Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13](F)[C:12]([F:16])=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Cl:17][C:18]1[CH:19]=[C:20]([OH:32])[CH:21]=[N:22][C:23]=1[O:24][CH2:25][CH:26]1[CH2:29][C:28]([F:31])([F:30])[CH2:27]1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CS(C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([O:32][C:13]2[C:12]([F:16])=[CH:11][C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[C:2]([F:1])[CH:14]=2)[CH:21]=[N:22][C:23]=1[O:24][CH2:25][CH:26]1[CH2:27][C:28]([F:30])([F:31])[CH2:29]1
Reactant: Oc1cnc(OCC2CC(F)(F)C2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cc(F)c(Oc2cnc(OCC3CC(F)(F)C3)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.7 %

Procedure:
tert-Butyl 2,4,5-trifluorobenzoate (Preparation 6, 0.200 g, 0.86 mmol), 5-chloro-6-[(3,3-difluorocyclobutyl)methoxy]pyridin-3-ol (Preparation 5, 0.258 g, 1.03 mmol) and potassium carbonate (0.178 g, 1.29 mmol) were suspended in DMSO (5.0 mL). The mixture was stirred at room temperature under nitrogen for 16 hours. EtOAc (50 mL) was added and the mixture was washed with water (3×150 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (0.400 g, 101%):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](Cl)=[C:7]3[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:8]3=[N:9][C:10]=2[CH:11]=1.[CH3:19][N:20]([CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH3:21].C1(O)C=CC=CC=1.[ClH:34]>CC(C)=O.C(O)C>[ClH:1].[ClH:34].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([NH:26][CH2:25][CH2:24][CH2:23][CH2:22][N:20]([CH3:21])[CH3:19])=[C:7]3[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:8]3=[N:9][C:10]=2[CH:11]=1
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2n1
Reactant: CN(C)CCCCN
Agent: Cl
Solvent: CCO
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Product: COc1ccc2nc3cc(Cl)ccc3c(NCCCCN(C)C)c2n1

Procedure:
A mixture of 4.2 g. of 7,10-dichloro-2-methoxypyrido [3,2-b]quinoline, 1.6 g. of dimethylaminobutylamine and 10 g. of phenol is stirred and heated on a steam bath for 3 hours. The reaction is cooled, 30 ml. of ethanol is added and this mixture is poured into a mixture of 300 ml. of acetone and 3.75 ml. of concentrated hydrochloric acid. The yellow precipitate is collected, washed with acetone, air-dried and recrystallized from 100 ml. of 95% alcohol giving the desired product as yellow crystals, mp. 237°-238° C. (dec.)
Reaction SMILES: [Cl:1][C:2]1[C:11]([F:12])=[C:10]([CH3:13])[C:9]([Cl:14])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[K+].Cl>CCO>[Cl:1][C:2]1[C:11]([F:12])=[C:10]([CH3:13])[C:9]([Cl:14])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(Cl)c(C)c(F)c1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(Cl)cc(C(=O)O)c(Cl)c1F
Temperature: 25 °C

Procedure:
The diazonium salt is heated under dry conditions in a glass flask. When the reaction has ended, the crude methyl 2,5-dichloro-3-fluoro-4-methylbenzoate is taken up in 100 ml of 50% strength EtOH, and 8.2 g of KOH are added. The mixture is boiled under reflux for 1 hour and, after cooling to room temperature, is acidified with HCl. The benzoic acid which has precipitated is isolated, dried and recrystallized from toluene. Yield: 11.3 g, melting point 195°-6°.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH:14]([OH:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CCCCOCCC=O)C=CC=CC=1>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCCC(O)CCOCCCCc1ccccc1
Agent: O=CCCOCCCCc1ccccc1
Product: C=CCCC(=O)CCOCCCCc1ccccc1
Yield: 88.6 %

Procedure:
Obtained from Intermediate 14 (0.41 g, 1.56 mmol) by the procedure described for the Intermediate 13. Purification by column chromatography with silica gel and methylene chloride/acetone (20:1) as eluent gave the title compound (0.36 g, 88%) as oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][Cl:25])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]([C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][Cl:25])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)C(C(O)CCCCCl)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCNCC1
Product: CCOC(=O)C(C(=O)CCCCCl)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared from (2R/S, 3R/S)-2-(1-tert-butoxycarbonyl-piperidin-4-yl)-7-chloro-3-hydroxy-heptanoic acid, ethyl ester (from Step A) using a procedure analogous to that described for Piperidine 8, Step D. RF: 0.30 (4:1 v/v hexanes/EtOAc); 1H-NMR (500 MHz) δ 1.09–1.22 (m, 2H), 1.27 (t, J=7.1, 3H), 1.45 (s, 9H), 1.55 (m, 1H), 1.63–1.79 (m, 5H), 2.29 (m, 1H), 2.46–2.75 (m, 4H), 3.30 (d, J=9.6, 1H), 3.51–3.54 (m, 2H), 4.06–4.21 (m, 4H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2([NH:17]C(OC(C)(C)C)=O)[CH2:16][CH2:15][CH2:14]2)[CH2:10][C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[NH2:17][C:13]1([CH:11]2[CH2:12][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9](=[O:25])[CH2:10]2)[CH2:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1(C2CC(=O)N(Cc3ccccc3)C2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: NC1(C2CC(=O)N(Cc3ccccc3)C2)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5.65 g (16.40 mmol) of 1-benzyl-4-(1-tert-butoxycarbonylaminocyclobutyl)-2-pyrrolidone cooled in an ice bath was added dropwise 50.0 ml of trifluoroacetic acid, followed by 1 hour of stirring at room temperature. Excess reagent was evaporated, and the resulting residue was mixed with toluene and subjected to azeotropic heating to yield the title compound quantitatively as a pale yellow oily substance.
Reaction SMILES: N[C:2]1[C:3]([CH3:13])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[OH:14]S(O)(=O)=O.N([O-])=O.[Na+]>O>[OH:14][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=S(=O)(O)O
Reactant: COC(=O)c1cc(N)c(C)cc1C
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(O)c(C)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl 5-amino-2,4-dimethylbenzoate (0.752 g, 4.20 mmol) in 5 mL water was cooled with an ice bath. H2SO4 (1.1 mL, 21 mmol) was added followed by a solution of sodium nitrite (0.301 g, 4.4 mmol) in 3 mL of water. The reaction was stirred in an ice bath for 30 min, and then in a 100° C. oil bath for 60 min. The reaction was cooled to rt and partitioned between EtOAc and brine. The organic phase was dried (Na2SO4) and concentrated to give the title compound as a yellow oil. 1H NMR (CDCl3) δ 7.48 (s, 1H), 7.00 (s, 1H), 5.95 (bs, 1H), 3.90 (s, 3H), 2.50 (s, 3H), 2.28 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:7][C:6](=[O:8])[C:5]2([CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[N:4]=1.C(Cl)Cl.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>C(Cl)Cl>[NH2:1][CH2:2][C:3]1[NH:7][C:6](=[O:8])[C:5]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:4]=1.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)N=C(CN)NC2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC1=NC2(CCNCC2)C(=O)N1
Reaction time: 0.5 h

Procedure:
For deprotection, 1E (1.0 equivalent) was dissolved in CH2Cl2 at 0° C., and slowly treated with a 1.6:1 solution of CH2Cl2/TFA (2:1 final ratio, 0.15 M). The reaction was completed in 30 minutes at 0° C. as determined by LCMS analysis. The volatiles were removed under reduced pressure to yield the respective 2-(aminomethyl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one (1G) as TFA salts which were used without further purification. ESI-MS: m/z 183.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2NC=CN=2)=[N:4][CH:5]=[CH:6][CH:7]=1.FC1N=C(C2NC=CN=2)C=CC=1.[Li]CCCC.FC1C=NC=CC=1.C([O:39]CC)C>O.CN(C=O)C>[F:1][C:2]1[C:3]([CH:8]=[O:39])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: Fc1cccnc1-c1ncc[nH]1
Agent: Fc1cccc(-c2ncc[nH]2)n1
Agent: Fc1cccnc1
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ncccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Fluoro-2-(1H-imidazol-2-yl)-pyridine, which is used as a starting material (e.g., in place 6-fluoro-2-(1H-imidazol-2-yl)-pyridine in the procedure given above) in the synthesis of certain compounds is prepared as follows: n-BuLi (2.5 M in hexane, 86 mL, 1.05 eq.) is added dropwise over a 90 minute interval to a solution of 3-fluoropyridine (20 g,.0.206 mol) and N,N,N′N′-tetramethylethylenediamine (31.3 mL, 0.206 mol) in ethyl ether (350 mL) at −78° C. under nitrogen. The mixture is stirred at this temperature for an additional 3 hours. Anhydrous DMF (45 mL) is then added at the same temperature. The mixture is allowed to warm to room temperature overnight. Water (170 mL) is added and organic layer separated. The aqueous layer is extracted with ether (3×200 mL), and then with ethyl acetate (2×200 mL). The combined organic layers are dried (MgSO4) and solvent removed in vacuo. The crude is purified by column chromatography (hexane:ether 2:1) to give 3-fluoro-pyridine-2-carbaldehyde as a yellowish oil.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[N:6]2[N:5]=1)=O.CS(O)(=O)=O.[CH3:30][O:31][C:32]1[CH:40]=[C:39]2[C:35]([CH2:36][N:37]([CH3:41])[CH2:38]2)=[CH:34][C:33]=1[NH2:42]>COCC(O)C>[CH3:30][O:31][C:32]1[CH:40]=[C:39]2[C:35]([CH2:36][N:37]([CH3:41])[CH2:38]2)=[CH:34][C:33]=1[NH:42][C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[N:6]2[N:5]=1
Reactant: COc1cc2c(cc1N)CN(C)C2
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Agent: CS(=O)(=O)O
Solvent: COCC(C)O
Product: COc1cc2c(cc1Nc1ncc3ccc(-c4ccccc4N(C)S(C)(=O)=O)n3n1)CN(C)C2
Temperature: 135 °C
Reaction time: 24 h

Procedure:
N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (90.00 mg, 0.247), methanesulfonic acid (0.048 mL, 0.74 mmol) and 6-methoxy-2-methyl-2,3-dihydro-1H-isoindol-5-ylamine (88.03 mg, 0.494 mmol) were combined in 1-methoxy-2-propanol (1.45 mL) in a capped tube and the reaction was stirred at 135° C. for 24 h. The product was isolated by reverse phase hplc and neutralization to the free amine to afford N-{2-[2-(6-methoxy-2-methyl-2,3-dihydro-1H-isoindol-5-ylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-N-methyl-methanesulfonamide as a brown amorphous solid (5 mg, 4%). 1H-NMR (CDCl3) δ 8.72 (s, 1H), 8.02 (s, 1H), 7.90 (m, 1H), 7.52 (m, 4H), 7.03 (d, J=4.5 Hz, 1H), 6.86 (d, J=4.5 Hz, 1H), 6.72 (s, 1H), 3.89 (m, 2H), 3.88 (s, 3H), 3.74 (m, 2H), 3.11 (s, 3H), 2.67 (s, 3H), 2.60 (s, 3H); LC/MS (ESI+): 479.1 (M+H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:37](=[O:40])(=[O:39])[NH2:38])=[CH:27][C:26]=2[F:41])[C:7](=[O:23])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[C:19]([F:22])([F:21])[F:20])[N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:42][C:43]1[CH:51]=[CH:50][CH:49]=[CH:48][C:44]=1[C:45](O)=[O:46].C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1>>[CH2:1]([C:5]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:37](=[O:40])(=[O:39])[NH:38][C:45](=[O:46])[C:44]3[CH:48]=[CH:49][CH:50]=[CH:51][C:43]=3[Cl:42])=[CH:27][C:26]=2[F:41])[C:7](=[O:23])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[C:19]([F:21])([F:20])[F:22])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Reactant: O=C(O)c1ccccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1F
Yield: 86 %

Procedure:
By the procedure of Example 51, 5-n-butyl-2,4-dihydro-4-[(3-fluoro-2'-sulfamoylbiphenyl-4-yl)methyl]-2-[5-nitro-2-(trifluoromethyl)-phenyl]-3H-1,2,4-triazol-3-one (from Step E) was reacted with 2-chlorobenzoic acid (3 equivalents), CDI (3 equiv), and DBU (3 equiv). Flash chromatography of the crude product on silica gel afforded an 86% yield of the title compound as a foam; homogeneous by TLC (95:5 CH2Cl2 --MeOH); mass spectrum (FAB) m/e 732 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH3:36])[CH:31]=[CH:30][C:29]=4[F:37])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH3:41]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][CH:2]([CH3:3])[CH3:41])[CH:31]=[CH:30][C:29]=4[F:37])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CNC)ccc4F)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CNCC(C)C)ccc4F)cc23)CC1
Yield: 62.9 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole-7-carboxamide trifluoroacetate, substituting 2-methyl-1-propanamine (53 μL, 0.524 mmol) for methanamine to afford 15 mg of the title compound (62.9%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([C@H:32]5[CH2:37][O:36][CH2:35][CH2:34][NH:33]5)=[CH:28][CH:27]=4)[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17]2)[CH:5]=[C:6]([F:15])[C:7]=1[CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[CH2:38]([O:45][CH2:46][CH:47]=O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CO.C([BH3-])#N.[Na+]>[CH2:38]([O:45][CH2:46][CH2:47][N:33]1[CH2:34][CH2:35][O:36][CH2:37][C@@H:32]1[C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:22]2[N:23]=[CH:24][C:19]3[CH:18]=[CH:17][N:16]([C:4]4[CH:3]=[C:2]([F:1])[C:7]([CH2:8][N:9]5[CH2:14][CH2:13][O:12][CH2:11][CH2:10]5)=[C:6]([F:15])[CH:5]=4)[C:20]=3[N:21]=2)=[CH:27][CH:28]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Fc1cc(-n2ccc3cnc(Nc4ccc([C@H]5COCCN5)cc4)nc32)cc(F)c1CN1CCOCC1
Reactant: O=CCOCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Fc1cc(-n2ccc3cnc(Nc4ccc([C@H]5COCCN5CCOCc5ccccc5)cc4)nc32)cc(F)c1CN1CCOCC1

Procedure:
The compound is obtained by treating [7-(3,5-difluoro-4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-((S)-4-morpholin-3-yl-phenyl)-amine (Example 511) with benzyloxyacetaldehyde in methanol and sodium cyanoborohydride at 60° C. HPLC: tR=0.78 min (Method G); MS-ES: (M+H)+=641
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:14][CH2:13][CH2:12][C:11](=O)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[BH4-].[Na+].C[O:19][C:20](OC)([N:22]([CH3:24])[CH3:23])[CH3:21]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:21][C:20]([N:22]([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2=CC(=O)CCC2)c1
Reactant: COC(C)(OC)N(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: COc1cccc(C2(CC(=O)N(C)C)CC=CCC2)c1

Procedure:
10 g of 3-(m-methoxyphenyl)-2-cyclohexen-1-ol obtained by reducing 3-(m-methoxyphenyl)-2-cyclohexene-1-one with sodium borohydride, are dissolved in 100 ml of xylene, whereupon 12 g of N,N-dimethylacetamide dimethyl acetal are added, and the mixture is boiled at reflux for 8 hours. After distillation of the solvent, the oil remaining behind is chromatographed on a 30-fold amount of silica gel. The fractions which are uniform in accordance with thin-layer chromatography and which are produced by elution with methylene chloride, are combined and evaporated, and there is obtained pure 1-(m-methoxyphenyl)-N,N-dimethyl-3-cyclohexene-1-acetamide in the form of a pale yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.[Cl:13]N1CCOCC1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:10]([Cl:13])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: ClN1CCOCC1
Reactant: COc1cc(Cl)ccc1C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Cl)c(Cl)cc1C(=O)O
Temperature: 0 °C
Yield: 16.9 %

Procedure:
To an ice cold solution of 4-chloro-2-methoxybenzoic acid (1.0 g, 5.36 mmol) in trifluoroacetic acid (7 ml) was added N-chloromorpholine (0.67 g, 5.5 mmol) dropwise, maintaining the internal temperature below 10° C. After stirring overnight at room temperature the trifluoroacetic acid was removed in vacuo and the residue partitioned between ethyl acethate and water. The organic layer was dried over magnesium sulfate, concentrated in vacuo and the residue recrystallised from methanol to afford the title compound as a white solid (200 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH2:17])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[Cl:16].[F:19][C:20]([F:31])([F:30])[C:21]([F:29])([F:28])[C:22]([F:27])([F:26])[C:23](O)=O.Cl>>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[CH:6][C:5]2[NH:17][C:23]([C:22]([F:26])([F:27])[C:21]([F:28])([F:29])[C:20]([F:31])([F:30])[F:19])=[N:18][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Oc2cccc(Cl)c2Cl)cc1N
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Product: FC(F)(F)C(F)(F)C(F)(F)c1nc2cc(Cl)c(Oc3cccc(Cl)c3Cl)cc2[nH]1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Compound number 140 (i.e., 6-chloro-5-(2,3-dichlorophenoxy)-2-heptafluoropropylbenzimidazole) was prepared as follows. 4-chloro-5-(2,3-dichlorophenoxyl)benzene-1,2-diamine (150 mg, 0.49 mmol, 1.00 equiv), heptafluorobutanoic acid (15 mL) and hydrogen chloride (3 mL) was placed into a 100-mL round-bottom flask. The resulting solution was stirred overnight at 110° C. in an oil bath. The reaction mixture was cooled to room temperature. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×100 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). The crude product was re-crystallized from EA/hexane in the ratio of 1/1. This resulted in 63.4 mg (27%) of 6-chloro-5-(2,3-dichlorophenoxy)-2-heptafluoropropylbenzimidazole as a white solid.
Reaction SMILES: [Cl:1][C:2]1([Cl:22])[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([C:17](=[N:19][OH:20])[CH3:18])=[N:12][N:13]2[CH3:16])=[CH:9][C:8]=1[F:21].[H-].[Na+].[CH3:25][O:26][C:27](=[O:40])[C:28]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38]Br)=[CH:29][O:30][CH3:31].C(O)(=O)C>CN(C)C=O>[CH3:25][O:26][C:27](=[O:40])[C:28]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][O:20][N:19]=[C:17]([C:11]1[C:10]2[C:14](=[CH:15][C:7]([O:6][CH2:5][CH:3]3[CH2:4][C:2]3([Cl:1])[Cl:22])=[C:8]([F:21])[CH:9]=2)[N:13]([CH3:16])[N:12]=1)[CH3:18])=[CH:29][O:30][CH3:31]
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Reactant: CC(=NO)c1nn(C)c2cc(OCC3CC3(Cl)Cl)c(F)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC=C(C(=O)OC)c1ccccc1CON=C(C)c1nn(C)c2cc(OCC3CC3(Cl)Cl)c(F)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 0.9 g of 1-[6-(2,2-dichlorocyclopropylmethoxy)-5-fluoro-1-methyl-1H-indazol-3-yl]-ethanone oxime in 10 ml of N,N-dimethylformamide is added dropwise to a suspension of 0.2 g of sodium hydride in 15 ml of N,N-dimethylformamide and the reaction mixture is stirred at room temperature for 15 minutes. Then 1.04 g of 2-(α-bromo-o-tolyl)-3-methoxyacrylic acid methyl ester in 10 ml of N,N-dimethylformamide are added dropwise and the reaction mixture is stirred at room temperature for a further 3 hours. The mixture is then acidified with acetic acid and concentrated by evaporation in vacuo at approx. 50° C. The residue is dissolved in ethyl acetate and the solution is washed twice with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in vacuo. Purification by flash chromatography (silica gel, ethyl acetate/hexane 1:1) yields the title compound having a melting point of 138-140° C.
Reaction SMILES: [C:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]1OCC[O:26]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CC(C)=O>[C:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=[O:26])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(Cc1ccccc1C1OCCO1)c1ccccc1Oc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)N(Cc1ccccc1C=O)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.1 %

Procedure:
In 40 ml of acetone was dissolved 2.81 g of N-acetyl-N-[2-(1,3-dioxolan-2-yl)benzyl]-2-phenoxyaniline synthesized in the same manner as in Example 3, and then 0.10 g of p-toluenesulfonic acid monohydrate was added, followed by stirring at room temperature for 6 hours. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, the acetone was concentrated under reduced pressure, and the residue was extracted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:3), dried and allowed to stand at room temperature to give 2.12 g of N-acetyl-N-(2-formylbenzyl)-2-phenoxyaniline as crystals.
Reaction SMILES: Cl.Cl.Cl.Cl.Cl.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([N:19]3[CH:28]([CH3:29])[CH2:27][C:26]4[C:21](=[CH:22][C:23]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[CH:24][CH:25]=4)[CH2:20]3)[N:16]=[C:15]([NH2:36])[N:14]=2)[CH2:9][CH2:8]1.[C:37](Cl)(=[O:40])[CH2:38][CH3:39]>>[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([N:19]3[CH:28]([CH3:29])[CH2:27][C:26]4[C:21](=[CH:22][C:23]([CH:30]5[CH2:31][CH2:32][N:33]([C:37](=[O:40])[CH2:38][CH3:39])[CH2:34][CH2:35]5)=[CH:24][CH:25]=4)[CH2:20]3)[N:16]=[C:15]([NH2:36])[N:14]=2)[CH2:9][CH2:8]1
Reactant: CC1Cc2ccc(C3CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 144 starting from 4-(4-methylpiperazin-1-yl)-6-(3-methyl-7-piperidin-4-yl-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-2-amine tetrahydrochloride HCl salt (Example 144, Step 3) and propanoyl chloride. LCMS (M+H)+: m/z=478.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][N:8]=[N+]=[N-])=[CH:5][C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][NH2:8])=[CH:5][C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: COc1ccc(-c2cc(CN=[N+]=[N-])ccc2OC)cc1
Solvent: CCO
Product: COc1ccc(-c2cc(CN)ccc2OC)cc1
Yield: 53.6 %

Procedure:
A solution of 4-methoxy-3-(4-methoxyphenyl)benzylazide (0.82 g, 3.07 mmol) in ethanol (50 mL) was hydrogenated under atmospheric pressure for 16 hours. The catalyst was filtered off, the solvent removed under reduced pressure and the crude purified by column chromatography (hexane/ethyl acetate 6/1) to afford 400 mg of title compound.