Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[N:29]=[C:28]([CH2:30][OH:31])[O:27][N:26]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:32]=[C:33]([C:36]([F:39])([F:38])[F:37])[CH:34]=[CH:35][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[I:40]N1C(=O)CCC1=O.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[N:29]=[C:28]([CH2:30][OH:31])[O:27][N:26]=4)[CH:23]=[C:24]([I:40])[C:19]=3[NH:18][C:17]3[N:32]=[C:33]([C:36]([F:38])([F:37])[F:39])[CH:34]=[CH:35][C:16]=3[CH2:15]2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(-c4noc(CO)n4)cc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3c(I)cc(-c4noc(CO)n4)cc32)cc1
Reaction time: 2 h

Procedure:
To a solution of {3-[6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-8-yl]-1,2,4-oxadiazol-5-yl}methanol (Example 437, 49 mg, 0.0877 mmol) (1.5 mL) and N-iodosuccinimide (21 mg) in DCM at 0° C. was added trifluoroacetic acid (30 mg, 0.263 mmol). After stirring for 2 h, the reaction was quenched with 10% aqueous Na2S2O3 and the product was extracted with EtOAc. The combined extracts were washed with water, brine, dried (MgSO4) and concentrated. The residue was purified by SiO2 column chromatography, eluting with 50% EtOAc in hexanes, to provide the title compound. LC/MS: m/e 586.0 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 8.55 (1H, d, J=1.8 Hz), 8.32 (1H, d, J=1.8 Hz), 7.64 (1H, d, J=7.6 Hz), 7.28 (1H, s), 7.20 (1H, J=7.5 Hz), 7.13 (2H, J=8.4 Hz), 6.86 (2H, J=8.5 Hz), 5.02 (2H, s), 4.30-5.0 (2H, br), 2.75 (1H, s br), 1.30 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:24]1[CH2:23][CH2:22][CH2:21][CH:20]([CH2:19][CH2:18][CH2:17][CH2:16][NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)[CH2:26][CH2:25]1
Reactant: BrCCCCC1CCCCCC1
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)C=Cc1ccc(NCCCCC2CCCCCC2)cc1

Procedure:
A mixture of ethyl p-aminocinnamate, 5.9 g. 4-bromobutylcycloheptane and one equivalent of anhydrous powdered potassium carbonate in 50 ml. hexamethylphosphoramide is heated for 20 hours at 60° C. The mixture is then cooled, diluted with water and extracted with ether. The combined ether extracts are dried, filtered and evaporated. Crystallization from acetonitrile provides the title compound as white crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:36].C(O)C.C(=O)([O-])[O-].[NH4+:44].[NH4+]>ClCCl.C(O)C>[ClH:36].[ClH:36].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:44])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: [NH4+]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 90 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)amide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 90% of theory, C27H28N6O3 (484.6); Rf value: 0.17 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=485; (M+2H)++=243; (M+H+Na)++=254.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[C:4]([NH2:11])[N:3]=1.[N:12]([O-])=[O:13].[Na+]>C(O)(=O)C.O>[N:12]([C:5]1[C:6]([O:8][CH2:9][CH3:10])=[N:7][C:2]([NH2:1])=[N:3][C:4]=1[NH2:11])=[O:13]
Reactant: CCOc1cc(N)nc(N)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOc1nc(N)nc(N)c1N=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
To a solution of the compound of example 54 (6.13 g, 39.8 mmoles) in 20% aqueous acetic acid (57 ml) was added dropwise a solution of NaNO2 (3.29 g) in water (13 ml) at 80° C. A pink precipitate was formed which was stirred at 80° C. for an additional 2 hours. The reaction mixture was cooled down in the refrigerator overnight and the resulting precipitate was filtered off, yielding the title compound as a pink powder (4.98 g, yield 68%). Spectral data are identical with those described e.g. by W. Pfleiderer et al. in Chem. Ber. (1961) 94, 12.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[S:7][CH:8]=[CH:9][N:10]=2)=O)[CH2:3][CH2:2]1.[BH3-]C#[N:13].[Na+].[OH-].[Na+]>CO>[CH:1]1([CH:4]([C:6]2[S:7][CH:8]=[CH:9][N:10]=2)[NH2:13])[CH2:3][CH2:2]1
Reactant: O=C(c1nccs1)C1CC1
Reactant: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(c1nccs1)C1CC1
Yield: 54 %

Procedure:
The title compound was synthesized according to General Method F, utilizing cyclopropyl(thiazol-2-yl)methanone (0.28 g, 1.8 mmol), NH4OAc (1.7 g, 22 mmol), NaCNBH3 (0.46 g, 7.3 mmol), and MeOH (30 mL). Aq. NaOH (2 M, 15 mL) was added and the product was extracted into EtOAc (3×40 mL). The combined EtOAc layer was dried (MgSO4), filtered, concentrated to dryness. Purification by flash chromatography (Biotage Isolera, 25 g HP-SIL, 60-100% EtOAc in hexanes) gave the title compound as a yellow oil (0.15 g, 55% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.63 (d, J=2.8 Hz, 1H), 7.18 (d, J=2.8 Hz, 1H), 3.50 (d, J=8.5 Hz, 1H), 2.35 (br. s., 2H), 1.03-1.16 (m, 1H), 0.48-0.63 (m, 2H), 0.26-0.47 (m, 2H); MS ESI 138.0 [M-NH2]+, calcd for [C7H10N2S—NH2]+138.0.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]1[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[C:27]([CH:33]([CH3:37])[C:34]([OH:36])=[O:35])[CH:26]=1)[CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][CH2:39]O>S(=O)(=O)(O)O>[CH2:38]([O:35][C:34](=[O:36])[CH:33]([C:27]1[CH:26]=[C:25]([C:16]2[CH:17]=[CH:18][C:19]([C:21]([F:23])([F:24])[F:22])=[CH:20][C:15]=2[CH2:14][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][CH3:13])[C:30]([O:31][CH3:32])=[CH:29][CH:28]=1)[CH3:37])[CH3:39]
Reactant: CCO
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C(=O)O)ccc1OC)C(=O)OCc1ccccc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
2-{2′-[(Benzyloxycarbonyl-ethyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-propionic acid (0.058 g, 0.11 mmol) in EtOH (3 mL) was treated with sulfuric acid (2 drops) at 70° C. for 1.5 hours to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]([CH:14]=O)=[CH:4][CH:3]=1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]([CH:14]=[N:17][OH:18])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-n2c(Cl)ccc2C=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-n2c(Cl)ccc2C=NO)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 115.4 %

Procedure:
A mixture of 5-chloro-1-(4-methylphenyl)pyrrole-2-carbaldehyde (365 mg), hydroxylamine hydrochloride (173 mg), and sodium acetate (204 mg) in 60% aqueous ethanol (6 ml) was stirred at 60° C. for one hour. The mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate. The mixture was washed with water, dried, and concentrated in vacuo to give a residue (450 mg) of 5-chloro-1-(4-methylphenyl)pyrrole-2-carbaldehyde oxime. A mixture of the residue and sodium acetate (30 mg) in acetic anhydride (5 ml) was stirred at 160° C. for one and half hours under nitrogen atmosphere. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluted by ethyl acetate:n-hexane =1/15) to yield 5-chloro-1-(4-methylphenyl)pyrrole-2-carbonitrile (325 mg) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:30][CH2:31][CH2:32]O.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:30][CH2:31][CH2:32][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Oc1cccc2[nH]ccc12
Reactant: OCCCl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClCCOc1cccc2[nH]ccc12
Temperature: 23 °C
Reaction time: 20 h
Yield: 39 %

Procedure:
To 2.0 g (1.5 mmol) 4-hydroxyindole in 50 mL THF at 0° C. is added 6.3 g (24 mmol) Ph3P, 1.51 mL (1.81 g, 22.53 mmol) 2-chloroethanol and 3.78 mL (4.19 g, 24.03 mmol) diethylazodicarboxylate. After stirring at 23° C. for 20 h, the dark reaction mixture is evaporated to a black oil. Diethyl ether (30 mL) is added, the dark solution stirred on a magnetic stir plate, and 200 mL hexanes is added (to precipitate Ph3PO). After stirring at 23° C. for 30 min, the mixture is filtered and the filtrate evaporated to a light yellow oil. Flash chromatography on SiO2 gel, eluting with hexanes/EtOAc (8/1 to 4/1), gives 1.13 g (5.78 mmol, a 39% yield) of the title compound as an off-white solid. MS (ES) m/z 196 (MH)+.
Reaction SMILES: COC1C=CC(C[S:8][CH2:9][CH:10]2[CH2:15][CH:14]([CH2:16][S:17]CC3C=CC(OC)=CC=3)[O:13][C:11]2=[O:12])=CC=1.N>CO.C1COCC1>[SH:8][CH2:9][CH:10]1[CH2:15][CH:14]([CH2:16][SH:17])[O:13][C:11]1=[O:12]
Reactant: COc1ccc(CSCC2CC(CSCc3ccc(OC)cc3)C(=O)O2)cc1
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: O=C1OC(CS)CC1CS
Temperature: 25 °C
Reaction time: 8 h
Yield: 230.9 %

Procedure:
Into a solution of 2,4-bis(4-methoxybenzylthiomethyl)-4-butanolide (mixture of cis and trans forms, 2.40 g) in a mixture of methanol (30 ml) and THF (10 ml), ammonia gas was bubbled for 30 minutes under ice-cooling. The mixture was stirred overnight at room temperature and concentrated in vacuo. The oily residue was purified by silica gel column chromatography to give 2.36 g (94%) of the following compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=2)=[CH:15][CH:14]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Product: O=[N+]([O-])c1cc(OCc2ccc(Cl)cc2)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 1-chloro-4-brommethyl benzene using the conditions described in Example 237C to provide 4-(4-chloro-benzyloxy)-1-chloro-2-nitro-benzene which was treated sequentially using the procedures from Examples 237D and 237E to provide the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][NH:12][CH2:13][CH2:14][N:15]([C:17]3[S:21][N:20]=[C:19]([N:22]4[CH:26]=[CH:25][N:24]=[CH:23]4)[N:18]=3)[CH3:16])=[CH:9][C:4]=2[O:3][CH2:2]1.[C:27](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][N:12]([CH3:27])[CH2:13][CH2:14][N:15]([C:17]3[S:21][N:20]=[C:19]([N:22]4[CH:26]=[CH:25][N:24]=[CH:23]4)[N:18]=3)[CH3:16])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN(CCNCCc1ccc2c(c1)OCO2)c1nc(-n2ccnc2)ns1
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CN(CCc1ccc2c(c1)OCO2)CCN(C)c1nc(-n2ccnc2)ns1
Temperature: 25 °C

Procedure:
N′-(2-Benzo[1,3]dioxol-5-yl-ethyl)-N-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-N-methyl-ethane-1,2-diamine (438 mg, 1.20 mmol) was dissolved in methanol (8 mL) and acetic acid (1.0 mL) and stirred at room temperature for 15 minutes. After this period, the sodium triacetoxyborohydride (750 mg, 3.60 mmol) was added and the reaction was allowed to stir at room temperature After this period, the reaction mixture was concentrated down under vacuum. The crude material was purified by Prep LCMS and the fractions were concentrated down. This material was then neutralized with 1M NaOH and extracted with DCM to afford 303 mg of N-(2-benzo[1,3]dioxol-5-yl-ethyl)-N′-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-N,N′-dimethyl-ethane-1,2-diamine. [M+H]+ 387.31; 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.62 (s, 1H), 7.05 (s, 1H), 6.66-6.53 (m, 3H), 5.85 (s, 1H), 3.12 (m, 3H), 2.68-2.60 (m, 6H), 2.31 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]12[CH2:14][CH:9]3[S:10][CH:11]([S:13][CH:7]([S:8]3)[CH2:6]1)[CH2:12]2)=O.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C>CCCCCC>[OH:2][CH2:3][C:5]12[CH2:12][CH:11]3[S:10][CH:9]([S:8][CH:7]([S:13]3)[CH2:6]1)[CH2:14]2
Reactant: COC(=O)C12CC3SC(C1)SC(C2)S3
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: OCC12CC3SC(C1)SC(C2)S3
Temperature: 0 °C
Yield: 99 %

Procedure:
A flame-dried, 25 mL round-bottomed flask equipped with a Teflon-coated magnetic bar and a septum with an argon inlet was charged with 270 mg (1.10 mmol) of 2,4,9-Trithia-tricyclo[3.3.1.13,7]decane-7-carboxylic acid methyl ester and 5 mL of dry toluene. Cooled by an ice bath, the solution was charged with 1.60 mL of 1.5 M (2.3 mmol) diisobutyl aluminum hydride in hexane. The solution was stirred at 0° C. until the complete consumption of the starting material was observed (monitored by TLC). The solution was quenched by 2 mL of methanol and allowed to warm to the ambient temperature. The filtration through a celite filter cake gave 240 mg (97%) of 7-hydroxymethyl-2,4,9-trithiaadamantane.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)#[N:2].[CH3:10][NH2:11].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(Cl)Cl>[CH3:10][NH:11][CH:6]1[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]1
Reactant: N#CC1CCC(=O)CC1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC1CCC(C#N)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89 %

Procedure:
To a solution of 4-cyanocyclohexanone (200 mg, 1.626 mmol) and CH3NH2 (2M in THF) (0.8 mL, 1.626 mmol) in THF:CH2Cl2 (1:1) (4.0 mL) at 0° C. was added NaBH(OAc)3 (689 mg, 3.252 mmol) and the resulting mixture was stirred at rt for 48 h. Subsequently, the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate, washed with water, brine, dried over Na2SO4 and concentrated to afford 200 mg (89%) of 4-(methylamino)cyclohexanecarbonitrile as a white solid. 1H NMR (400 MHz, DMSO-d6) 2.91 & 2.61 (two signals, 1H) 2.23-2.24 (m, 3H) 1.02-1.99 (m, 9H); ELSD/MS (Method 3) (m/z): [M+H]+ 139.06.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:13][C:14]2([NH:17]C(=O)OC(C)(C)C)[CH2:16][CH2:15]2)[CH2:10][CH2:11][OH:12])=[CH:4][C:3]=1[C:25]([NH:27][CH2:28][C:29]12[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[CH2:30]1)[CH2:36]2)=[O:26].Cl.N>CO.O1CCOCC1>[NH2:17][C:14]1([CH2:13][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:4]=2)[C:25]([NH:27][CH2:28][C:29]23[CH2:30][CH:31]4[CH2:32][CH:33]([CH2:34][CH:35]([CH2:37]4)[CH2:36]2)[CH2:38]3)=[O:26])[CH2:10][CH2:11][OH:12])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)NC1(CN(CCO)Cc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: CO
Product: NC1(CN(CCO)Cc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.3 %

Procedure:
[1-[[[[4-Chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]-methyl](2-hydroxyethyl)amino]methyl]cyclopropyl]-carbamic acid, 1,1-dimethylethyl ester (Example 71d, 0.302 g) was dissolved in methanol (10 ml) and 4N HCl in dioxane (10 ml) was added. The mixture was stirred for 14 h at room temperature, then poured into 25% aqueous ammonia solution and concentrated under reduced pressure to give the free base. This was purified by column chromatography over silica (eluting with 19:1:0.1 dichloromethane/methanol/ammonia) to afford the title compound as an oil (0.230 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](S(C)(=O)=O)[N:3]=1.[C:23]1([OH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([O:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1
Reactant: Oc1ccccc1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(Oc2ccccc2)nc(N)nc1-c1ccc2c(c1)OCO2

Procedure:
From 2-amino-4-benzo[1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, phenol and DBU in DME. ES-MS m/e (%): 333 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:8]2=[O:23])[S:5][CH:6]=1.[Br:24]N1C(=O)CCC1=O>C(#N)C>[Br:24][C:6]1[S:5][C:4]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[C:8]2=[O:23])=[N:3][C:2]=1[CH3:1]
Reactant: Cc1csc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1Br
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 1-(4-methylthiazol-2-yl)-3-(4-(trifluoromethyl)benzyl)-imidazolidin-2-one (1.40 g, 4.10 mmol) in acetonitrile (40 mL) was added N-bromosuccinimide (0.73 g, 4.10 mmol). The reaction mixture was stirred at 0 for 1 h, quenched with 10% sodium thiosulfate solution (10 mL), diluted with ethyl acetate (200 mL), washed with water and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound as a colorless solid in 69% yield (1.20 g): mp 107-108° C. (ethyl acetate/hexanes): 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J=7.8 Hz, 2H), 7.39 (d, J=7.8 Hz, 2H), 4.51 (s, 2H), 4.08-3.99 (m, 2H), 3.47-3.41 (m, 2H), 2.25 (s, 3H): MS (ES+) m/z 420.1 (M+1), 422.1 (M+1).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([CH:29]3[CH2:31][C:30]3([F:33])[F:32])=[O:28])[CH:24]=2)[N:19](C2CCCCO2)[N:18]=1>C(Cl)Cl>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([CH:29]3[CH2:31][C:30]3([F:33])[F:32])=[O:28])[CH:24]=2)[NH:19][N:18]=1
Reactant: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)C1CC1(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1)C1CC1(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.8 %

Procedure:
TFA (0.1 mL, 1.587 mmol) was added to a solution of N-(3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2,2-difluorocyclopropanecarboxamide (10 mg, 0.023 mmol) in CH2Cl2 (4 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (6 mg). 1H NMR (400 MHz, CD3OD): δ 8.69 (s, 1H), 7.82 (m, 2H), 7.70 (d, 1H, J=8.8 Hz), 7.56-7.50 (m, 3H), 2.82-2.73 (m, 1H), 2.21-2.12 (m, 1H), 1.94-1.85 (m, 1H); ESI-MS [M+H]+: 354.2.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([F:26])=[CH:10][N:11]3[C:16]([C:17]=2[CH3:18])=[C:15]([CH:19]2[CH2:21][CH2:20]2)[CH:14]=[C:13]([C:22]([OH:24])=[O:23])[C:12]3=[O:25])[CH2:4]1.C([O-])(=O)C.[Na+].CO[C:34]1(OC)[CH2:38][CH2:37][CH2:36]O1>C(OCC)(=O)C>[CH:19]1([C:15]2[CH:14]=[C:13]([C:22]([OH:24])=[O:23])[C:12](=[O:25])[N:11]3[C:16]=2[C:17]([CH3:18])=[C:8]([N:5]2[CH2:6][CH2:7][C@H:3]([N:2]4[CH:34]=[CH:38][CH:37]=[CH:36]4)[CH2:4]2)[C:9]([F:26])=[CH:10]3)[CH2:20][CH2:21]1
Reactant: Cc1c(N2CC[C@H](N)C2)c(F)cn2c(=O)c(C(=O)O)cc(C3CC3)c12
Reactant: COC1(OC)CCCO1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1c(N2CC[C@H](n3cccc3)C2)c(F)cn2c(=O)c(C(=O)O)cc(C3CC3)c12
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
A mixture of 25 mg 8-(3(S)-aminopyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride (from Example 257) and 40 mg of sodium acetate in 0.7 mL of ethyl acetate was heated to 100° C. To this solution was added 0.009 mL of dimethoxytetrahydrofuran dropwise, and the reaction was stirred at 110° C. for 5 min, then quenched by addition of water. The mixture was extracted twice with methylene chloride, and the extract was washed with water, dried over MgSO4 and concentrated. The residue was purified by preparative TLC, eluting with 100:10 chloroform:methanol, to give 13.6 mg of the title product as a yellow solid after removal of the solvent. MS 395 (M-Cl)+. 1H NMR (CDCl3) δ: 0.67 (m, 2H), 1.00 (m, 2H), 2.20 (m, 1H), 2.46 (m, 1H), 2.56 (m, 1H), 2.66 (s, 3H), 3.89 (m, 1H), 3.99 (m, 2H0, 4.15 (m, 1H), 4.86 (m, 1H), 6.23 (t, 2H, J=2 Hz), 6.79 (t, 2H, J=2 hz), 8.32 (s, 1H), 9.15 (d, 1H, J=10 Hz), 13.83 (br, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[C:36]([CH3:41])=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[C:36]([CH3:41])=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ncccc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Product: Cc1ncccc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)ccc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(2-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K5) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow oil (322 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[F:12])(=[O:3])[CH3:2].[CH3:13][C:14]1[CH:15]=[C:16]([NH:23][C:24](=[O:30])[C@:25]([OH:29])([CH3:28])[CH2:26]Br)[CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21]>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:28][C@@:25]([OH:29])([CH3:26])[C:24]([NH:23][C:16]2[CH:17]=[CH:18][C:19]([N+:20]([O-:22])=[O:21])=[C:14]([CH3:13])[CH:15]=2)=[O:30])=[CH:7][C:6]=1[F:12])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(O)cc1F
Reactant: Cc1cc(NC(=O)[C@@](C)(O)CBr)ccc1[N+](=O)[O-]
Product: CC(=O)Nc1ccc(OC[C@](C)(O)C(=O)Nc2ccc([N+](=O)[O-])c(C)c2)cc1F

Procedure:
(2S)-3-(4-Acetylamino-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared according to the method B as described in Example 3e starting from 4-acetylamino-3-fluorophenol and N-[3-methyl-4-(nitro)phenyl]-(2R)-3-bromo-2-hydroxy-2-methylpropanamide. 1H NMR (DMSO-d6): 1.42 (3H, s), 2.02 (3H, s), 2.53 (3H, s), 3.97 (1H, d, J=9.7 Hz), 4.21 (1H, d, J=9.7 Hz), 6.23 (1H, bs), 6.72 (1H, m), 6.90 (1H, m), 7.56 (1H, m), 7.88 (1H, dd, J=9.0 Hz and 2.2 Hz), 7.93 (1H, d, J=2.2 Hz), 8.03 (1H, d, J=9.0 Hz), 9.51 (1H, s), 10.15 (1H, bs).