Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[CH3:37][C:38]1[S:39][C:40]([C:44](=O)[CH3:45])=[C:41]([CH3:43])[N:42]=1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:44]([C:40]2[S:39][C:38]([CH3:37])=[N:42][C:41]=2[CH3:43])[CH:45]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CC(=O)c1sc(C)nc1C
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(C)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)s1
Yield: 12 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(2,4-dimethyl-thiazol-5-yl)-ethanone (40 mg, 0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (14 mg, 12% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11]C(C)([O-])C.[K+].C(Cl)(Cl)Cl.C1C=CC=CC=1>C(O)(C)(C)C.O>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([N+:8]#[C-:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(C)(C)O
Product: [C-]#[N+]c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 60 %

Procedure:
p-nitroaniline (5 gms; 0.036 mole) and potassium-t-butoxide (20 gms; 0.18 mole) were dissolved with stirring in t-butanol (1 liter). Chloroform (8 ml: 0.07 mole) was then added dropwise and the reaction allowed to proceed with stirring for 1 hr. Benzene (200 ml) and water were added until phase separation occured. The benzene phase was separated. The aqueous phase was extracted with two 100 ml portions of benzene. The combined benzene extract was washed with water and concentrated to a final volume of about 100 ml. in a rotatory evaporator. The concentrated benzene solution was passed through an activated-alumina column (2.5 × 25 cm), the yellow-orange fractions collected and evaporated to dryness. The yellowish brown solid (3.5 gms; 60% yield) was stored in a closed vessel, at -5°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH:6]=O)#[N:2].[OH:12][NH2:13].C([O-])(=O)C.[Na+]>C(O)C.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH:6]=[N:13][OH:12])#[N:2]
Reactant: NO
Reactant: N#Cc1cc(C=O)ccc1F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#Cc1cc(C=NO)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
To a solution of 3-cyano-4-fluorobenzaldehyde (2.50 g) in ethanol (40 mL) was added a solution of hydroxyamine (1.46 g) in water (10 mL), a solution of sodium acetate (2.75 g) in water (10 mL). The mixture was stirred at rt, overnight. Ethanol was removed and the white precipitate was filtered, washed with water and air dried to leave 3-cyano-4-fluorobenzaldehydeoxime (2.05 g). CI mass spectrum z (rel. intensity) 165 (M+H, 100).
Reaction SMILES: Br[C:2]1[CH:14]=[N:13][C:5]2[NH:6][CH2:7][C:8]([CH3:12])([CH3:11])[N:9]=[CH:10][C:4]=2[CH:3]=1.[CH3:15][N:16]([CH2:21][C:22]1[O:23][C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[C:26]=1[CH3:27])[C:17](=[O:20])[CH:18]=[CH2:19].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:11][C:8]1([CH3:12])[CH2:7][NH:6][C:5]2[N:13]=[CH:14][C:2](/[CH:19]=[CH:18]/[C:17]([N:16]([CH3:15])[CH2:21][C:22]3[O:23][C:24]4[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=4[C:26]=3[CH3:27])=[O:20])=[CH:3][C:4]=2[CH:10]=[N:9]1
Reactant: CC1(C)CNc2ncc(Br)cc2C=N1
Reactant: C=CC(=O)N(C)Cc1oc2ccccc2c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)C=NC(C)(C)CN3)oc2ccccc12
Reaction time: 0.17 h
Yield: 21.1 %

Procedure:
A suspension of 7-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-e][1,4]diazepine (255 mg, 1.00 mmol) and N-methyl-N-(3-methylbenzofuran-2-ylmethyl)acrylamide (0.28 g, 1.2 mmol) in propionitrile (5.0 mL) and DMF (1.3 mL) was de-oxygenated with Ar for 10 min. The mixture was treated with (i-Pr)2EtN (0.38 mL, 2.2 mmol) and was de-oxygenated with Ar for 5 min. Pd(OAc)2 (22 mg, 0.10 mmol) and P(o-tol)3 (63 mg, 0.21 mmol) were added simultaneously, and the mixture was de-oxygenated a third time for 5 min. The mixture was heated to reflux overnight, then allowed to cool. The mixture was diluted with EtOAc (50 mL) and washed with H2O (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated to an orange oil. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 96:4) followed by trituration with Et2O gave the title compound (85 mg, 21%) as a yellow powder and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ8.44-8.43 (m, 1H), 8.25 (s, 1H), 8.19-8.15 (m, 1H), 8.06 (s, 1H), 7.58-7.08 (m, 6H), 4.99-4.79 (m, 2H), 3.18-2.92 (m, 5H), 2.27 (s, 3H), 1.16 (s, 6H); MS (ESI) m/e 403 (M+H)+.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10]O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[C:1]([NH:8][CH2:9][CH2:10][Br:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)NCCBr
Temperature: 0 °C
Yield: 159.2 %

Procedure:
To an ice-cooled solution of (N-Boc)-2-aminoethanol (2.5 g, 15.5 mmol) and carbon tetrabromide (7.5 g, 22.7 mmol) in dry benzene (25 ml), was added triphenyl phosphine (4.7 g, 17.9 mmol) in small portions over 10-15 min. After 30 min. solvent was evaporated and the product immediately purified by silica gel column chromatography to get (N-Boc)-2-aminoethylbromide (5.53 g, 790%).
Reaction SMILES: [Cl:1]Cl.[Cl:3][CH2:4][C:5]([F:14])([F:13])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8]>>[Cl:3][CH:4]([Cl:1])[C:5]([F:13])([F:14])[C:6]([F:11])([F:12])[C:7]([F:9])([F:8])[F:10]
Reactant: FC(F)(F)C(F)(F)C(F)(F)CCl
Reactant: ClCl
Product: FC(F)(F)C(F)(F)C(F)(F)C(Cl)Cl

Procedure:
For example, to prepare 1,1-dichloro-2,2,3,3,4,4,4-heptafluorobutane, 2,2,3,3,4,4,4-heptafluorobutanol and p-toluenesulfonyl chloride are reacted to form 2,2,3,3,4,4,4-heptafluorobutyl-p-toluenesulfonate. Then, N-methylpyrrolidone, lithium chloride, and the 2,2,3,3,4,4,4-heptafluorobutyl-p-toluenesulfonate are reacted to form 1-chloro-2,2,3,3,4,4,4-heptafluorobutane. Finally, chlorine and the 1-chloro-2,2,3,3,4,4,4-heptafluorobutane are reacted to form the 1,1-dichloro-2,2,3,3,4,4,4-heptafluorobutane.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]1)=[O:8].[CH:19]1([CH2:22][NH:23][CH2:24][C:25]2[NH:26][C:27](=[O:35])[C:28]3[CH2:34][O:33][CH2:32][CH2:31][C:29]=3[N:30]=2)[CH2:21][CH2:20]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[CH:19]1([CH2:22][N:23]([CH2:24][C:25]2[NH:26][C:27](=[O:35])[C:28]3[CH2:34][O:33][CH2:32][CH2:31][C:29]=3[N:30]=2)[C:16](=[O:18])[CH2:15][N:12]2[CH2:11][CH2:10][CH:9]([C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[O:8])[CH2:14][CH2:13]2)[CH2:21][CH2:20]1
Reactant: O=C(O)CN1CCC(C(=O)c2ccccn2)CC1
Reactant: O=c1[nH]c(CNCC2CC2)nc2c1COCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1ccccn1)C1CCN(CC(=O)N(Cc2nc3c(c(=O)[nH]2)COCC3)CC2CC2)CC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 41.8 %

Procedure:
To a solution of compound [4-(pyridine-2-carbonyl)-piperidin-1-yl]-acetic acid (178 mg, 0.72 mmol) and 2-[(cyclopropylmethyl-amino)-methyl]-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (169 mg, 0.72 mmol) in DMF (5 mL) and DCM (5 mL) at 0° C. is added DIPEA (0.50 mL, 2.87 mmol) and then HATU (313 mg, 0.82 mmol). The reaction is then stirred at 25° C. for 36 hours. The solvent was removed under vacuum and then solubilized in methanol and filtered. The compound was then purified by reverse phase using sunfire C18 ODB using water acetonitrile and TFA as a buffer to afford the title compound (140 mg). 1H NMR (400 MHz, MeOD) δ: 8.68 (s, 1H), 7.99 (m, 2H), 7.59 (s, 1H), 4.68 (s, 1H), 4.57 (s, 2H), 4.49 (s, 1H), 3.97 (t, J=5.6 Hz, 3H), 3.51 (d, J=7.1 Hz, 1H), 3.40 (s, 2H), 3.36 (s, 2H), 3.35-3.31 (m, 2H), 3.30 (d, J=11.6 Hz, 2H), 2.68-2.58 (m, 2H), 2.37-2.24 (m, 2H), 1.96-1.91 (m, 2H), 1.13-0.97 (m, 1H), 0.62-0.45 (m, 2H), 0.33-0.22 (m, 2H). HRMS calculated for C25H31N5O4=465, 2376. found (ESI, [M+H]+), 465, 2369. LRMS m/z: ES+=466.0 (M+H), retention time 1.04.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28][OH:29])=[CH:23][C:22]=3[F:30])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[C:31]([NH:38][C@H:39]([C:43](O)=[O:44])[CH:40]([CH3:42])[CH3:41])([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28][O:29][C:43](=[O:44])[C@@H:39]([NH:38][C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH:40]([CH3:42])[CH3:41])=[CH:23][C:22]=3[F:30])[CH2:19][CH2:20]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(CO)cc3F)CC2)CC1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)cc3F)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
10-1 (0.5 g, 1.19 mmol), Boc-L-valine (0.27 g, 1.28 mmol), DMAP (36 mg) and EDC(0.27 g) were combined in 10 mL of DCM and stirred at room temperature for 18 h. The mixture was concentrated and purified by flash LC(eluent: 0 to 40% EtOAc in hexane with 0.1% of triethylamine) to afford 42-1 as a colorless oil: LC-MS 525.2 (MH-Boc), tR=10.38 (Method 2). EC50: 928 nM.
Reaction SMILES: [OH:1][N:2]=[C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:17])=[C:10]([O:14][CH3:15])[CH:11]=2)[CH2:6]1)[NH2:4].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([O:1][N:2]=[C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:17])=[C:10]([O:14][CH3:15])[CH:11]=2)[CH2:6]1)[NH2:4])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(cc1OC)CC(C(N)=NO)C2
Product: COc1cc2c(cc1OC)CC(C(N)=NOC(C)=O)C2
Temperature: 0 °C

Procedure:
A suspension of 6.6 g (28 mmol) 2,3-dihydro-N'-hydroxy-5,6-dimethoxy-1H-indene-2-carboximidamide was stirred in 50 ml of acetic acid anhydride for 1 hour at room temperature. The suspension was subsequently poured out into 500 ml of ice water and, after 2 hours stirring, was drawn off and washed to neutral with water.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[CH:20]=[N:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[C:28](N=C(N(C)C)N(C)C)([CH3:31])([CH3:30])[CH3:29].BrCC(C)C>C(#N)C>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([C:19]3[CH:20]=[N:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])[CH2:29][CH:28]([CH3:31])[CH3:30])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Reactant: Cc1cc(C)c(NS(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)cn1
Solvent: CC#N
Solvent: CC(C)CBr
Product: Cc1cc(C)c(N(CC(C)C)S(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.9 %

Procedure:
4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}-N-(4,6-dimethyl-3-pyridinyl)benzenesulfonamide (100 mg, 0.258 mmol) and 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (44.2 mg, 0.258 mmol) were dissolved in acetonitrile (1 mL). The mixture was stirred at room temperature for 1 hour, then 1-bromo-2-methylpropane (0.028 mL, 0.258 mmol) was added. The reaction was stirred at room temperature for 20 hours, then additional 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (44.2 mg, 0.258 mmol) and 1-bromo-2-methylpropane (0.028 mL, 0.258 mmol) were added. The reaction was heated to 60° C. and stirred for a further 2 hours. The solvent was removed in vacuo and the residue was partitioned between water (5 mL) and dichloromethane (5 mL). The organic layer was separated, concentrated and purified by mass directed autoprep (formic acid modifier). The required fractions were combined and concentrated to provide the title compound (17 mg) as a colourless oil. LCMS (2 min, formic) Rt 1.04 mins, m/z (ES+) 444 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[S:5][C:6]3[CH:12]=[C:11]([O:13]C)[C:10]([CH3:15])=[CH:9][C:7]=3[N:8]=2)[CH2:3][CH2:2]1.[Br:16]C1C2SC=NC=2C=C(C)C=1O.COC1C(C)=CC2N=CSC=2C=1>>[Br:16][C:12]1[C:6]2[S:5][C:4]([CH:1]3[CH2:3][CH2:2]3)=[N:8][C:7]=2[CH:9]=[C:10]([CH3:15])[C:11]=1[OH:13]
Reactant: Cc1cc2ncsc2c(Br)c1O
Reactant: COc1cc2sc(C3CC3)nc2cc1C
Agent: COc1cc2scnc2cc1C
Product: Cc1cc2nc(C3CC3)sc2c(Br)c1O

Procedure:
Compound 15 was prepared from compound 6B by the method used to prepare compound 5D from compound 5B as outlined in Example 1. LCMS-ESI+: calc'd for C141H10BrNOS: 284.0 (M+H+). Found: 284.2 (M+H+).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH3:19][NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](O)=[O:27])[N:25]=1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:26]([C:24]3[N:25]=[C:21]([NH:20][CH3:19])[S:22][CH:23]=3)=[O:27])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: CNc1nc(C(=O)O)cs1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: CNc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Yield: 8.28 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(methylamino)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.389 g, 1.343 mmol) and 2-(methylamino)thiazole-4-carboxylic acid (255 mg, 1.612 mmol). The product was purified by Flash-chromatography and triturated using diethyl ether. Yield 8.28%. 1H-NMR (400 MHz; DMSO-d6): δ 1.21 (d, 3H), 2.85 (d, 3H), 4.28-4.43 (m, 3H), 6.96 (d, 1H), 7.18 (s, 1H), 7.59 (q, 1H), 7.84 (d, 1H), 7.91 (d, 1H), 7.95-7.96 (m, 2H), 8.08 (dd, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C@H:10]2[C@H:15]([N:16]([CH3:31])[C:17](=[O:30])[C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[CH2:14][CH2:13][NH:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9].[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([C:45](O)=[O:46])[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(#N)C.O.C(N(CC)CC)C>[Cl:2][C:3]1[CH:4]=[C:5]([C@H:10]2[C@H:15]([N:16]([CH3:31])[C:17]([C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)=[CH:22][CH:23]=3)=[O:30])[CH2:14][CH2:13][N:12]([C:45]([CH:42]3[CH2:43][CH2:44][N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH2:40][CH2:41]3)=[O:46])[CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CN(C(=O)c1ccc(N2CCOCC2)cc1)[C@@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C(=O)c1ccc(N2CCOCC2)cc1)[C@@H]1CCN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 78.6 %

Procedure:
To a solution of N-[(3R,4R)-3-(3,4-dichlorophenyl)piperidin-4-yl]-N-methyl-4-morpholin-4-ylbenzamide monohydrochloride (800 mg) obtained in Example 614, step 3, 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (566 mg) and triethylamine (684 μL) in acetonitrile (5 mL) were added WSC.HCl (473 mg) and HOBt (378 mg), and the mixture was stirred at room temperature for 14 hr. To the reaction solution was added water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (855 mg, 79%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=3)[N:7]([CH2:20][CH2:21][CH2:22][CH2:23]O)[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:12]4[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=4)[CH2:23][CH2:22][CH2:21][CH2:20][N:7]3[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3cc(Cl)cc(Cl)c3)n(CCCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 26 h
Yield: 93.3 %

Procedure:
To a solution of 4-[4-chloro-2-[(3,5-dichlorophenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butan-1-ol (Reference Example 42; 7.0 mg, 0.015 mmol) in pyridine (1.0 mL) was added methanesulfonyl chloride (0.050 mL, 0.064 mmol) dropwise at 0° C. The mixture was warmed to room temperature and stirred for 26 hr. Aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The resulting crude mesylate was dissolved in N,N-dimethylformamide (1.0 mL) and potassium carbonate (11 mg, 0.077 mmol) was added. The mixture was stirred at 80° C. for 16 hr. Water was added and the mixture was extracted with ethyl acetate. Organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 5-20% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound (6.1 mg, 0.014 mmol, 93%) as a colorless amorphous.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[C:17]([CH3:18])=[CH:16][N:15]=[C:14](Cl)[N:13]=2)=[CH:10][CH:11]=1.[CH3:21][C:22]1([CH3:31])[CH2:27][CH:26]([NH2:28])[CH2:25][C:24]([CH3:30])([CH3:29])[NH:23]1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[C:17]([CH3:18])=[CH:16][N:15]=[C:14]([NH:28][CH:26]3[CH2:27][C:22]([CH3:31])([CH3:21])[NH:23][C:24]([CH3:30])([CH3:29])[CH2:25]3)[N:13]=2)=[CH:10][CH:11]=1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: COC(=O)CCCc1ccc(-c2nc(Cl)ncc2C)s1
Product: COC(=O)CCCc1ccc(-c2nc(NC3CC(C)(C)NC(C)(C)C3)ncc2C)s1
Yield: 60 %

Procedure:
4-{5-[5-Methyl-2-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-thiophen-2-yl}-butyric acid methyl ester was prepared analogous to Step C of Method A, starting from 4-[5-(2-chloro-5-methyl-pyrimidin-4-yl)-thiophen-2-yl]-butyric acid methyl ester and added 2,2,6,6-tetramethyl-piperidin-4-ylamine. Yield: 60%.
Reaction SMILES: [C:1]([C:4]12[CH2:13][CH:8]([C:9]([CH3:12])=[CH:10][CH2:11]1)C(=O)[CH2:6][CH:5]2[CH3:15])([CH3:3])=[CH2:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:28][O:29][CH:30](OC)[O:31][CH3:32].C([O-])(O)=O.[Na+]>CO>[C:1]([C:4]12[CH2:13][CH:8]([C:30]([O:31][CH3:32])([O:29][CH3:28])[CH2:15][CH:5]1[CH3:6])[C:9]([CH3:12])=[CH:10][CH2:11]2)([CH3:3])=[CH2:2]
Reactant: C=C(C)C12CC=C(C)C(C1)C(=O)CC2C
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=C(C)C12CC=C(C)C(C1)C(OC)(OC)CC2C
Yield: 93 %

Procedure:
A soln. of 1.5 g of 5-isopropenyl-4,8-dimethylbicyclo[3.3.1]non-7-en-2-one (7.3 mmol), 1.4 g para-toluenesulfonic acid mono hydrate (7.4 mmol 1 eq.), and 0.78 g trimethylorthoformate (7.4 mmol, 1 eq.) in 50 ml methanol was heated at 60° C. for 66 h. The reaction mixture was then cooled and poured into aq. sat. NaHCO3 soln. (20 ml). Extraction with MTBE (2×80 ml) followed by washing of the aq. phases with H2O and aq. sat. NaCl soln., drying of org. phases (MgSO4) led to 1.8 g of crude product. FC (SiO2, Hexane/MTBE 30:1) gave 1.7 g (92%) of compound 5 as colorless liquid. The boiling point of the end product is 130° C. at 0.08 mbar. Rf (hexane/MTBE 8:1) 0.57.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:5]=[C:4]([Cl:20])[N:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C(O)C>[Cl:20][C:4]1[N:3]=[C:2]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:5]=1
Reactant: C1COCCN1
Reactant: FC(F)(F)Oc1ccc(Nc2cc(Cl)nc(Cl)n2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: FC(F)(F)Oc1ccc(Nc2cc(Cl)nc(N3CCOCC3)n2)cc1
Temperature: 30 °C
Yield: 73.6 %

Procedure:
A mixture of compound (2,6-dichloro-pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine (0.4 g, 1.23 mmol), morpholine (0.1 g, 1.16 mmol) and triethyl amine (0.5 ml, 3.66 mmol) in solvent ethanol (10 mL) was refluxed for 12 hours under nitrogen atmosphere. The reaction mixture was cooled to temperature in the range of 20-40° C. and concentrated under vacuum. The crude compound was passed through the silica gel by using 8-10% ethylacetate in pet-ether to afford the compound (6-chloro-2-morpholin-4-yl-pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine (0.32 g, 69%) as white solid.
Reaction SMILES: [Al].[H-].[Li+].[CH2:4]([O:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([CH3:39])([CH3:38])[C:33](OCC)=[O:34])=[CH:28][CH:27]=2)[CH2:20][CH2:19]1)[CH3:5].[H-]>C1COCC1.O>[CH2:4]([O:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([CH3:38])([CH3:39])[CH2:33][OH:34])=[CH:30][CH:31]=2)[CH2:20][CH2:19]1)[CH3:5]
Reactant: CCOCCn1c(C2CCN(CCc3ccc(C(C)(C)C(=O)OCC)cc3)CC2)nc2ccccc21
Agent: [Al]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCCn1c(C2CCN(CCc3ccc(C(C)(C)CO)cc3)CC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.7 %

Procedure:
1 g of aluminium and lithium hydride was dissolved in 30 ml of THF and 3 g of ethyl 2-[4-(2-(4-(1-(2-ethoxyethyl)benzimidazole-2-yl)piperidine-1-yl)ethyl)phenyl]-2-methylpropanoate were added dropwise thereto. This was stirred for four hours at room temperature and some milliliters of water were added to eliminate excess hydride. The solution was filtered and the filtrate was washed with a saturated sodium chloride solution. This was dried and concentrated. The residue was redissolved in chloroform and washed with water, dried and concentrated. The residue was purified by flash-chromatography using a hexane/ether/isopropyl-amine mixture (2/7.5/0.5) as an eluent, to yield 1.5 g of 1-(2-ethoxyethyl)-2-[1-(2-(4-(1,1-dimethyl-2-hydroxyethyl)phenyl)ethyl)piperidine-4-yl]-1H-benzimidazole.