Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Cl)(C)C.[Cl:6][C:7]1[CH:35]=[CH:34][C:33](I)=[CH:32][C:8]=1[C:9]([N:11]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH2:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2)=[O:10].[CH2:37]([C@@H:39]1[O:41][CH2:40]1)[Cl:38]>O1CCCC1.C(=O)(O)[O-].[Na+].O>[Cl:6][C:7]1[CH:35]=[CH:34][C:33]([CH2:40][C@H:39]([OH:41])[CH2:37][Cl:38])=[CH:32][C:8]=1[C:9]([N:11]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH2:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2)=[O:10]
Reactant: COc1ccc(CN(CC23CC4CC(CC(C4)C2)C3)C(=O)c2cc(I)ccc2Cl)cc1
Reactant: ClC[C@H]1CO1
Agent: CC(C)[Mg]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(CC23CC4CC(CC(C4)C2)C3)C(=O)c2cc(C[C@H](O)CCl)ccc2Cl)cc1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
iso-Propylmagnesium chloride solution (2M in tetrahydrofuran, 72.9 mL) was added to a stirred solution of 2-chloro-5-iodo-N-[(4-methoxyphenyl)methyl]-N-(tricyclo [3.3.1.13,7]dec-1-ylmethyl)benzamide (Example 15a) (72.87 g) in anhydrous tetrahydrofuran (1 L) at 0° C. under nitrogen. After 30 minutes, copper(I) bromide dimethylsulphide complex (0.68 g) followed by (R)-(−)epichlorohydrin (11.4 mL) were added. The mixture was warmed to 30° C. for 2 hours then diluted with saturated sodium bicarbonate solution (1 L) and water (500 mL) then extracted with ethyl acetate (2×1 L). Organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The residual oil was dissolved in methanol (600 mL), stirred overnight and the precipitated solid filtered and dried in vacuo to give the titled compound (52.25 g).
Reaction SMILES: Br[CH:2]([CH3:37])[C:3]([C:5]1[CH:6]=[C:7]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[C:8](=[O:22])[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:10]=1[CH3:11])=O.C([O:44][CH2:45][C:46]([NH2:48])=[S:47])(=O)C(C)(C)C>CCO>[CH3:36][S:33]([C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:23]([C:7]2[C:8](=[O:22])[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:19])[F:21])[CH:13]=3)[C:10]([CH3:11])=[C:5]([C:3]3[N:48]=[C:46]([CH2:45][OH:44])[S:47][C:2]=3[CH3:37])[CH:6]=2)=[O:24])=[CH:28][CH:29]=1)(=[O:35])=[O:34]
Reactant: Cc1c(C(=O)C(C)Br)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)C(=O)OCC(N)=S
Solvent: CCO
Product: Cc1sc(CO)nc1-c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
5-(2-Bromopropanoyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (Example 53 (b), 0.06 g, 0.10 mmol), 2-amino-2-thioxoethyl pivalate (0.022 g, 0.125 mmol), EtOH (2 ml) and a magnetic stirrer bar were placed in a tube designed for microwave synthesis. The vial was sealed and the mixture was heated in a CEM Discover Microwave apparatus (100 W, 80 ° C.) for 40 minutes, giving complete conversion of the starting material to a single product according to LC-MS. The solvents were evaporated to give a crude mixture which was purified on silica giving 0.045 g (76%) of the intermediate pivalyl ester. This compound was dissolved in THF (2 ml) and water (2 ml). To this solution was added NaOH (0.2 mmol, 0.1 ml of a 2M solution), and the mixture was stirred at room temperature overnight. The THF was evaporated off and the water phase was acidified, extracted, and lo the extracts were evaporated. Purification by preparative HPLC gave pure fractions which were freeze-dried to give the title compound (0.040 g, 68%) as a white solid.
Reaction SMILES: CS[C:3](=[O:12])[C:4]([C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)=[O:5].C(=O)([O-])[O-:14].[Na+].[Na+].Cl>O>[NH2:11][C:8]1[S:9][CH:10]=[C:6]([C:4](=[O:5])[C:3]([OH:12])=[O:14])[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: CSC(=O)C(=O)c1csc(N)n1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1nc(C(=O)C(=O)O)cs1
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To 10.1 g of 2-(2-aminothiazol-4-yl)thioglyoxylic S-acid methyl ester and 80 ml of water was added 10.6 g of sodium carbonate with ice-cooling, and the resulting mixture was stirred at the same temperature for 1 hour. Subsequently, the thus obtained reaction mixture was adjusted to pH 2.5 with 6N hydrochloric acid at the same temperature. The deposited crystals were collected by filtration, washed with water, and then dried to obtain 6.2 g (67.8% yield) of 2-(2-aminothiazol-4-yl)glyoxylic acid having a melting point of above 200° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C:27](=[O:28])[CH2:26][CH:25]([C:29]([OH:31])=O)[CH2:24]3)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.Cl.[F:33][C:34]1([F:41])[C:38]([F:40])([F:39])[CH2:37][NH:36][CH2:35]1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:24][CH:25]([C:29]([N:36]4[CH2:37][C:38]([F:40])([F:39])[C:34]([F:41])([F:33])[CH2:35]4)=[O:31])[CH2:26][C:27]3=[O:28])=[CH:19][CH:18]=2)=[O:16])[CH2:13][CH2:14]1
Reactant: FC1(F)CNCC1(F)F
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(C(=O)O)CC4=O)cc3)CC2)c(C)c1
Agent: Cl
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(C(=O)N5CC(F)(F)C(F)(F)C5)CC4=O)cc3)CC2)c(C)c1
Yield: 30.8 %

Procedure:
Using 1-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-5-oxopyrrolidine-3-carboxylic acid (100 mg) described in Example 333 and 3,3,4,4-tetrafluoropyrrolidine hydrochloride (43 mg) and by the reaction and treatment in the same manner as in Example 86, the title compound (40 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][CH2:7][C:8]([OH:10])=O)=[O:5].[C:11]([CH:13]1[CH2:15][NH:14]1)#[N:12].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:1][O:2][CH2:3][C:4]([NH:6][CH2:7][C:8]([N:14]1[CH2:15][CH:13]1[C:11]#[N:12])=[O:10])=[O:5]
Reactant: N#CC1CN1
Reactant: COCC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: COCC(=O)NCC(=O)N1CC1C#N

Procedure:
2.94 g. N-Methoxyacetylglycine are dissolved in 29 ml. tetrahydrofuran and mixed, with stirring and ice cooling, with 1.36 g. 2-cyanoaziridine and 4.3 g. dicyclohexylcarbodiimide, whereafter the reaction mixture is stirred for 2 hours. After filtering off the dicyclohexylurea, from the filtrate there are obtained 2.8 g. of crystals which, for purification, are dissolved in ethyl acetate and reprecipitated with ligroin. There is thus obtained 1-(N-methoxyacetylglycyl)-2-cyanoaziridine; M.p. 70°-72° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30]O)=[CH:24][CH:23]=1.[C:32]([NH:39][C:40]([N:49]1[CH:53]=[CH:52][CH:51]=[N:50]1)=[N:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.CCCC(C)C>C(Cl)Cl>[C:45]([O:44][C:42](=[O:43])[N:41](/[C:40](=[N:39]/[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])/[N:49]1[CH:53]=[CH:52][CH:51]=[N:50]1)[CH2:30][CH2:29][CH2:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=1)([CH3:48])([CH3:47])[CH3:46]
Reactant: COc1ccc(CCCO)cc1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCC(C)C
Product: COc1ccc(CCCN(C(=O)OC(C)(C)C)/C(=N/C(=O)OC(C)(C)C)n2cccn2)cc1
Temperature: 4 °C
Reaction time: 0.08 h

Procedure:
PS-Triphenylphosphine (6.40 g, 12.03 mmol) is added to a solution of 3-(4-methoxyphenyl)-1-propanol (1.00 g, 6.02 mmol) in DCM (300 mL), followed by N,N′-di-Boc-1H-pyrazole-1-carboxamidine (1.87 g, 6.02 mmol). The reaction mixture is cooled to 4° C., and di-tert-butyl azodicarboxylate (1.39 g, 6.02 mmol) is added portionwise. The reaction is stirred for 5 minutes at 4° C., and then allowed to warm to RT. The resulting yellow suspension is stirred at RT overnight. The reaction is filtered to remove the PS-triphenylphosphine, which is rinsed with MeOH (20 mL). The combined filtrates are concentrated in vacuo to afford a colourless oil. iso-Hexane (50 mL) is added, and a fine cream solid precipitates out of solution, which is removed by filtration. The filtrate is concentrated in vacuo, and the resulting white solid is washed with iso-hexane (50 mL). The iso-hexane is concentrated in vacuo, and the resulting pale yellow oil is purified by chromatography (SiO2, EtOAc in iso-hexane, 0%-25%) to afford the title compound crude as a colourless oil. The oil is used in further reactions with no further purification. [M+H]+ 459.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[NH4+:34].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)Cl.O.CO.C(Cl)(Cl)Cl>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:18][CH2:19][CH:20]([CH3:21])[CH3:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:34])[C:8]=2[N:17]=1)[CH3:2]
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3ccccc3c2n1NCC(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1NCC(C)C
Reaction time: 1.5 h

Procedure:
A solution of N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)isobutylamine (1.16 g, 3.89 mmol) in 30 mL of CH2Cl2 was treated with MCPBA (1.25 g, 5.05 mmol, 77% max). After 1.5 h, the reaction mixture was treated with 15 mL of concentrated NH4OH solution and p-toluenesulfonyl chloride (0.78 g, 4.08 mmol). After 30 min the reaction mixture was diluted with CH2Cl2 and water, and the phases were separated. The organic portion was washed with 2% Na2CO3 solution and water. The combined aqueous washes were back extracted with CHCl3 (2×). The combined organic portions were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield a brown foam. Chromatography (SiO2, 97:3 CHCl3:MeOH) yielded 2-ethoxymethyl-N1-isobutyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.049 g) as an off white solid. mp 137–140° C.; 1H NMR (300 MHz, DMSO-d6, 350 K) δ 8.47 (dd, J=8.1, 0.9 Hz, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.45–7.36 (m, 1H), 7.28–7.19 (m, 1H), 6.67 (t, J=6.2 Hz, 1H), 6.22 (s, 2H), 4.76 (s, 2H), 3.64 (q, J=7.0 Hz, 2H), 3.02 (t, J=6.4 Hz, 2H), 1.97 (s, J=6.7 Hz, 1H), 1.19 (t, J=7.0 Hz, 3H), 1.05 (d J=6.7 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) δ 151.9, 148.9, 144.8, 131.9, 126.9, 125.7, 123.8, 120.8, 114.2, 65.4, 62.8, 59.6, 26.7, 20.5, 14.9; MS (APCI) m/z 314 (M+H)+; Anal. Calcd for C17H23N5O: C, 65.15; H, 7.40; N, 22.35; Found: C, 64.88; H, 7.39; N, 22.38.
Reaction SMILES: [OH-].[Na+:2].[ClH:3].[NH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[C:12]2[CH:13]=[CH:14][N:15]=[C:16]([OH:21])[C:17]=2[CH:18]=[CH:19][CH:20]=1)(=[O:10])=[O:9]>CO>[Cl-:3].[Na+:2].[NH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[C:12]2[CH:13]=[CH:14][N:15]=[C:16]([OH:21])[C:17]=2[CH:18]=[CH:19][CH:20]=1)(=[O:9])=[O:10]
Reactant: Cl
Agent: NCCNS(=O)(=O)c1cccc2c(O)nccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: [Cl-]
Reaction time: 0.5 h

Procedure:
A 1N NaOH solution (5.96 mL) is added slowly to a stirred suspension of 1-hydroxy-isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide hydrochloride (1.81 g, 5.96 mmol) in CH3OH (10 mL) at ambient temperature under nitrogen. The resultant mixture is allowed to stir for 30 minutes. The mixture is then concentrated at 50° C. under vacuum to give a 1.87 g of the title compound (96% yield) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH:21]1[CH:26]=[C:25]2[CH:27]=[CH:28][CH:29]=[C:30]([SH:31])[C:24]2=[CH:23][CH:22]=1>>[C:30]1([S:31][C:16]2[N:15]=[C:14]([NH:13][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)[CH:19]=[N:18][CH:17]=2)[C:24]2[C:25](=[CH:26][CH:21]=[CH:22][CH:23]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Sc1cccc2ccccc12
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Product: COc1cc(Nc2cncc(Sc3cccc4ccccc34)n2)cc(OC)c1OC
Yield: 32 %

Procedure:
Using Method X with 150 mg of 2-(3,4,5-trimethoxyphenylamino)-6-chloropyrazine and 1-thionaphthol, the title compound was obtained (68 mg). Yield: 32%. 1H NMR (250 MHz, DMSO-d6) δ 3.60 (s, 3H), 3.61 (s, 6H), 6.94 (s, 2H), 7.25 (s, 1H), 7.57-7.63 (m, 3H), 7.91 (s, 1H), 7.95 (dd, 1H, J1=1.2 Hz, J2=7.1 Hz), 8.03-8.07 (m, 1H), 8.11 (d, 1H, J=8.3 Hz), 8.26-8.30 (m, 1H), 9.54 (s, 1H). 13C NMR (62.9 MHz, DMSO-d6) δ 55.55, 60.09, 96.41, 124.82, 126.23, 126.58, 126.74, 127.65, 128.90, 129.90, 130.63, 131.09, 132.52, 133.33, 133.97, 134.60, 136.13, 151.27, 152.55, 152.74. m/z 420.1 [(M+H)+ calcd for C23H21N3O3S 419.1].
Reaction SMILES: [O:1]=[C:2]1[C@H:8]([NH:9][C:10](=[O:16])OC(C)(C)C)[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:17]([NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[O:18].C(O)(C(F)(F)F)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+].[Cl:49][C:50]1[CH:59]=[C:58]2[C:53]([C:54]([N:61]3[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]3)=[CH:55][C:56]([NH2:60])=[N:57]2)=[CH:52][CH:51]=1>>[NH2:60][C:56]1[CH:55]=[C:54]([N:61]2[CH2:62][CH2:63][N:64]([C:10]([NH:9][C@H:8]3[CH2:7][CH2:6][CH2:5][CH2:4][N:3]([C:17]([NH:19][CH2:20][C:21]([F:22])([F:23])[F:24])=[O:18])[C:2]3=[O:1])=[O:16])[CH2:65][CH2:66]2)[C:53]2[C:58](=[CH:59][C:50]([Cl:49])=[CH:51][CH:52]=2)[N:57]=1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCCN(C(=O)NCC(F)(F)F)C1=O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(C(=O)NCC(F)(F)F)C3=O)CC2)c2ccc(Cl)cc2n1

Procedure:
As described for example 213, [(3R)-hexahydro-2-oxo-1-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1H-azepin-3-yl]-carbamic acid, 1,1-dimethylethyl ester, TFA, triphosgene, NaHCO3 (sat.), and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product as a light yellow solid. LC-MS: 542 (M++1). 1H NMR (CDCl3,): δ 1.44 (m, 1H), 1.64 (m, 1H), 1.82˜2.02 (m, 4H), 3.14 (m, 4H), 3.31 (dd, 1H), 3.68 (m, 4H), 3.98 (m, 2H), 4.84 (dd, 1H), 4.88–5.00 (m, 3H), 5.80 (d, 1H), 6.03 (s, 1H), 7.16 (dd, 1H), 7.60 (d, 1H), 7.71 (d, 1H), 9.54 (t, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]#[N:11].B>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH2:11]
Reactant: N#CCc1c(F)cccc1F
Agent: B
Solvent: C1CCOC1
Product: NCCc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 23 h
Yield: 67.4 %

Procedure:
2,6-Difluorophenylacetonitrile (15.8 g, 100 mmol) was dissolved in tetrahydrofuran (75 mL) at room temperature. The solution was cooled in an ice bath and borane.THF complex (100 mL, 100 mmol) was added dropwise over 15 minutes under nitrogen atmosphere. The ice bath was removed after borane addition was complete and the mixture was stirred at room temperature for 23 hours under nitrogen atmosphere. Saturated aqueous ammonium chloride solution (20 mL) was added dropwise with stirring over 30 minutes. The reaction mixture was filtered through diatomaceous earth, concentrated to an oil, redissolved in ethyl acetate/water, and adjusted to pH 1.0 with concentrated hydrochloric acid. The mixture was filtered through diatomaceous earth and the ethyl acetate layer extracted with 1N hydrochloric acid (4×10 mL). The combined acidic aqueous extracts were washed with ethyl acetate (2×50 ml). Solid sodium chloride was added to the acidic aqueous extracts, adjusted to pH 9.0 with solid sodium bicarbonate and 5N sodium hydroxide solution, and the mixture extracted with methylene chloride (7×50 mL). The combined methylene chloride extracts were washed with brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 10.6 g (68%) of the titled product as a nearly colorless oil:
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[NH:3][N:2]=1.Br[CH2:13][CH2:14][OH:15]>>[OH:15][CH2:14][CH2:13][N:3]1[C:4](=[O:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:1]=[N:2]1
Reactant: OCCBr
Reactant: O=c1[nH]nnc2ccccc12
Product: O=c1c2ccccc2nnn1CCO

Procedure:
3-(2-hydroxyethyl)-1,2,3-benzotriazin-4(3H)one was prepared according to the general procedure outlined in example 1, step 1. Starting from 1,2,3-benzotriazin-4(3H)one (1.5 g, 10 mmol) and 2-bromoethanol (1.68 mL, 20 mmol), 1.20 g (63%); off white solid; m.p. 114° C., MS: 191.9 (M+H)+
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:13]([NH:17][OH:18])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([N+:17]([O-:18])=[CH:9][C:8]1[CH:11]=[CH:12][C:5]([S:2]([NH2:1])(=[O:4])=[O:3])=[CH:6][CH:7]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)NO
Reactant: NS(=O)(=O)c1ccc(C=O)cc1
Product: CC(C)(C)[N+]([O-])=Cc1ccc(S(N)(=O)=O)cc1

Procedure:
Using 4-aminosulfonylbenzaldehyde and N-tert-butylhydroxylamine and following the procedures described herein, the title compound was prepared as a white powder, m.p. 219.1-219.4° C.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][OH:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[C:22](F)=[CH:23][C:24]([F:34])=[C:25]([CH:33]=1)[C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:27].CC(C)([O-])C.[K+].C1COCC1.CS(C)=O>CS(C)=O.CCOC(C)=O>[CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][O:19][C:22]2[C:21]([Cl:20])=[CH:33][C:25]([C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:27])=[C:24]([F:34])[CH:23]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1-benzhydrylazetidin-3-yl)methanol (40.4 mg, 0.159 mmol) and 5-chloro-2,4-difluoro-N-methylsulfonyl-benzamide (43.0 mg, 0.159 mmol) in DMSO (0.80 mL) at rt was added potassium tert-butoxide in 1:10 THF-DMSO (0.38 mL, 0.93 M). The mixture was stirred at rt for 1 hr. LCMS showed major product. Diluted with EtOAc, the contents were washed with 1:4 mixture of 1M HCl and 1M NaH2PO4 (2×) and brine (1×), dried (Na2SO4). After filtration and concentration, the crude was purified with HPLC (55.7 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@H:29]([C:37]([CH3:40])([CH3:39])[CH3:38])/[CH:30]=[CH:31]/[C:32]([O:34]CC)=[O:33])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.[Li+].[OH-].Cl>O1CCOCC1>[F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:37]([CH3:40])([CH3:39])[CH3:38])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)/C=C/[C@H](Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)[C@@H](/C=C/C(=O)O)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Temperature: 100 °C

Procedure:
To a solution of (S,E)-ethyl 4-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhex-2-enoate, 42a, (0.064 g, 0.112 mmol) in dioxane (2 mL) was added LiOH (2 mL of 2N solution). After heating at 100° C. for 2 hours, the mixture was acidified to pH 6 with 2N HCl. The aqueous phase was extracted with ethyl acetate (3×), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified via preparatory HPLC (CH3CN/H2O—TFA modifier) to afford 35 mg of the desired product as a TFA-salt: 1H NMR (300 MHz, MeOD) δ 8.54 (s, 1H), 8.50-8.18 (m, 3H), 7.18 (dd, J=15.7, 7.1 Hz, 1H), 6.08 (dd, J=15.7, 1.3 Hz, 1H), 5.21 (t, J=22.5 Hz, 1H), 1.12 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, (M+H) 388.23.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
To a stirred solution of methyl 3-amino-2-methyl-5-bromobenzoate (4.06 g, 16.6 mmol) in DCE (60 ml) under a nitrogen atmosphere was added oxan-4-one (3.07 ml, 33.3 mmol) followed by acetic acid (5.71 ml, 99.8 mmol) and the reaction was left to stir for 5 min before the addition of sodium triacetoxyborohydride (10.6 g, 49.9 mmol). The reaction was stirred for 3 h at room temperature whereupon distilled water (50 ml) was added and the solution was neutralised with solid NaHCO3. The phases were separated and then the aqueous phase was washed with EtOAc (2×100 ml), the combined organics were then dried using Na2SO4, filtered and evaporated. The residue was purified by FCC using silica and eluting with a 10% to 40% EtOAc in heptane gradient to afford the title compound as an off-white solid (3.88 g, 71%). LC-MS 100%, 2.10 min (3.5 minute LC-MS method), m/z=327.9/329.8, 1H NMR (500 MHz, Chloroform-d) δ 7.23 (d, J=1.9 Hz, 1H), 6.84 (d, J=1.7 Hz, 1H), 4.02 (dt, J=11.7, 3.5 Hz, 2H), 3.87 (s, 3H), 3.65 (d, J=7.2 Hz, 1H), 3.59-3.45 (m, 3H), 2.23 (s, 3H), 2.05 (d, J=13.8 Hz, 2H), 1.51 (ddd, J=24.1, 10.8, 4.2 Hz, 2H).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([C:10]1[CH:11]=[C:12]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH:18]([CH3:22])[NH:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[K+]>CCO>[CH3:8][CH:7]([CH3:9])[CH2:6][CH:5]([C:10]1[CH:11]=[C:12]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH:18]([CH3:22])[NH:17]2)[CH:15]=1)[C:4]([OH:33])=[O:3]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCC(C)N2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCC(C)N2)c1
Temperature: 80 °C

Procedure:
To 4-Methyl-2-[5-(6-methyl-piperidin-2-yl)-4′-trifluoromethyl-biphenyl-3-yl]-pentanoic acid ethyl ester, compounds 6c in EtOH (4 mL) was added 2M KOH (162 μL, 0.324 mmol). The reaction was heated to 80° C. for 2 hours, cooled to room temperature, and concentrated in vacuo. Purification via Gilson HPLC, followed by salt exchange with aqueous 1N HCl gave the product as a white solid. 1H NMR (300 MHz, MeOD) δ ppm 0.96 (dd, J=6.59, 1.70 Hz, 6 H) 1.39 (d, J=6.41 Hz, 3 H) 1.49-1.63 (m, 2 H) 1.65-1.80 (m, 1 H) 1.85 (d, J=4.14 Hz, 1 H) 2.06 (dt, J=13.56, 7.72 Hz, 5 H) 3.35-3.49 (m, 1 H) 3.83 (t, J=7.72 Hz, 1 H) 4.36 (dd, J=12.06, 2.64 Hz, 1 H) 7.53-7.57 (m, 1 H) 7.73 (s, 2 H) 7.76-7.88 (m, 4 H) Calcd for C25H30F3NO2 (M+H) 433.51, Found 434.2.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([F:27])[C:25]=1[F:26])[C:20](O)=[O:21]>>[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([F:27])[C:25]=1[F:26])[C:20]([NH:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1)=[O:21]
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Reactant: Nc1cc(C(F)(F)F)cc2[nH]c(=O)[nH]c12
Product: O=C(Nc1cc(C(F)(F)F)cc2[nH]c(=O)[nH]c12)c1cc(F)c(F)c(F)c1

Procedure:
4-Amino-6-trifluoromethyl-1,3-dihydro-benzoimidazol-2-one (2.17 g, 10 mmol, Example 61a) and 3,4,5-trifluoro-benzoic acid (1.94 g, 11 mmol, Aldrich) reacted under the conditions of Example 65 to give the title compound as a white solid. MS (ESI, pos. ion) m/e: 376 (M+1), (ESI, neg. ion) m/z: 374 (M−1)