-(trifluoromethyl)benzaldehyde (1.00 g, 3.86 mmol, 1.00 equiv), tert-butyl (2S)-2-methylpiperazine-1-carboxylate (0.850 g, 4.24 mmol, 1.10 equiv), 1,2-dichloroethane (20 mL). The mixture was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (2.40 g, 11.3 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with H2O (20 mL), extracted with dichloromethane (3×15 mL). The organic layers were combined and washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (20/80) to provide 1.70 g (99% yield) of tert-butyl (2S)-2-methyl-4-[[4-(morpholin-4-yl)-2-(trifluoromethyl)phenyl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 444 [M+H]+.
Reaction SMILES: [CH3:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.ClS(O)(=O)=O.[CH3:17][N:18]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].[Cl:30]([OH:34])(=[O:33])(=[O:32])=[O:31]>>[Cl:30]([OH:34])(=[O:33])(=[O:32])=[O:31].[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:3](=[N:2][CH3:1])[C:22]2[N:18]([CH3:17])[C:19]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][C:21]=2[CH3:23])=[CH:5][CH:6]=1
Reactant: CCOC(=O)Cc1cc(C)cn1C
Reactant: CN=C(Cl)c1ccc(Cl)cc1
Agent: O=S(=O)(O)Cl
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCOC(=O)Cc1cc(C)c(C(=NC)c2ccc(Cl)cc2)n1C

Procedure:
The title compound was prepared as in Example X from N-methyl 4-chlorobenzimidoyl chloride (7.52 g, 40 mmole), chlorosulfonic acid (0.47 g, 4 mmole), ethyl 1,4-dimethyl-1H-pyrrole-2-acetate (7.25 g, 40 mmole), and 70% perchloric acid (7.0 g, 48 mmole) to yield 6.6 g (38%) of a green solid, m.p. 126°-130° C. (dec).
Reaction SMILES: Cl.Cl.[C:3]([N:6]1[CH2:11][CH2:10][N:9]([NH2:12])[CH2:8][CH2:7]1)(=[O:5])[CH3:4].[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[C:3]([N:6]1[CH2:11][CH2:10][N:9]([NH:12][S:20]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: CC(=O)N1CCN(N)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(NS(=O)(=O)c2ccc(F)cc2)CC1
Yield: 47.8 %

Procedure:
To a mixture of 1-acetyl-4-aminopiperazine dihydrochloride (540 mg) and 4-fluorobenzenesulfonyl chloride (535 mg) in dichloromethane (5 ml) was added triethylamine (1.2 ml) in a few minutes with stirring in an ice bath. After stirring for half an hour at the same temperature, the mixture was washed with brine, dried, and concentrated in vacuo. The residue was crystallized from ethanol and recrystallized from a mixture of ethanol and diethyl ether to Yield N-(4-acetyl-1-piperazinyl)-4-fluorobenzenesulfonamide (360 mg) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]N1C(=O)CCC1=O>ClCCl>[NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1c(F)cccc1C(=O)O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Nc1c(F)cc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
A solution of 2-amino-3-fluorobenzoic acid (10.85 g, 70 mmol) in dichloromethane (175 mL) was added N-bromosuccinimide (12.46 g, 70 mmol), and the mixture was stirred at RT for 2 h. LCMS showed the reaction was completed. The precipitate was filtered and washed with dichloromethane (100 mL*3) to give the title compound (12.7 g, 78%) as a grey solid, which was directly used in the next step without further purification. MS (ES+) C7H5BrFNO2 requires: 233, 235. Found: 232, 234 [M−H]−.
Reaction SMILES: C1C2C=CS(=O)(=O)C=2C=C([N+]([O-])=O)C=1.CC(C)(C)COC([SiH3])N1C([C:29]2[N:33]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:32]3[CH:42]=[CH:43][CH:44]=[CH:45][C:31]=3[N:30]=2)C2C(=CC=CC=2)N1.[N+:49]([C:52]1[CH:60]=[C:59]2[C:55]([C:56]([Sn](C)(C)C)=[N:57][N:58]2[CH2:61][O:62][CH2:63][CH2:64][Si:65]([CH3:68])([CH3:67])[CH3:66])=[CH:54][CH:53]=1)([O-:51])=[O:50].IN1C2C=CC=CC=2N(COCC[Si](C)(C)C)C1>[Cu]I.C1COCC1>[N+:49]([C:52]1[CH:60]=[C:59]2[C:55]([C:56]([C:29]3[N:33]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:40])([CH3:41])[CH3:39])[C:32]4[CH:42]=[CH:43][CH:44]=[CH:45][C:31]=4[N:30]=3)=[N:57][N:58]2[CH2:61][O:62][CH2:63][CH2:64][Si:65]([CH3:68])([CH3:67])[CH3:66])=[CH:54][CH:53]=1)([O-:51])=[O:50]
Reactant: C[Si](C)(C)CCOCn1nc([Sn](C)(C)C)c2ccc([N+](=O)[O-])cc21
Reactant: CC(C)(C)COC([SiH3])N1Nc2ccccc2C1c1nc2ccccc2n1COCC[Si](C)(C)C
Agent: [Cu]I
Agent: C[Si](C)(C)CCOCN1CN(I)c2ccccc21
Agent: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)C=C2
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c2ccc([N+](=O)[O-])cc21
Yield: 82 %

Procedure:
Preparation of 6-nitro-1-[2-(trimethyl-silanyl-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]1-H-benzoimidazol-2-yl}-1-H-indazole: 6-Nitro-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-(trimethyl-stannanyl)-1-H-indazole (7.50 g, 16.4 mmol), 3-iodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzimidazole (6.50 g, 17.4 mmol), and copper(I) iodide (313 mg, 1.64 mmol) were combined with dry THF (150 mL) in a flask purged with argon. Tetrakis(triphenylphosphine)palladium(0) was added, and the reaction stirred at reflux under argon for 23 h. The reaction was cooled and adsorbed directly onto silica gel (˜16 g). Purification by silica gel chromatography (4% to 15% ethyl acetate/hexanes) gave 7.28 g (82%) of 6-nitro-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzoimidazol-2-yl}-1-H-indazole as a light yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.91 (d, 1H, J=9.0 Hz), 8.59 (d, 1H, J=1.8 Hz), 8.22 (dd, 1H, J=8.7, 1.8 Hz), 7.92-7.89 (m, 1H), 7.66-7.62 (m, 1H), 7.40-7.36 (m, 2H), 6.24 (s, 2H), 5.90 (s, 2H), 3.68-3.59 (m, 4H), 0.94 (t, 2H, J=8.1 Hz), 0.86 (t, 2H, J=8.1 Hz), −0.04 (s, 9H), −0.15 (s, 9H). Anal. (C26H37N5O4Si2) C, H, N. Calculated: C, 57.85; H, 6.91; N, 12.97. Found: C, 57.60; H, 6.81; N, 12.82.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-:3].[Cl-].[C:5]1([OH:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.O>ClC1C=CC=C(Cl)C=1>[Cl:1][C:5]1[CH:14]=[C:9]([Cl:3])[CH:8]=[CH:7][C:6]=1[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[CH2:6][CH2:7]1
Reactant: [Cl-]
Reactant: Oc1cccc2ccccc12
Agent: [Al+3]
Solvent: Clc1cccc(Cl)c1
Solvent: O
Product: O=C1CCC(c2ccc(Cl)cc2Cl)c2ccccc21
Temperature: 65 °C
Yield: 142.5 %

Procedure:
In a suspension of 60 g (0.45 mole) of aluminium chloride in 100 ml of metadichlorobenzene, 28.8 g (0.2 mole) of α-naphthol are introduced in 10 minutes: the temperature rises from 20° to 45° C. The medium is heated for 1 hour 30 mins at 65° C. then hydrolysed with 400 ml of water. After decantation, the organic phase is separated and concentrated in a vacuum from 2 to 5 torrs at 80° C. The residue is dissolved in 100 ml of isopropanol and the resultant solution cooled at 0° C. for 2 hours. The light beige solid formed is separated by filtration and dried to obtain 41.5 g of the expected compound.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[CH:19].[CH3:20]OS(OC)(=O)=O.O>O1CCCC1>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[C:19][CH3:20]
Reactant: C#Cc1ccccc1Br
Reactant: COS(=O)(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC#Cc1ccccc1Br
Reaction time: 0.5 h

Procedure:
1M Lithium hexamethyldisilazide solution (6 mL) was added to 1-bromo-2-ethynylbenzene (1 g) in 20 mL tetrahydrofuran at room temperature, and the reaction was stirred 30 minutes. (CH3)2SO4 (0.58 mL) was added and the reaction was stirred 30 minutes. The reaction was poured into 20 mL water, extracted with 2×50 mL ether, and the combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:13](=O)[CH2:14][C:15](=O)[CH3:16])[C:9]([CH3:19])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:20][CH2:21][CH2:22][NH:23][NH2:24]>>[OH:20][CH2:21][CH2:22][N:23]1[C:13]([C:10]2[C:9]([CH3:19])=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]=2[OH:12])=[CH:14][C:15]([CH3:16])=[N:24]1
Reactant: NNCCO
Reactant: CC(=O)CC(=O)C1C(=O)N(c2ccccc2)N=C1C
Product: Cc1cc(-c2c(C)nn(-c3ccccc3)c2O)n(CCO)n1

Procedure:
Prepare the title compound from 1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione and 2-hydroxy-ethyl hydrazine according to the procedure of Example 28.
Reaction SMILES: [Cl:1][C@H:2]1[C@H:6]([CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[C@@H:5]([CH2:19][OH:20])[C@H:4]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:3]1.[H][H]>CCOC(C)=O.O=[Pt]=O>[Cl:1][C@H:2]1[C@H:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])[C@@H:5]([CH2:19][OH:20])[C@H:4]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:3]1
Reactant: [H][H]
Reactant: C=CCOC(=O)CCC/C=C\C[C@@H]1[C@@H](CO)[C@H](OC2CCCCO2)C[C@H]1Cl
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCCOC(=O)CCCCCC[C@@H]1[C@@H](CO)[C@H](OC2CCCCO2)C[C@H]1Cl
Yield: 98.2 %

Procedure:
A solution of 1 g (2.49 mmol) of alcohol 4 in 13 mL of EtOAc and Adam's catalyst (22 mg) was stirred under 30 psi of hydrogen gas in a Parr apparatus over 21 h. The mixture was then filtered to remove the catalyst through a plug of silica gel with EtOAc as solvent. The filtrate was then concentrated in vacuo yield the propyl ester 11 (990 mg) as an oil; 1H NMR (CDCl3); 0.94 (t, J=7.3 Hz, 3H), 1.20-1.94 (m, 31H), 2.17 (m, 2H), 2.32 (m, 4H), 3.46-4.12 (m, 8H), 4.03 (t, J=6.6 Hz, 2H), 4.13-4.38 (m, 2H), 4.59 (m, 1H), 4.73 (m, 1H).
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][NH2:12])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.[CH3:13][C:14]([CH3:21])([CH3:20])[C:15](=O)[CH2:16][C:17]#[N:18]>CCO>[C:14]([C:15]1[CH:16]=[C:17]([NH2:18])[N:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[NH:2][N:3]=[CH:4]3)[N:12]=1)([CH3:21])([CH3:20])[CH3:13]
Reactant: NNc1ccc2[nH]ncc2c1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2ccc3[nH]ncc3c2)n1
Yield: 60 %

Procedure:
A mixture of (1H-indazol-5-yl)-hydrazine hydrochloride and 4,4-dimethyl-3-oxo-pentanenitrile (19 g, 1.05 eq) in EtOH (200 mL) was heated at reflux overnight. The reaction was concentrated and the residue purified by column chromatography to yield 3-t-butyl-1-(1H-indazol-5-yl)-1H-pyrazol-5-amine (23 g, 60% for two steps). 1H NMR (300 MHz, DMSO-d6): δ 8.24 (s, 1 H), 8.06 (s, 1 H), 7.75 (d, J=9.0 Hz, 1 H), 7.45 (dd, J=9.0 Hz, 1.8 Hz, 1 H), 5.7 (s, 1H), 1.31 (s, 9 H); MS (ESI) m/z: 256 (M+H+).
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([O:6][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([Cl:19])=[CH:21][CH:22]=1)=[O:5]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CN(CC(=O)O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CC(=O)OCc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
The product from step 2 (220 mg, 1.3 mmol) was dissolved in DMF (7 mL) and Cs2CO3 (652 mg, 2.0 mmol) added, followed by 4-chlorobenzyl chloride (214 mg, 1.3 mmol). Allow reaction mixture to stir at ambient temperature over 18 hours. The reaction mixture was diluted with EtOAc and washed several times with brine. The organic layer was dried (Na2SO4), filtered and concentrated to afford the title compound as a yellow oil (68%). MS (ES+) m/z 290 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH3:13]O>S(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:13])=[O:9])=[CH:11][CH:12]=1
Reactant: CO
Reactant: O=C(O)C=Cc1ccc(Br)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)/C=C/c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-bromocinnamic acid (16 g) in methanol (150 mL), thionyl chloride (30 mL) was added at 0° C. The reaction mixture was warmed to room temperature and refluxed for 3 hours. After cooling to room temperature, the solvents were evaporated to dryness. The crude compound obtained was used as such for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9]3[C:15](=[O:16])[N:14]([CH3:17])[C:13]4[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=4[O:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.[N:22]1([CH2:28][CH2:29]Cl)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([CH2:29][CH2:28][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:9]3[C:15](=[O:16])[N:14]([CH3:17])[C:13]4[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=4[O:11][C:10]=3[C:5]2=[CH:4][CH:3]=1
Reactant: ClCCN1CCCCC1
Reactant: CN1C(=O)c2[nH]c3cc(Cl)ccc3c2Oc2ccccc21
Product: CN1C(=O)c2c(c3ccc(Cl)cc3n2CCN2CCCCC2)Oc2ccccc21

Procedure:
In the same way as described in example 19, 3-chloro-7-methyl-7H-indolo[3,2-b][1,5]benzoxazepin-6(5H)-one was alkylated with piperidinoethyl chloride. The crude solid base was recrystallized from acetonitrile, mp. 160°-162°.
Reaction SMILES: FC1C=C(C=CC=1OCCN1CCCCC1)CNC1C=CC=CC=1C1CCC2C(=CC=C(OC)C=2)C1.[CH2:37]([N:39]([CH2:58][C:59]1[CH:64]=[CH:63][C:62]([O:65][CH2:66][CH2:67][N:68]2[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]2)=[C:61]([F:74])[CH:60]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH:46]1[CH2:55][CH2:54][C:53]2[C:48](=[CH:49][CH:50]=[C:51]([O:56]C)[CH:52]=2)[CH2:47]1)[CH3:38]>>[CH2:37]([N:39]([CH2:58][C:59]1[CH:64]=[CH:63][C:62]([O:65][CH2:66][CH2:67][N:68]2[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]2)=[C:61]([F:74])[CH:60]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH:46]1[CH2:55][CH2:54][C:53]2[CH:52]=[C:51]([OH:56])[CH:50]=[CH:49][C:48]=2[CH2:47]1)[CH3:38]
Reactant: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1ccccc1C1CCc2cc(OC)ccc2C1
Agent: COc1ccc2c(c1)CCC(c1ccccc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1ccccc1C1CCc2cc(O)ccc2C1
Yield: 86.7 %

Procedure:
Synthesized from [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine according to an analogous synthetic method to Example 36, ethyl[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (332 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (280 mg).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([CH:19]4[CH2:21][CH2:20]4)[C:13]=3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Cl)(C)C.[C:28]([O:32][C:33](=[O:52])[N:34]([C:43]1[CH:48]=[CH:47][C:46]([CH:49]=[O:50])=[C:45]([F:51])[N:44]=1)[C:35]1[CH:36]=[N:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1)([CH3:31])([CH3:30])[CH3:29].O>O1CCCC1>[C:28]([O:32][C:33](=[O:52])[N:34]([C:43]1[CH:48]=[CH:47][C:46]([CH:49]([C:12]2[C:13]3[C:18]([CH:19]4[CH2:21][CH2:20]4)=[N:17][CH:16]=[N:15][C:14]=3[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:11]=2)[OH:50])=[C:45]([F:51])[N:44]=1)[C:35]1[CH:36]=[N:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2c(C3CC3)ncnc21
Reactant: COc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C=O)c(F)n2)cn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn(S(=O)(=O)c4ccccc4)c4ncnc(C5CC5)c34)c(F)n2)cn1
Temperature: -5 °C
Yield: 90 %

Procedure:
To a solution of 7-benzenesulfonyl-4-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (32, 0.760 g, 1.79 mmol) in 5.43 mL of tetrahydrofuran at −40° C. under nitrogen, isopropylmagnesium chloride (0.892 mL, 2.0 M in tetrahydrofuran, 1.78 mmol) is added slowly. The reaction is allowed to warm to −5° C. over 75 minutes, then cooled to −45° C. and (6-fluoro-5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-yl)-carbamic acid tert-butyl ester (57, 0.38 g, 1.1 mmol) in 2.0 mL of tetrahydrofuran is added. The reaction is allowed to warm to room temperature over 2 hours, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (75, 0.64 g). MS (ESI) [M+H+]+=647.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH3:10])=[CH:4][N:3]=1.[C:11]([Zn]C#N)#[N:12].CN(C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:10][O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]#[N:12])=[N:3][CH:4]=1
Reactant: N#C[Zn]C#N
Reactant: COCc1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COCc1ccc(C#N)nc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
A mixture of 2-chloro-5-(methoxymethyl)pyridine (0.831 g, 5.27 mmol), tetrakis (1.219 g, 1.055 mmol), dicyanozinc (0.929 g, 7.91 mmol) and DMF (17.58 ml) was stirred at 100° C. for 3 hrs. The reaction was treated with water and extracted with EtOAc. The organic portion was dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by column chromatography, eluting with 10-40% EtOAc/Heptanes to give the title compound (550 mg, 3.71 mmol, 70.4%). MS m/z=149.1 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][Mg]Cl.Cl[CH2:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:14]#[N:15].Br>COCCOC>[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][C:19]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:18]2[C:11](=[CH:12][C:13]([C:14]#[N:15])=[CH:16][CH:17]=2)[CH2:10][O:27]1
Reactant: N#Cc1ccc(C(=O)c2ccc(F)cc2)c(CCl)c1
Reactant: CN(C)CCC[Mg]Cl
Agent: Br
Solvent: COCCOC
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Yield: 75 %

Procedure:
A solution of freshly prepared 3-dimethylaminopropylmagnesium chloride (0.6 M in THF, 7.6 ml) was added to a cooled solution of 3-chloromethyl-4-(4-fluoro-benzoyl)-benzonitrile (0.5 g) in ethylene glycol dimethyl ether (4 ml) so that the temperature did not raise above −40° C. The mixture was stirred for 30 minutes at −15° C. and 100 minutes at room temperature before 0.5N hydrobromic acid was added to adjust the pH to 10. The phases were separated and the aqueous phase was extracted twice with toluene (25 ml). The combined organic phases were dried over sodium sulfate, filtered and dried in vacuo to give a viscous oil (0.44 g, 75%). Spectral and analytical data were in accordance with the literature.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[C:21]([Cl:23])[N:20]=[C:19](S(C)(=O)=O)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:28]#[N:29].[Na+].O>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[C:21]([Cl:23])[N:20]=[C:19]([C:28]#[N:29])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2cc(Cl)nc(S(C)(=O)=O)n2)CC1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCOc2cc(Cl)nc(C#N)n2)CC1
Reaction time: 10 h

Procedure:
To a solution of the crude 4-[2-(6-chloro-2-methanesulfonylpyrimidin-4-yl oxy)ethyl]-piperidine-1-carboxylic acid tert-butyl ester (4.9 g) and NaCN (14 mmol) in CH2Cl2:H2O (50 mL, 4:1) is added TBAB (tetrabutylammonium bromide) (0.06 mmol) at room temperature. After stirring at the same temperature for 10 h, TBAB (0.19 mml) is added to the reaction mixture. The reaction mixture is stirred at room temperature for 2 h and H2O is added. The organic layer is separated, dried over MgSO4 and evaporated in vacuo. The resulting residue is purified by silica gel column chromatography to give 4-[2-(6-chloro-2-cyanopyrimidin-4-yloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester; 1H-NMR (CDCl3), δ: 1.14-1.28 (2H, m), 1.45 (9H, s), 1.56-1.78 (7H, m), 2.69 (2H, t), 4.11 (2H, m), 4.49 (2H, t), 6.93 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N:12]2[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]2[CH3:18])=[CH:4][C:3]=1[C:19]#N.[H-].C([Al+]CC(C)C)C(C)C.C[OH:32]>O1CCCC1.C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N:12]2[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]2[CH3:18])=[CH:4][C:3]=1[CH:19]=[O:32]
Reactant: Cc1cn(-c2cc(C#N)c(N)c(C(F)(F)F)c2)c(C)n1
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cn(-c2cc(C=O)c(N)c(C(F)(F)F)c2)c(C)n1
Temperature: 0 °C

Procedure:
To an ice-cooled stirred solution of 1-(4-amino-3-cyano-5-trifluoromethylphenyl)-2,4-dimethylimidazole (0.7 g) in tetrahydrofuran (10 cm3) was added 3.5 cm3 of a 1.5M solution of diisobutyl aluminium hydride in toluene. The mixture was heated at 40° for 2 hours, cooled in ice, treated with methanol (2 cm3), and evaporated in vacuo. The residue was treated with water (25 cm3) and 2M hydrochloric acid (5 cm3), and heated on a steam bath for five minutes. The solution was then cooled, basified to pH 8 with aqueous sodium carbonate solution, and extracted with chloroform:methanol, 20:1 (3×30 cm3). The combined organic extracts were dried (MgSO4), evaporated in vacuo, and the residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with ethyl acetate:methanol, 50:1, to afford 1-(4-amino-3-formyl-5-trifluoromethylphenyl)-2,4-dimethylimidazole, m.p. 200°-202°, (0.391 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][CH2:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[O:22][CH3:23])=[NH:11])[S:7][CH:8]=1.CN1CCOCC1.[CH3:31][O:32][C:33](Cl)=[O:34]>C1COCC1>[CH3:31][O:32][C:33](=[O:34])[NH:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][CH2:13][C:14]2[C:15]([O:22][CH3:23])=[CH:16][CH:17]=[CH:18][C:19]=2[O:20][CH3:21])=[NH:11])[S:7][CH:8]=1
Reactant: COC(=O)Cl
Reactant: COc1cccc(OC)c1CNC(=N)Nc1nc(CN)cs1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)NCc1csc(NC(=N)NCc2c(OC)cccc2OC)n1

Procedure:
To 360 mg (1.12 mmol) N-[4-(aminomethyl)-1,3-thiazole-2-yl]-N′-(2,6-dimethoxybenzyl)guanidine hydrochloride, Example 154 free base, in 13.5 ml THF were added 0.2 ml NMM, and 0.1 ml chloroformic acid methyl ester in 1.5 ml THF were added drop-wise with stirring. Following completion of the reaction, the mixture was concentrated, was diluted with dichloromethane, was washed with saturated NaCl solution, was dried and was concentrated. Chromatography of the crude product on silica gel (dichloromethane/methanol 0-1%) yielded 140 mg; ESI-MS [M+H+]=380.05.