Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1.[CH3:10][C:11]([C:14]1[CH:15]=[C:16]([S:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[S:31][CH2:32][C:33](N(C)CCC2C=CC=CN=2)=[O:34])[CH:17]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:19]=1)([CH3:13])[CH3:12]>>[CH3:23][C:20]([C:18]1[CH:17]=[C:16]([S:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[S:31][CH2:32][C:33]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=2)=[O:34])[CH:15]=[C:14]([C:11]([CH3:10])([CH3:12])[CH3:13])[CH:19]=1)([CH3:21])[CH3:22]
Reactant: CN(CCc1ccccn1)C(=O)CS[C@@H]1CCCC[C@H]1Sc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Reactant: Cc1cccc(CN)n1
Product: Cc1cccc(CNC(=O)CS[C@@H]2CCCC[C@H]2Sc2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1

Procedure:
Substituting 2-aminomethyl-6-methylpyridine for the 2-(2-methylaminoethyl)pyridine of Example 16, and following the procedure described therein, gives trans-2-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]cyclohexyl]thio]-N-[(6-methylpyridine-2-yl)methyl]acetamide. ##STR99##
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:24][CH3:25])=[CH:12][C:13]2[O:18][C:17](=[O:19])[C:16]3[CH2:20][CH2:21][CH2:22][C:15]=3[C:14]=2[CH:23]=1)(=O)=O.[C:26]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O)(C)C.C([O-])(=O)/C=C/C([O-])=O>C(O)C>[CH3:25][O:24][C:11]1[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:35]2[CH2:36][CH2:37][CH:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:33][CH2:34]2)=[CH:23][C:14]2[C:15]3[CH2:22][CH2:21][CH2:20][C:16]=3[C:17](=[O:19])[O:18][C:13]=2[CH:12]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCOS(C)(=O)=O)CCC3
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CCO
Solvent: CC(C)O
Product: COc1cc2oc(=O)c3c(c2cc1OCCCN1CCC(c2ccccc2)CC1)CCC3
Yield: 65 %

Procedure:
Method B (60 h at 25° C.); starting materials: 2,3-dihydro-8-[3-(methanesulfonyloxy)propoxy]-7-methoxy-cyclopenta[c][1]-benzopyran-4(1H)-one (example 82) and 4-phenylpiperidine; yield 65%; fusion point 164°-166° C. (from isopropanol). Fumarate: method E; yield 86%; fusion point 195°-198° C. (from ethanol).
Reaction SMILES: C(O[N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([OH:17])=O)C1C=CC=CC=1.[CH3:18][NH2:19]>O1CCCC1>[CH3:18][NH:19][C:15]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][NH:9]1)=[O:17]
Reactant: O=C(O)C1CCCCN1OCc1ccccc1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)C1CCCCN1

Procedure:
The general procedure of Referential Example 131 was repeated through use of N-benzyloxypiperidine-2-carboxylic acid (2.0 g) and 1.0 M methylamine in tetrahydrofuran (4 mL), to thereby give the title compound as an oily product (970 mg, quantitative amount).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][CH:14]([N:20]=[C:21]=[S:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH:12][C:21]([NH:20][CH:14]([CH3:13])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[S:22])(=[O:10])=[O:11]
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Reactant: CCCCCC(C)N=C=S
Agent: Cl
Product: CCCCCC(C)NC(=S)NS(=O)(=O)c1sc(Cl)cc1N
Yield: 43 %

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and 1-methylhexyl isothiocyanate by a procedure analogous to the procedure described in example 3-a; a syrup was obtained (yield 43%), 1H-NMR (DMSO-d6): δ0.85 (t, 3H, CH3), 1.10 (d, 3H, CH3), 1.25 (m, 6H), 1.45 (m, 2H), 4.25 (m, 1H, CH), 6.50 (br, 2H, NH2), 6.65 (s, 1H, H-4), 7.93 (br, 1H, NH), 11.3 (br s, 1H, NH).
Reaction SMILES: [CH3:1][O:2][C:3]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=[O:4].[CH3:15][C@H:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][C@H:16]([CH3:15])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:11])=[CH:8][CH:7]=1)=[O:4]
Reactant: COC(=O)Oc1ccc(C(=O)O)cc1
Reactant: CCCCCC[C@H](C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCC[C@@H](C)OC(=O)c1ccc(OC(=O)OC)cc1

Procedure:
Compound 2 (15.0 g, 77 mmol), (S)-(+)-octan-2-ol (10.0 g, 77 mmol) and diethyl azodicarboxylate (3.4 g, 77 mmol) were dissolved in THF (250 ml) and triphenylphosphine (22.3 g, 85 mmol) in THF (50 ml) was added dropwise with stirring. The reaction mixture was left stirring under nitrogen until no further reaction was visible by TLC. The solvent was then removed in vacuo and the resulting slurry was purified by column chromatography [petroleum ether (bp 40-60° C.): dichloromethane (12:1)] on silica to yield a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>C1COCC1.O>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH:10][C:9]2[CH:8]=[C:7]([CH3:11])[N:6]=[C:5]3[S:12][C:2]([CH3:1])=[C:3]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=4)[C:4]=23)(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: COc1cccc(-c2c(C)sc3nc(C)cc(N)c23)c1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)c4ccc(Br)cc4)c23)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.7 %

Procedure:
To a solution of 2,6-dimethyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (Description 4) (100 mg, 0.352 mmol) in THF (2 mL) cooled in an ice bath was added LiHMDS (1M solution in THF) (0.774 mL, 0.774 mmol). The resulting reaction mixture was stirred for 45 min before addition of 4-bromobenzenesulfonyl chloride (225 mg, 0.879 mmol). The reaction mixture was then stirred at RT for a further 12 h. The reaction mixture was diluted with water (15 mL) and the aqueous layer re-extracted with DCM (30 mL×3). The organics were combined, dried over a phase separating column and concentrated. To the residue was added MeOH (ca. 0.5 mL) and a solid crashed-out which was collected by filtration and rinsed with MeOH (ca. 2 mL). The solid was then dried, to afford the title compound (104 mg). LCMS (A) m/z: 503/505 [M+1]+, Rt 1.11 min (basic).
Reaction SMILES: [CH2:1]([N:3]([CH2:34][CH3:35])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([O:29]CC)=[O:28])=[CH:23][CH:22]=3)[CH:13]=[CH:14][C:15]=2[O:16][CH2:17][CH2:18][CH2:19][OH:20])=[CH:6][C:5]=1[CH2:32][CH3:33])[CH3:2].[OH-].[Na+].Cl>O1CCCC1.O>[CH2:34]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([OH:29])=[O:28])=[CH:25][CH:26]=3)[CH:13]=[CH:14][C:15]=2[O:16][CH2:17][CH2:18][CH2:19][OH:20])=[CH:6][C:5]=1[CH2:32][CH3:33])[CH3:35]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCO)c(-c3ccc(N(CC)CC)c(CC)c3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(-c2cc(-c3ccc(C(=O)O)cc3)ccc2OCCCO)ccc1N(CC)CC
Reaction time: 0.5 h
Yield: 31.4 %

Procedure:
Into a 25 mL three-necked flask under a nitrogen atmosphere, equipped with a magnetic stirrer, are placed 270 mg (0.57 mmol) of ethyl 4″-diethylamino-3″-ethyl-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate (Example 10d) and 22 mg (5.7 mmol) of solid sodium hydroxide in 5.4 mL of tetrahydrofuran. The reaction medium is heated at the reflux temperature of the tetrahydrofuran for 5 hours. The reaction medium is concentrated under vacuum. The crude reaction product obtained is taken up in water and the pH of the medium thus obtained is adjusted to pH=4 by addition of hydrochloric acid solution in a proportion of 1 mol/L. The precipitate obtained, after stirring for 30 minutes, is purified by chromatography on silica (eluent: 40/60 heptane/ethyl acetate) to give, after evaporation of the fractions, 80 mg (yield=31%) of 4″-diethylamino-3″-ethyl-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic acid in the form of a cream-colored powder (m.p.=204° C.).
Reaction SMILES: [CH3:1]S(C)(=O)=C.[C:6]1([CH:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][CH:14]=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[O:15]1[CH:14]([CH2:13][CH:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:1]1
Reactant: O=CCC(c1ccccc1)c1ccccc1
Reactant: C=S(C)(C)=O
Product: c1ccc(C(CC2CO2)c2ccccc2)cc1

Procedure:
The 1,2-epoxy-4,4-diarylbutane starting materials can alternatively be prepared by reaction of dimethylsulfonium methylide or dimethyloxosulfonium methylide with an appropriate diarylalkyl aldehyde or a diarylalkyl ketone. For example, reaction of an aldehyde such as 3,3-diphenylpropanal with either dimethylsulfonium methylide or dimethyloxosulfonium methylide in approximately equimolar amounts provides 1,2-epoxy-4,4-diphenylbutane. Similarly, reaction of a diarylalkyl ketone such as methyl-(2,2-diphenylethyl) ketone with either dimethylsulfonium methylide or dimethyloxosulfonium methylide provides 1,2-epoxy-4,4-diphenyl-2-methylbutane. Such reactions typically are carried out in a solvent such as dimethyl sulfoxide or tetrahydrofuran, and normally at a reduced temperature of about 0° C. Dimethylsulfonium methylide is prepared by reaction of trimethylsulfonium iodide with methylsulfinylcarbanion, while demethyloxosulfonium methylide is prepared by reaction of trimethyloxosulfonium iodide with sodium hydride. Such reactions are more fully discussed by Corey et al., J. Am. Chem. Soc., 84, 867(1962) and J. Am. Chem. Soc., 84, 3782 (1962).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[O:15][C:14]([CH2:16][CH2:17][C@@H:18]([NH:30]C(=O)OC(C)(C)C)[CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[N:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[O:15][C:14]([CH2:16][CH2:17][C@@H:18]([NH2:30])[CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][CH:21]=4)=[N:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1nnc(-c2ccc3cnccc3c2)o1)Cc1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](CCc1nnc(-c2ccc3cnccc3c2)o1)Cc1ccc(C(F)(F)F)cc1
Yield: 90.9 %

Procedure:
tert-Butyl(R)-4-(5-(isoquinolin-6-yl)-1,3,4-oxadiazol-2-yl)-1-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate (0.060 g, 0.12 mmol) was stirred with 10 mL TFA in 10 mL DCM for 1 hour. After removing the solvent, the remaining residue was made basic with 2 M ammonia in MeOH and purified by chromatography on silica gel (4% 2M ammonia MeOH solution in DCM) to give the desired product as a white solid (0.045 g, 93%). LCMS (API-ES) m/z: 413 (M+H+); 1H NMR (400 MHz, CD3OD) δ ppm 1.87-1.97 (m, 1H), 2.17-2.27 (m, 1H), 2.63-2.79 (m, 2H), 2.91-2.98 (m, 1H), 3.12 (dd, J=13.40, 5.18 Hz, 1H), 4.18-4.25 (m, 1H), 7.50 (d, J=8.02 Hz, 2H), 7.64 (d, J=8.02 Hz, 2H), 7.92 (d, J=5.67 Hz, 1H), 8.14-8.19 (m, 1H), 8.22-8.27 (m, 1H), 8.50 (d, J=5.48 Hz, 1H), 9.30 (s, 1H), one H was obscured.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([OH:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:12][CH:11]=1)([O-])=O>CO.[Pt](=O)=O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([OH:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:12][CH:11]=1
Reactant: O=C(O)CCC(O)c1ccc(-c2ccccc2[N+](=O)[O-])cc1
Agent: O=[Pt]=O
Solvent: CO
Product: Nc1ccccc1-c1ccc(C(O)CCC(=O)O)cc1

Procedure:
6 gm (0.02 mol) of 4-(2'-nitro-4-biphenylyl)-4 -hydroxy-butyric acid (m.p. 114°-115° C.) were hydrogenated in 60 ml of methanol in the presence of 0.6 gm of platinum dioxide as a catalyst, at room temperature and atmospheric pressure. After absorption of the calculated quantity of hydrogen, the catalyst was vacuum-filtered off, and the solvent was distilled off. The residue, which solidified after some time, was recrystallized from methanol, yielding 4-(2' -amino-4-biphenylyl)-4-hydroxy-butyric acid, m.p. 102°-103° C. Melting point of the cyclohexylamine salt: 157°-158° C. (decomp,; precipitated from ethyl acetate and recrystallized from ethyl acetate/isopropanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:11])=[O:10])=[CH:16][CH:15]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)cc1
Reaction time: 16 h
Yield: 68.6 %

Procedure:
To a solution of 4-methoxybenzenesulfonyl chloride (5.0 g, 24 mmol) and 4-chloroaniline (3.1 g, 24 mmol) in dichloromethane (24 mL) at 0° C. was added triethylamine (3.4 mL, 24 mmol) over 10 minutes. The ice bath was removed, and the mixture was stirred for 16 hr. The mixture was diluted with dichloromethane (100 mL) and the combined solution was washed with water (50 mL) and brine (50 mL). The organic solution was dried over MgSO4, filtered, and evaporated, and the crude product was purified by silica gel chromatography (15-60% EtOAc/Hex). Product-containing fractions were pooled, evaporated, and dried under high vacuum to yield 4.9 g (69%) of the product as a tan-colored oil: 1H-NMR (CDC3) δ 10.17 (s, 1H), 7.71 (d, 2H), 7.61 (d, 2H), 7.04 (d, 2H), 6.96 (d, 2H), 2.19 (s, 3H).
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH:35]1([CH2:38]Br)[CH2:37][CH2:36]1>CN(C)C=O>[CH:35]1([CH2:38][N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][CH:24]([N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:32])[CH2:3][CH2:4]2)=[O:9])[CH2:37][CH2:36]1
Reactant: BrCC1CC1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2CC1CC1)N1CCC(N2CCCC2)CC1
Yield: 53 %

Procedure:
The title compound was synthesized in analogy to example 51, from (4,4-difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 169), sodium hydride and cyclopropylmethyl bromide in N,N-dimethylformamide, to give the desired product as a yellow solid (53%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[C:12]2=[N:13][NH:14][C:15](=[O:20])[C:16]3[CH:17]=[CH:18][CH:19]=[C:10]([C:11]=32)[NH:9][CH:8]1[C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.C(O)(=O)C.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.[BH3-]C#N.[Na+]>C(#N)C>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[C:12]2=[N:13][NH:14][C:15](=[O:20])[C:16]3[CH:17]=[CH:18][CH:19]=[C:10]([C:11]=32)[NH:9][CH:8]1[C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:27][CH:28]=1
Reactant: C1CCNC1
Reactant: Cn1ccnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: Cn1ccnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.4 %

Procedure:
A mixture of 4-(9-(1-methyl-1H-imidazol-2-yl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (80 mg, 0.22 mmol), acetic acid (60 uL) and pyrrolidine (1.05 g, 15 mmol) in acetonitrile (7 mL) was stirred at room temperature for 4 hr. To this mixture was added NaCNBH3 (36 mg, 0.67 mmol) at 0° C. After the addition, the mixture was stirred at room temperature for 4 hr. Upon removal of solvents under reduced pressure, the residue was washed with ethyl acetate and filtered. The filtrate was concentrated to give the title compound as a white solid (21 mg, yield 22%). LC-MS (ESI) m/z: 427 (M+1)+. 1H-NMR: (400 MHz, DMSO-d6&D2O) δ (ppm): 1.66 (d, J=2.8 Hz, 4H), 2.37 (s, 4H), 3.38 (s, 3H), 3.50 (s, 2H), 4.62 (d, J=10 Hz, 1H), 4.90 (d, J=10.4 Hz, 1H), 6.72 (s, 1H), 6.87 (s, 1H), 7.15-7.20 (m, 3H), 7.29-7.32 (m, 3H), 7.36-7.38 (m, 1H), 7.54-7.58 (m, 1H), 12.15 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.[CH2:10]([N:17]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@H:18]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2B2OC(C)(C)C(C)(C)O2)[O:20][CH2:19]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:37]([N:17]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@H:18]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[C:2]2[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=2)[O:20][CH2:19]1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CC1(C)OB(c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)OC1(C)C
Reactant: OCc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCc1ccc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)cn1

Procedure:
A mixture of (5-bromopyridin-2-yl)methanol (0.205 g, 1.09 mmol), (3S)-N,N-dibenzyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-3-amine (0.13 M in isopropanol, 8.4 mL, 1.09 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(ii)dichloride dichloromethane complex (0.045 g, 0.05 mmol), and 2 M potassium carbonate (1.64 mL, 3.28 mmol) was irradiated in a microwave synthesizer at 140° C. for 20 min. The solution was filtered through a pad of celite and concentrated in vacuo. The residue was purified by column chromatography using a gradient of ethyl acetate in heptane. The crude was dissolved in chloroform and insoluble material was removed. The solvent was evaporated in vacuo yielding an oil, 0.360 g (76%); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.46 (d, 1 H), 7.79 (dd, 1 H), 7.54 (d, 1 H), 7.24-7.34 (m, 8 H), 7.06-7.22 (m, 3 H), 6.69-6.83 (m, 2 H), 5.51 (t, 1 H), 4.64 (d, 2 H), 4.28-4.39 (m, 1 H), 3.99-4.10 (m, 1 H), 3.59-3.74 (m, 4 H), 2.86-3.11 (m, 1 H), 2.39-2.49 (m, 1 H); MS (APPI/APCI) m/z 437[M+H+].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][CH2:14][CH2:15][CH3:16])[CH:12]=1)[C:6]([O:8]C)=[O:7])#[N:2].[OH-].[Li+]>CO.O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][CH2:14][CH2:15][CH3:16])[CH:12]=1)[C:6]([OH:8])=[O:7])#[N:2]
Reactant: CCCOc1cc(C#N)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCOc1cc(C#N)cc(C(=O)O)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A solution of methyl 3-cyano-5-propoxybenzoate (1.5 g, 6.8 mmol) in methanol-tetrahydrofuran (1:2, 30 mL) was treated with 0.5 M lithium hydroxide (16 mL, 8.2 mmol). The reaction was stirred at 70° C. for 30 minutes and then the solvent was removed in vacuo. The residue was dissolved in a small amount of water and then acidified (pH˜4) by the addition of 2N hydrogen chloride. The precipitate was collected and dried to afford 1.2 g (86%) of 3-cyano-5-propoxybenzoic acid.
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:17][C:18]2[C:19]([CH3:24])=[N:20][NH:21][C:22]=2[CH3:23])=[CH:9]1)=O)(C)(C)C.[N:25]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[C:26]=[O:27].C(O)(=O)C>ClCCl>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][NH:25][C:26]([N:21]2[C:22]([CH3:23])=[C:18]([CH2:17][C:10]3[C:11]4[C:12](=[N:13][CH:14]=[CH:15][CH:16]=4)[NH:8][CH:9]=3)[C:19]([CH3:24])=[N:20]2)=[O:27])=[CH:30][CH:31]=1
Reactant: COc1ccc(CN=C=O)cc1
Reactant: Cc1n[nH]c(C)c1Cc1cn(C(=O)OC(C)(C)C)c2ncccc12
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(CNC(=O)n2nc(C)c(Cc3c[nH]c4ncccc34)c2C)cc1
Reaction time: 0.5 h

Procedure:
3-(3,5-dimethyl-1H-pyrazol-4-ylmethyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (514, 10 mg, 0.03 mmol) was dissolved in dichloromethane (0.5 mL). 1,8-Diazabicylo[5.4.0]unde-7-ene (6 mg, 0.04 mmol) was added. 1-Isocyanatomethyl-4-methoxy-benzene (545, 6.5 mg, 0.04 mmol) was added. The reaction was allowed to proceed at room temperature for 30 minutes. Acetic acid (0.2 mL) was added to the: reaction. The solvents were removed under reduced pressure. The residue was dissolved in dimethyl sulfoxide (0.2 mL) and purified by reverse phase HPLC on a Phenomenex column (50mm×10 mm ID), eluting with water with 0.1% trifluoroacetic acid and 20-100% acetonitrile with 0.1% trifluoroacetic acid over 16 minutes at a flow rate of 6 mL/minute to provide the desired compound P-0135. MS (ESI) [M+H+]+=390.3.
Reaction SMILES: [CH2:1]([C:5]1[C:14](=[O:15])[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:29]([O:31]C)=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:33](O)(=O)C>[OH-].[Na+]>[CH2:1]([C:5]1[C:14](=[O:15])[C:13]2[CH2:12][CH:11]([CH3:33])[CH2:10][CH2:9][C:8]=2[N:7]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[C:24]([C:29]([OH:31])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:21][CH:22]=2)[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(Cc2ccc(-c3ccccc3C(=O)OC)cc2)c2c(c1=O)CCCC2
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCCc1cn(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2c(c1=O)CC(C)CC2
Temperature: 60 °C

Procedure:
Using the procedure of Example 31, 0.4 g of product A of Example 32 in 10 ml of 2N sodium hydroxide were reacted. The mixture was stirred over-night at about 60° C. and the medium was cooled to ambient temperature, acidified with glacial acetic acid, decanted, impasted in a solution of 2N hydrochloric acid, separated, dried and crystallized from 50 ml of an ethanol-water 49-1 mixture to obtain 0.220 g of the expected product melting at 255° C.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])[CH3:3].[K+].Cl[C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)=[CH:17][CH:16]=2)[C:11]([Cl:34])=[CH:10][N:9]=1.O>CC(O)C>[Cl:34][C:11]1[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C@@H:21]3[O:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)=[CH:19][CH:20]=2)=[N:13][C:8]([O:4][CH:2]([CH3:3])[CH3:1])=[N:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Nc3nc(Cl)ncc3Cl)cc2)C1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)Oc1ncc(Cl)c(Nc2ccc([C@H]3CN(C(=O)OC(C)(C)C)CCO3)cc2)n1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a stirred solution of potassium tert.-butoxide (116 mg, 1.03 mmol) in propan-2-ol (2 mL) was added (S)-tert-butyl 2-(4-(2,5-dichloropyrimidin-4-ylamino)phenyl)morpholine-4-carboxylate (110 mg, 0.26 mmol) and the mixture was shaken at 90° C. overnight. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and evaporated. The residue was purified by column chromatography (silica gel, 5 to 15% ethyl acetate in heptan, 10 g ISCO column). White foam (58 mg, 50%). MS (ISP): 449.3 ([{35Cl}M+H]+), 451.1 ([{37Cl}M+H]+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16](=[O:21])[NH:17][CH:18]3[CH2:20][CH2:19]3)[CH:13]=[CH:12][C:11]=2[CH3:22])=[O:8])[S:5][CH:6]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25](OB(C2C=CC=CC=2)O)[CH:24]=1>>[CH:18]1([NH:17][C:16]([C:14]2[CH:13]=[CH:12][C:11]([CH3:22])=[C:10]([NH:9][C:7]([C:4]3[S:5][CH:6]=[C:2]([C:25]4[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=4)[CH:3]=3)=[O:8])[CH:15]=2)=[O:21])[CH2:20][CH2:19]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(Br)cs1
Reactant: OB(Oc1cccnc1)c1ccccc1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(-c2cccnc2)cs1

Procedure:
The title compound was prepared by coupling 4-bromo-N-(5-(cyclopropylcarbamoyl)-2-methylphenyl)thiophene-2-carboxamide with commercially available 3-pyridylphenylboronic acid using the method described in Step B of Example 136 to afford a white solid (Example 204). HPLC Ret time=1.91 min. LCMS [M+H]+ 378.22.