Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]([C:21]3[CH:22]=[N:23][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:25][CH:26]=3)=[N:19][CH:20]=2)=[C:11]([F:40])[C:10]=1[F:41])C1C=CC=CC=1>C1COCC1>[F:40][C:11]1[C:10]([F:41])=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=1[C:15]1[CH:20]=[N:19][C:18]([C:21]2[CH:22]=[N:23][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:25][CH:26]=2)=[N:17][CH:16]=1
Reactant: CCCCCCCCCCCCOc1ccc(-c2ncc(-c3ccc(OCc4ccccc4)c(F)c3F)cn2)cn1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOc1ccc(-c2ncc(-c3ccc(O)c(F)c3F)cn2)cn1
Yield: 59.6 %

Procedure:
The hydrogenation of 2.5 mmol of 5-(4-benzyloxy-2,3-difluorophenyl)-2-(6-dodecyloxypyridin-3-yl)pyrimidine in 50 ml of THF is carried out analogously to the procedure indicated for precursor 14, giving 0.7 g (60%) of a colorless solid, m.p. 111-118° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.4 %

Procedure:
A mixture of 22.16 g (0.186 mol) of 4-cyanophenol, 32.07 g (0.192 mol) of ethyl bromoacetate, 27.6 g (0.199 mol) of K2CO3 and acetone (250 ml) is stirred at room temperature for 12 hours. After filtration, the solvent is evaporated off under vacuum and the residue is partitioned between an organic phase (ethyl acetate) and an aqueous phase (water). The organic layer is dried (MgSO4) and concentrated under vacuum to give 36.42 g (95%) of ethyl 4-cyanophenoxyacetate (white solid, melting point: 49-50° C.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:32]=[CH:31][C:11]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH2:23][CH2:22][C:21]4=[O:30])[CH2:16][CH2:15]3)=[O:13])=[C:10]([O:33][CH3:34])[CH:9]=2)[CH2:3][CH2:2]1.[C:35](OC(=O)C)(=[O:37])[CH3:36].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:35]([N:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:32]=[CH:31][C:11]([C:12]([N:14]3[CH2:15][CH2:16][CH:17]([N:20]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH2:23][CH2:22][C:21]4=[O:30])[CH2:18][CH2:19]3)=[O:13])=[C:10]([O:33][CH3:34])[CH:9]=2)[CH2:3][CH2:2]1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(OC2CCNCC2)ccc1C(=O)N1CCC(N2C(=O)CCc3ccccc32)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC2CCN(C(C)=O)CC2)ccc1C(=O)N1CCC(N2C(=O)CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(1-(4-(4-piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-3,4-dihydro-2(1H)-quinolinone (150 mg, 0.27 mmol) from Example 190 in methylene chloride (10 mL) was added acetic anhydride (0.050 mL, 0.54 mmol) and DIEA (0.050 mL, 0.27 mmol) and the reaction was stirred at ambient temperature for 2 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with water (2×) and brine, and was dried over anhydrous MgSO4. The solvent was removed under reduced pressure to give the title compound as an amorphous solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([S:26](=[O:33])(=[O:32])[N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:14][C:10]=1[C:11](Cl)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:34][C:35]1[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=1[NH2:37]>>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15]([S:26](=[O:32])(=[O:33])[N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:14][C:10]=1[C:11]([NH:37][C:36]1[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=1[Cl:34])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1Cl
Reactant: CCCN(C)S(=O)(=O)c1cc(C(=O)Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Product: CCCN(C)S(=O)(=O)c1cc(C(=O)Nc2ccccc2Cl)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
2.10 Reaction of 2,4-dibenzyloxy-5-(N-methyl-N-propylsulfamoyl)benzoyl chloride with 2-chloroaniline gives the compound 2,4-dibenzyloxy-5-(N-methyl-N-propylsulfamoyl)-N-(2-chlorophenyl)benzamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](OC2C(F)=C(F)C=C(F)C=2F)=[O:29])([C:16]2[CH:21]=CC=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH:41]1[C:45]2=[C:46]3[C:50](=[CH:51][CH:52]=[C:44]2[NH:43][CH:42]=1)[NH:49][CH:48]([C:53]([O:55][CH3:56])=[O:54])[CH2:47]3.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([N:43]2[C:44]3[C:45](=[C:46]4[C:50](=[CH:51][CH:52]=3)[NH:49][CH:48]([C:53]([O:55][CH3:56])=[O:54])[CH2:47]4)[CH:41]=[CH:42]2)=[O:29])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[CH2:21])[CH:17]=[CH2:18])=[CH:7][CH:8]=1
Reactant: COC(=O)C1Cc2c(ccc3[nH]ccc23)N1
Reactant: COc1ccc(C(NCCCCCC(=O)Oc2c(F)c(F)cc(F)c2F)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=C)C(NCCCCCC(=O)n1ccc2c3c(ccc21)NC(C(=O)OC)C3)(c1ccccc1)c1ccc(OC)cc1
Reaction time: 15 h
Yield: 80.3 %

Procedure:
A solution of 7 (0.6 g, 1.1 mmol) was combined with 0.24 g (1.2 mmol) methyl pyrrolo[4,5-e]indoline-7-carboxylate (Boger et al, supra) and 0.1 ml triethylamine in 5 ml of anhydrous CH2Cl2. The mixture was kept at room temperature for 15 h and concentrated under vacuum. The resultant solid, which was the desired product, was washed with 50% ethyl acetate/50%hexane to remove unreacted starting materials and 2,3,5,6-tetrafluorophenol. Drying under vacuum afforded 0.51 g (77%) of the title compound as a pale-yellow, crystalline solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:31]=[CH:30][C:9]([C:10]([NH:12][NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]3)=[CH:17][CH:16]=2)=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]1[CH:31]=[CH:30][C:9]([C:10]2[S:41][C:14]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]4)=[CH:17][CH:16]=3)=[N:13][N:12]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C(=O)NNC(=O)c2ccc(N3CCC(N(C)C)C3)cc2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCCCOc1ccc(-c2nnc(-c3ccc(N4CCC(N(C)C)C4)cc3)s2)cc1

Procedure:
A mixture of N′-(4-butoxybenzoyl)-4-(3-dimethylaminopyrrolidin-1-yl)benzo-hydrazide (100 mg), Lawesson's reagent (191 mg) and toluene (5 ml) was boiled under reflux for 4 hours. Volatiles were removed, and the residue was purified by preparative HPLC. The product with the molecular weight of 422.60 (C24H30N4OS) was obtained in this way; MS (ESI): 423 (M+H+).
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[N:16]1([CH2:20][C@@H:21]([NH2:29])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH2:19][CH2:18][CH2:17]1>>[N:16]1([CH2:20][C@@H:21]([NH:29][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: N[C@H](CN1CCC1)c1cccc(F)c1
Agent: Cl
Product: NC(=O)c1ccnc2c(N[C@H](CN3CCC3)c3cccc(F)c3)ncnc12

Procedure:
Compound 68 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with (S)-2-azetidin-1-yl-1-(3-fluoro-phenyl)-ethylamine hydrochloride to give the title compound. LC/MS [367 (M+H)]1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.07 (d, 1H), 9.01 (d, 1H), 8.56 (s, 1H), 8.39 (d, 1H), 8.17 (s, 1H), 7.34 (m, 3H), 7.07 (m, 1H), 5.36 (m, 1H), 3.13 (m, 4H), 2.86 (m, 1H), 1.96 (m, 2H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11](OCC)=[O:12].[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O>C1COCC1>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[CH2:10][CH2:11][OH:12]
Reactant: CCOC(=O)CC1Cc2ccccc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCCC1Cc2ccccc2C1
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
A solution of ester 148 (68.8 g, 337 mmol) in dry THF (250 mL) was added to dropwise to a suspension of LiAlH4 (20.0 g, 501 mmol) in dry THF (500 mL) at 0° C. and the resulting mixture was stirred for 1.5 h. EtOAc was added to quench excess LiAlH4 and then aqueous H2SO4 solution (10%, 1 L) was added and the organic fraction separated. The aqueous solution was extracted with EtOAc (3×250 mL), and the combined organic fraction dried and the solvent evaporated to give alcohol 149 (54.5 g, 100%) (lit. Tanaka, et. al., J. Med. Chem. 1994, 37, 2071-2078) as a yellow oil: 1H NMR δ 7.16-7.25 (m, 2H, Harom), 7.09-7.14 (m, 2H, Harom), 3.74 (t, J=6.8 Hz, 2H, CH2O), 3.03-3.10 (m, 2H, CH2), 2.53-2.66 (m, 3H, CH2, CH), 1.82 (q, J=6.8 Hz, 2H, CH2), OH not observed.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:7]2.[C:20](Cl)(Cl)=[O:21].C(N(CC)CC)C>C1COCC1>[O:21]=[C:20]1[N:10]2[C:11]3[C:6]([CH2:7][CH:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:9]2)=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1]1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)OC(=O)NC1CNc2c(N)cccc2C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1Cc2cccc3[nH]c(=O)n(c23)C1
Reaction time: 0.08 h

Procedure:
t-Butyl (8-amino-1,2,3,4-tetrahydro-3-quinolyl)carbamate (2.70 g) was dissolved in THF (100 mL) and stirred while a solution of phosgene in THF (20.7 mL of 0.40 M, 0.093 mol) was added. After 5 minutes, triethylamine (2.08 g, 0.020 mol) was added and the solution stirred for an additional 10 minutes. The THF was removed under reduced pressure and the material was partitioned between chloroform (250 mL) and water (20 mL). The chloroform was washed with 4N sodium hydroxide (5 mL) and evaporated. The crude material was combined with that of an earlier reaction (0.002 mol scale) and purified by chromatography on silica gel in 1% methanol:chloroform to give 2.28 g of product. Crystallization from methanol:ether (1:1) gave 1.60 g (54%) white solid, mp 235°-236° C. Anal. Calcd. for C15H19N3O3 : C, 62.26; H, 6.62; N, 14.52. Found: C, 61.65 ; H, 6.94; N, 14.23.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[CH:19][C:20]([CH:21]=O)=[C:14]3[N:13]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[NH:23]1[CH2:29][C:27](=[O:28])[NH:26][C:24]1=[O:25].N1CCCCC1>CCO>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[CH:19][C:20]([CH:21]=[C:29]4[NH:23][C:24](=[O:25])[NH:26][C:27]4=[O:28])=[C:14]3[N:13]=2)=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(Nc2ccn3ncc(C=O)c3n2)cc1
Reactant: O=C1CNC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)Oc1ccc(Nc2ccn3ncc(C=C4NC(=O)NC4=O)c3n2)cc1
Temperature: 70 °C

Procedure:
To 5-(4-isopropoxyphenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (70 mg, 0.236 mmol) in EtOH was added hydantoin (23.6 mg, 0.236 mmol) and piperidine (23.9 μL, 0.236 mmol). The mixture was heated at 70° C. overnight. The solid formed was isolated by filtration and air dried to yield 5-((5-(4-isopropoxyphenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=379)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.Cl[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[CH2:7]1[C:8]2[C:4](=[CH:3][C:2]([O:1][CH2:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Oc1ccc2c(c1)CCC2
Reactant: O=C(CCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(COc1ccc2c(c1)C=CC2)c1ccccc1

Procedure:
Using the method of Example 1, step A, 5-hydroxyindane is reacted with α-chloroacetophenone in benzene in the presence of sodium carbonate to provide α-(5-indenoxy)acetophenone as a yellow solid.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[N:13](CC3C=NC=CC=3)[CH2:12][C@@H:11]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]([S:28]([C:31]3SC=[CH:34][CH:35]=3)(=[O:30])=[O:29])[CH2:9][C:8]=2[CH:36]=1)#[N:3].[C:37]1(C)[C:38](S(Cl)(=O)=O)=CC=[CH:41][CH:42]=1>>[CH3:41][C:42]1[CH:37]=[CH:38][C:31]([S:28]([N:10]2[CH2:9][C:8]3[CH:36]=[C:4]([C:2]#[N:3])[CH:5]=[CH:6][C:7]=3[NH:13][CH2:12][C@H:11]2[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:29])=[O:30])=[CH:35][CH:34]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1cccs1)[C@H](Cc1ccccc1)CN2Cc1cccnc1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)N2Cc3cc(C#N)ccc3NC[C@H]2Cc2ccccc2)cc1

Procedure:
The title compound was prepared from Compound A of Example 23 and toluenesulfonyl chloride following the procedure of Compound B of Example 23.
Reaction SMILES: C([O-])([O-])=[O:2].[K+].[K+].OO.[C:9]([C:11]1[CH:12]=[C:13]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1)[C:19]1[CH2:18][CH2:17][CH:16]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH2:15][C:14]2=1)#[N:10]>CS(C)=O.O>[F:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][N:20]1[C:21]2[CH:22]=[CH:23][C:11]([C:9]([NH2:10])=[O:2])=[CH:12][C:13]=2[C:14]2[CH2:15][CH:16]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH2:17][CH2:18][C:19]1=2
Reactant: O=C([O-])[O-]
Reactant: CC(C)C(=O)NC1CCc2c(c3cc(C#N)ccc3n2Cc2cccc(F)c2)C1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)C(=O)NC1CCc2c(c3cc(C(N)=O)ccc3n2Cc2cccc(F)c2)C1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Add K2CO3 (0.26 g, 1.93 mmol) and 30% H2O2 (2.0 mL) portionwise to N-(6-cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl)isobutyramide (Example 51) (1.50 g, 3.85 mmol) in DMSO while cooling in an ice bath. Stir for 18 h and add more H2O2 with warming to 50° C. if needed to facilitate complete reaction. Dilute with water and collect the precipitate by filtration (1.45 g, 92%). Recrystallize from EtOAc to yield a white solid. MS (ES): m/z 408 (M+1); m.p.=192-194° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=2[F:19])[CH:5]=[N:4][N:3]=[N:2]1>C1COCC1.[Pd]>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=2[F:19])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: O=[N+]([O-])c1ccc(NCCCn2cnnn2)c(F)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(NCCCn2cnnn2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
To a solution of N-(3-(1H-tetrazol-1-yl)propyl)-2-fluoro-4-nitroaniline (0.36 g, 1.35 mmol) in THF (10 mL) was added catalyst Pd/C (0.12 g). The reaction mixture was stirred at rt under H2 overnight. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as red oil (0.20 g, 63%).
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][CH:9]=1)[CH3:7])C.[OH-].[K+]>C(O)C>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]([CH:6]([CH3:7])[CH2:5][C:4]([OH:22])=[O:3])=[CH:9][CH:10]=1
Reactant: CCOC(=O)CC(C)c1ccc(-c2ccc(F)cc2F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
3.04 g. of 3-(2',4'-difluoro-4-biphenylyl)butyric acid ethyl ester and 1 g. of KOH in 25 ml. of ethanol are heated under reflux for 2 hours. The mixture is evaporated. The residue is dissolved in water and the solution is washed with ether and acidified to pH 3 with hydrochloric acid and worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:18])[N:11]([CH2:13][C:14]([O:16]C)=[O:15])[CH:12]=2)=[CH:4][CH:3]=1.Br[CH2:20][CH:21]([OH:26])[C:22]([F:25])([F:24])[F:23].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:20][CH:21]([OH:26])[C:22]([F:25])([F:24])[F:23])[C:10](=[O:18])[N:11]([CH2:13][C:14]([OH:16])=[O:15])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: OC(CBr)C(F)(F)F
Reactant: COC(=O)Cn1cc(-c2ccc(Cl)cc2)[nH]c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)Cn1cc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Temperature: 25 °C

Procedure:
A quantity of 1.0 g (3.75 mmol) of methyl [4-(4-chlorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]acetate (prepared according to WO 2007/134862 Example 323A) was dissolved with 796 mg (4.13 mmol) of 3-bromo-1,1,1-trifluoropropan-2-ol in 50 ml of acetone, 1.47 g (4.50 mmol) of caesium carbonate were added at RT, and the mixture was heated under reflux for 16 h. For work-up, it was cooled to RT and admixed with 50 ml of water. It was neutralised by addition of 1M hydrochloric acid and extracted with three times 50 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC [Method 19]. This gave 171 mg (13% of theory) of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1([CH3:25])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:22]2[CH2:23][CH2:24][C:19]([O:18][CH3:17])([CH3:25])[CH2:20][CH2:21]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: COC1(C)CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC1(C)CCN(Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.4 %

Procedure:
A mixture of 4-bromobenzyl bromide (0.44 g, 1.74 mmol), triethylamine (0.37 mL, 2.61 mmol) and 4-methoxy-4-methylpiperidine (0.45 g, 3.49 mmol)in THF (10 mL) was stirred at ambient temperature for 16 h. The solvent was evaporated and the resultant residue was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound as a yellow oil (0.50 g, 96%). 1H NMR (CDCl3, 300 MHz): 7.45-7.39 (m, 2H), 7.22-7.17 (m, 2H), 3.44 (s, 2H), 3.17 (s, 3H), 2.52-2.42 (m, 2H), 2.36-2.25 (m, 2H), 1.79-1.70 (m, 2H), 1.59-1.47 (m, 2H), 1.13 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][C:10](=[O:25])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[CH:19][N:20](C)C)=[C:14]([C:23]#[N:24])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].N[C:28]1[CH:42]=[CH:41][C:31]([C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:33])=[CH:30][CH:29]=1>C(O)(=O)C.C(=O)(O)[O-].[Na+]>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][C:10](=[O:25])[NH:11][C:12]1[CH:13]=[C:14]2[C:15](=[CH:16][CH:17]=1)[N:18]=[CH:19][N:20]=[C:23]2[NH:24][C:28]1[CH:29]=[CH:30][C:31]([C:32](=[O:33])[NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:41][CH:42]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=Nc1ccc(NC(=O)CCNC(=O)OC(C)(C)C)cc1C#N
Reactant: Nc1ccc(C(=O)Nc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1ccc2ncnc(Nc3ccc(C(=O)Nc4ccccc4)cc3)c2c1
Yield: 23.9 %

Procedure:
1 g of 2-[3-cyano-4-(dimethylamino-methylene amino)-phenylcarbamoyl]-ethyl-carbamic acid t-butylester (see, Journal of Medicinal Chemistry 2004, 44:2719) dissolved in 6 ml of acetic acid was reacted with 650 mg of 4-amino-N-phenyl-benzamide at 60° C. for 3 hours, and the resulting residue was stirred in 100 ml of saturated aqueous sodium bicarbonate solution at room temperature for 30 mins. The reacted solution was extracted with 30 ml of ethylacetate 3 times, dried over anhydrous magnesium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-chloroform:methanol=15:1) to obtain the title compound (350 mg, 25%).
Reaction SMILES: CN1CCCC1.[F:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]2[C:26]([CH3:27])=[N:25][C:18]3[N:19]=[C:20]([S:23][CH3:24])[N:21]=[CH:22][C:17]=3[CH:16]=2)=[CH:10][C:9]=1[NH:28][C:29](=O)[O:30]C(C)=C.Cl.[F:36][C:37]([F:45])([F:44])[C:38]([CH3:43])([CH3:42])[CH2:39][CH2:40][NH2:41]>C1COCC1.CCOC(C)=O>[F:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]2[C:26]([CH3:27])=[N:25][C:18]3[N:19]=[C:20]([S:23][CH3:24])[N:21]=[CH:22][C:17]=3[CH:16]=2)=[CH:10][C:9]=1[NH:28][C:29]([NH:41][CH2:40][CH2:39][C:38]([CH3:43])([CH3:42])[C:37]([F:45])([F:44])[F:36])=[O:30]
Reactant: CC(C)(CCN)C(F)(F)F
Reactant: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(SC)nc3nc2C)c(C)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1ncc2cc(-c3cc(NC(=O)NCCC(C)(C)C(F)(F)F)c(F)cc3C)c(C)nc2n1
Temperature: 65 °C
Yield: 75.1 %

Procedure:
Add 1-methylpyrrolidine (1.214 mL, 11.54 mmol) in a mixture of prop-1-en-2-yl (2-fluoro-4-methyl-5-(7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl)phenyl)carbamate (0.92 g, 2.31 mmol) and 4,4,4-trifluoro-3,3-dimethylbutan-1-amine hydrochloride (0.487 g, 2.54 mmol) in THF (23 mL) and heat at 65° C. for 4 h. Cool the mixture to RT, dilute with EtOAc, wash with brine (2×), dry over MgSO4, concentrate to dryness and purify via silica gel chromatography (0-50% EtOAc/Hexanes) to afford the title compound (860 mg, 75% yield). MS (m/z): 496.2 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][OH:20])[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=2)[CH2:3][CH2:2]1.O[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1>>[CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][O:20][C:22]2[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=2)[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:16])([F:17])[F:15])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1ccc(O)cc1
Reactant: N#Cc1ccc(N(CCO)CC2CC2)cc1C(F)(F)F
Product: N#Cc1ccc(N(CCOc2ccc(C=O)cc2)CC2CC2)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1C from 4-[(cyclopropylmethyl)(2-hydroxyethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-hydroxybenzaldehyde, then used directly for the step below, step B.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[C:15]2[CH2:14][CH2:13][N:12]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[Cl:22].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[C:23]([NH:1][CH2:2][CH2:3][NH:4][C:5]1[C:15]2[CH2:14][CH2:13][N:12]([C:16](=[O:21])[C:17]([F:19])([F:18])[F:20])[CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[Cl:22])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCNc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCNc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1ccccc1

Procedure:
Dissolve 6-(2-amino-ethylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (70 mg, 0.208 mmol) in DCM (4 mL). Add benzoyl chloride (24 μL, 0.208 mmol), and triethylamine (44 μL, 0.312 mmol) and stir at ambient temperature for 24 h under nitrogen atmosphere. Dilute with DCM and add 1M aqueous HCl. Extract the aqueous layer with DCM. Dry the organic layer over MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 7:3 and 1:1) to obtain 6-(2-benzoylamino-ethylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.