Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [PH2:1]([OH:3])=[O:2].[CH:4](=[N:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:5]([CH3:7])[CH3:6]>C(O)C>[CH:9]([NH:8][CH:4]([P:1]([OH:3])[OH:2])[CH:5]([CH3:7])[CH3:6])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)C=NC(c1ccccc1)c1ccccc1
Reactant: O=[PH2]O
Solvent: CCO
Product: CC(C)C(NC(c1ccccc1)c1ccccc1)P(O)O
Reaction time: 1 h

Procedure:
Hypophosphorous acid (100%, 15.8 parts) dissolved in absolute ethanol was added to a stirred solution of 41.3 parts isobutylidenebenzhydrylamine in absolute ethanol. An exothermic reaction occurred. After standing one hour the reaction was filtered and the white solid dried in vacuo. There was obtained DL-1-benzhydrylamino-2-methylpropanephosphonous acid, melting point 191° (dec.).
Reaction SMILES: COC1C=CC(C[N:8]([C:32]2[S:33][CH:34]=[CH:35][N:36]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:20]([C:21]4[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=4[C:23]([O:25][CH3:26])=[O:24])[CH2:19][CH2:18][O:17][C:16]=3[CH:31]=2)(=[O:11])=[O:10])=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[S:33]1[CH:34]=[CH:35][N:36]=[C:32]1[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]2[N:20]([C:21]3[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=3[C:23]([O:25][CH3:26])=[O:24])[CH2:19][CH2:18][O:17][C:16]=2[CH:31]=1)(=[O:10])=[O:11]
Reactant: COC(=O)c1ccccc1N1CCOc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 33.3 %

Procedure:
To a solution of methyl 2-(7-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)benzoate (From example 254, step 1; 1.2 g, 2.784 mmol) in DCM (40 mL) was added TFA (2.0 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 5 h. After completion, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (20 mL) and the aqueous layer was extracted with DCM (2×20 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by combiflash column chromatography (column size: 12 g; elution: 0-50% ethyl acetate in hexane) to get methyl 2-(7-(N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)benzoate as a yellow solid (400 mg, 42.7%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]([CH2:22][CH2:23]Br)[CH2:10][CH2:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:14][CH2:13]1)=[O:5])[CH3:2].[O-]CC.[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:23][CH2:22][N:9]([CH2:10][CH2:11][CH:12]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:14][CH2:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CCCN(CCBr)CCC1COc2ccccc2C1
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(CCC2COc3ccccc3C2)CC1
Temperature: 25 °C

Procedure:
At room temperature and while stirring, a solution of 11.94 g (30 mmol) of N-(3-ethoxycarbonylpropyl)-N-(2-bromoethyl)-N-[2-(chroman-3-yl)ethyl]-amine in 40 ml of absolute dimethylformamide is added dropwise within a period of 20 minutes to a suspension of 2.72 g (40 mmol) of sodium ethoxide in 30 ml of dimethylformamide. The reaction mixture is stirred for 16 hours at room temperature and then concentrated to dryness by evaporation under a high vacuum. Diethyl ether is added to the residue and extraction is carried out with cold 2N hydrochloric acid. The combined hydrochloric acid extracts are extracted by shaking with dichloromethane and the dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. The crude product is obtained as the residue and is chromatographed on 500 g of silica gel (0.040-0.063 mm) using ethyl acetate as the eluant. The eluate is concentrated by evaporation to yield 1-[2-(chroman-3-yl)ethyl]-piperidine-4-carboxylic acid ethyl ester in the form of a colourless oil. The 1-[2-(chroman-3-yl)ethyl]-piperidine-4-carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from ethanol/diethyl ether and melts at 182°-186°.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]=[CH:13][C:14]([F:17])([F:16])[F:15])(=O)=O)=CC=1.[F:19][C:20]([F:30])([F:29])[CH2:21][CH2:22][S:23]([CH2:26][C:27]#[N:28])(=[O:25])=[O:24].[H-].[Na+].Cl>O1CCCC1>[F:15][C:14]([F:17])([F:16])[CH:13]=[CH:12][CH2:11][CH:26]([S:23]([CH2:22][CH2:21][C:20]([F:19])([F:29])[F:30])(=[O:24])=[O:25])[C:27]#[N:28]
Reactant: N#CCS(=O)(=O)CCC(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)OCC=CC(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(CC=CC(F)(F)F)S(=O)(=O)CCC(F)(F)F
Reaction time: 24 h
Yield: 51.5 %

Procedure:
To a solution of 1.7 g of 4,4,4-Trifluoro-2-butenyl p-toluenesulfonate and 1.2 g of (3,3,3-trifluoropropylsulfonyl)acetonitrile in 30 ml of tetrahydrofuran, 0.2 g of sodium hydride (60% in oil) was added at room temperature, and stirred at the same temperature for 1 day. To the reaction mixture, 10% hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.95 g of 6,6,6-trifluoro-2-(3,3,3-trifluoropropylsulfonyl)-4-hexenenitrile (hereinafter referred to as the present compound (19)).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].[K].[CH2:15](Br)[CH2:16][CH:17]([CH3:19])[CH3:18]>CN(C=O)C>[CH2:15]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c[nH]1
Reactant: CC(C)CCBr
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc([N+](=O)[O-])cn1CCC(C)C
Temperature: 100 °C
Reaction time: 5 h
Yield: 85.1 %

Procedure:
Ethyl 4-nitro-1H-pyrrole-2-carboxylate (2.022 g, 10.983 mmol; see Example 1, step (i) above) was dissolved in DMF (30 mL, dry) to which potassium (0.569 g, 14.552 mmol) was added with stirring under nitrogen. The reaction mixture was heated at 100° C. for 1 h and then the temperature was allowed to reach 50° C. Isoamyl bromide (2.498 g, 16.538 mmol) was then added, followed by KI (2.197 g, 14.552 mmol). The temperature was raised to 100° C. and stirring continued for 5 h, after which time the temperature was allowed to return to room temperature. The reaction mixture was then stirred overnight, following which the solvent was removed under reduced pressure at 50° C. The crude product was dissolved in DCM and the salt extracted with water. The organic extract was dried over MgSO4, filtered and the solvent removed under reduced pressure at 30° C. The crude product obtained was chromatographed over silica gel using 1/2 n-hexane/DCM as eluant. Material with Rf=0.3 was collected and the solvent was removed under reduced pressure to give white crystalline material (2.377 g, 85% yield). M.p. 46-47° C. (Lit. m.p. 46-47° C.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.CCO[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH2:23]([O:22][C:20]([C:14](=[CH:13][NH:1][C:2]1[C:3]([O:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:21])[CH3:24]
Reactant: COc1ncccc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1cccnc1OC)C(=O)OCC
Temperature: 60 °C
Yield: 82.6 %

Procedure:
3-amino-2-methoxypyridine (12.0 g) was reacted with diethyl ethoxymethylene malonate (23.0 g) at a temperature of 120° C. to 130° C. for 30 minutes while distilling ethanol produced during the reaction. After completion of the reaction, the reaction mixture was cooled to 60° C., and poured into petroleum ether (200 ml) and cooled to 0° C. The resulting precipitates were filtered to give 23.5 g (82%) of the titled compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH3:23])[C:15](=[O:22])[N:16]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]3=[CH:10][CH:9]=2)=[CH:4][CH2:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:57][N:58]1[CH:62]=[CH:61][N:60]=[C:59]1[C:63](O)=[O:64]>CN1C(=O)CCC1>[CH3:21][C:18]([CH3:20])([CH3:19])[CH2:17][N:16]1[C:11]2[C:12](=[N:13][C:8]([C:5]3[CH2:6][CH2:7][CH:2]([NH:1][C:63]([C:59]4[N:58]([CH3:57])[CH:62]=[CH:61][N:60]=4)=[O:64])[CH2:3][CH:4]=3)=[CH:9][CH:10]=2)[N:14]([CH3:23])[C:15]1=[O:22]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CCC(N)CC3)nc21
Reactant: Cn1ccnc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccnc1C(=O)NC1CC=C(c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a round bottom flask were added 5-(4-Aminocyclohex-1-en-1-yl)-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (17-2) (0.0010 g, 0.028 mmol), DIPEA (0.050 mL, 0.286 mmol), HATU (0.0013 g, 0.034 mmol), 1-methyl-1H-imidazole-2-carboxylic acid (0.00467 g, 0.037 mmol), and NMP (1 mL). The reaction was stirred at room temperature overnight (˜14 hours), the reaction mixtures were then filtered & purified by reverse-phase chromatography (5-95% 0.1% TFA in H2O:acetonitrile) to give N-{4-[1-(2,2-Dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]cyclohex-3-en-1-yl}-1-methyl-1H-imidazole-2-carboxamide (17-3). HRMS m/z (M+H): calculated=423.2503; observed=423.2507.
Reaction SMILES: [NH2:1][C:2](=[O:36])[C@@H:3]([NH:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.Br[C:38]1[CH:39]=[CH:40][C:41]([C:44]#[N:45])=[N:42][CH:43]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[NH2:1][C:2](=[O:36])[C@@H:3]([NH:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:38]2[CH:43]=[N:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=2)=[CH:7][CH:6]=1
Reactant: N#Cc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)nc2)cc1)C(N)=O
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
A solution of (S)-tert-butyl 2-((S)-1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)piperidine-1-carboxylate (0.150 g) in dioxane (1 mL) was added to a stirred solution of 5-bromopicolinonitrile (0.055 g) and bis[bis(1,2-diphenylphosphino)ethane]palladium (0) (0.003 g) in dioxane (1 mL) under nitrogen. The resulting mixture was stirred for 10 min. A solution of potassium carbonate (0.124 g) in water (0.75 mL) was added and the resulting solution was stirred at 75° C. for 16 h. The cooled mixture was evaporated to dryness. The residue was taken up in ethyl acetate and washed with saturated brine, dried over sodium sulfate and adsorbed onto silica. The crude product was purified by flash silica chromatography, eluting with 3:1 ethyl acetate/isohexane). Pure fractions were evaporated to dryness to afford the subtitle compound (0.113 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)#[N:10].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:14]2[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Clc1cc(I)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2ccnc(Cl)c2)cc1
Temperature: 150 °C
Yield: 72.8 %

Procedure:
2-Chloro-4-iodopyridine (1.6 mmol), 4-cyanophenyl boronic acid (2.5 mmol), 2 M potassium carbonate (3.3 mmol), tetrakis(triphenyphosphine)palladium(0) (0.01 mmol) and dioxane (8 mL) were combined in a vial and heated by microwave for 10 min at 150° C. The crystallized product was filtered and subsequently dried in vacuo to yield 250 mg of 4-(2-chloropyridin-4-yl)-benzonitrile as yellow needles. 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J=5.1 Hz, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.72 (d, J=8.2 Hz, 2H), 7.55 (m, 1H), 7.43 (dd, J=5.2, 1.4 Hz, 1H); EIMS 214 m/z (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.O[C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][N:30]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:36][O:35][C:33](=[O:34])[C:32]1[CH:37]=[CH:38][C:29]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:30][CH:31]=1
Reactant: COC(=O)c1ccc(O)nc1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)nc1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and methyl 6-hydroxynicotinate (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. Colorless oil (78%). MS (Turbo Spray): m/z=526.2 [M+H].
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[O:29]([C:31]#[N:32])[K]>CC#N.O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:31](=[O:29])[NH2:32])[CH2:21]3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCCNC3)n2)c1
Reactant: N#CO[K]
Solvent: O
Solvent: CC#N
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCCN(C(N)=O)C3)n2)c1
Reaction time: 4 h
Yield: 6.8 %

Procedure:
To a mixture of 2-(3-acetamidophenylamino)-4-(piperidin-3-ylmethylamino)pyrimidine-5-carboxamide (40 mg, 0.104 mmol) in CH3CN (2 mL), a solution of KOCN (50 mg, 0.617 mmol) in H2O (1 mL) was added. The mixture was stirred at 70 C for 4 h. It was then purified by HPLC to give the titled compound (3 mg). MS 427.4 (M+H); UV 202.2, 248.6 nm.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(CC)CC.[C:39]([C:41]1[CH:42]=[C:43]([S:47](Cl)(=[O:49])=[O:48])[CH:44]=[CH:45][CH:46]=1)#[N:40]>C(Cl)Cl>[C:39]([C:41]1[CH:42]=[C:43]([S:47]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]4[C:17]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=5)=[CH:18][CH:19]=[CH:20][CH:21]=4)=[O:15])=[CH:11][CH:12]=3)[CH2:2][CH2:3]2)(=[O:49])=[O:48])[CH:44]=[CH:45][CH:46]=1)#[N:40]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cccc(S(=O)(=O)N2CCN(c3ccc(NC(=O)c4ccccc4-c4ccc(C(F)(F)F)cc4)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.3 %

Procedure:
To a stirred solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (0.318 g) in CH2Cl2 (20 mL) containing. Et3N (90 mg) was added dropwise 3-cyano-benzenesulfonyl chloride (0.179 g) and the mixture was stirred at room temperature for 48 hours. The solution was then washed with water, with brine, dried over Na2SO4, filtered and evaporated. The residue was then purified by flash chromatography eluting with CH2Cl2 to give the title compound (0.39 g) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:7])[CH2:4][CH2:5][NH2:6].[Cl:8][C:9]1[C:10]([F:34])=[N:11][C:12](NCC(OC)=O)=[C:13]([Cl:27])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[C:18]([CH:24]([CH3:26])[CH3:25])[CH:17]=1>>[Cl:8][C:9]1[C:10]([F:34])=[N:11][C:12]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:7])=[C:13]([Cl:27])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH:24]([CH3:26])[CH3:25])[CH:17]=1
Reactant: COC(=O)CNc1nc(F)c(Cl)c(Oc2ccc(OC)c(C(C)C)c2)c1Cl
Reactant: COC(=O)CCN
Product: CC(C)c1cc(Oc2c(Cl)c(F)nc(NCCC(=O)O)c2Cl)ccc1O

Procedure:
By use of β-alanine methyl ester in place of glycine methyl ester for the preparation of Compound 1e followed by deprotection as described for example 2.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[CH3:32])[CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:27][CH2:26][C:25]2[CH:29]=[CH:30][C:31]([CH3:32])=[C:23]([CH3:22])[CH:24]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: Cc1ccc(CCBr)cc1C
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(CCN2CCC(C(C(N)=O)(c3ccccc3)c3ccccc3)C2)cc1C
Temperature: 25 °C

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.5 g--see Preparation 8), 3,4-dimethylphenethyl bromide (0.4 g--see Preparation 18), anhydrous potassium carbonate (0.5 g) and acetonitrile (10 ml) was heated under reflux for 2 hours. On cooling to room temperature, water (80 ml) was added and the mixture was extracted with dichloromethane (3×70 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a yellow oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 4%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as an oil, yield, 0.22 g.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][S:18][C:17]([CH3:22])([CH3:21])[CH:16]2[C:23]([O-:25])=[O:24])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][S:18][C:17]([CH3:21])([CH3:22])[CH:16]2[C:23]([OH:25])=[O:24])(=[O:13])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)C2C(=O)[O-])cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)C2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of tert-butyl 4-({[4-(2-butynyloxy)phenyl]sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylate (0.31 g, 0.71 mmol) in dichloromethane (7 mL) was added trifluoroacetic acid (3 mL) and the resulting mixture was stirred at room temperature for 1 hour, after which the solvents were evaporated and toluene was added. The toluene and excess trifloroacetic acid were removed to give 0.25 g of (3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid, which was used for the next step without further purification. Yield: 92.6%. mp 129-131° C. %. Electrospray Mass Spec 381.8(M−H)−.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[CH3:18][CH:19]([OH:21])[CH3:20]>>[CH:19]([O:21][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1)([CH3:20])[CH3:18]
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: CC(C)O
Product: CC(C)Oc1nc(Nc2cc[nH]n2)cc2ccccc12

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and propan-2-ol to give (1-isopropoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 269(MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([O:20]CC)=[O:19].[OH-].[Na+].O>C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(Cl)cc2Cl)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: Nc1c(CC(=O)O)cccc1Oc1ccc(Cl)cc1Cl
Yield: 73.8 %

Procedure:
A mixture of ethyl 2-[2-amino-3-(2,4-dichlorophenoxy)phenyl]acetate (3.1 g.), sodium hydroxide (730 mg.) and water (40 ml.) was treated in a similar manner to that of Example 5-(2). The resultant residue was pulverized with benzene, collected by filtration and dried to give 2-[2-amino-3-(2,4-dichlorophenoxy)phenyl]acetic acid (2.1 g.). mp 123° to 124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)=[C:6]([CH:10]=1)[C:7]([NH:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1Oc1cncc(Cl)c1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Oc2cncc(Cl)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-[(5-chloropyridin-3-yl)oxy]benzoic acid (step 1) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 8.41 (1H, d, J=2.0 Hz), 8.28 (1H, d, J=2.5 Hz), 8.13 (1H, d, J=2.8 Hz), 7.96 (2H, d, J=8.4 Hz), 7.45 (1H, dd, J=8.7, 2.8 Hz), 7.37–7.28 (1H, m), 7.31 (2H, d, J=8.4 Hz), 7.20 (1H, dd, J=2.5, 2.0 Hz), 6.90 (1H, d, J=8.7 Hz), 5.37–5.22 (1H, m), 3.91 (3H, s), 1.51 (3H, d, J=6.9 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[O:5][CH2:4][CH2:3]1.C([Li])CCC.Cl[C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:22]=1>O1CCCC1.CCCCCC>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:22]=3)[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCO2
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCO3)nc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Reaction vessels used in this procedure were flame dried under vacuum and all operations were carried out in an oxygen-free, argon or nitrogen atmosphere. To a solution of 509.4 mg (2.74 mmol) of 4,4-dimethyl-6-ethynylchroman in 4 ml of dry tetrahydrofuran at 0° C. was added dropwise 1.72 ml of 1.6M (2.75 mmol) of n-butyl lithium in hexane. Stirring was commenced at 0° C. for 30 minutes and at room temperature for 15 minutes, after which the solution was cooled again to 0° C. and then treated with a solution of 380 mg (2.79 mmol) of fused zinc chloride in 5 ml of dry tetrahydrofuran using a double ended needle. The resulting solution was stirred at 0° C. for 1 hour and then at room temperature for 15 minutes. A solution of 628.6 mg (2.74 mmol) of ethyl 6-chloronicotinate in 4 ml of dry tetrahydrofuran was transferred by double ended needle into a suspension of 380 mg (0.33 mmol) of tetrakistriphenylphosphine palladium in 5 ml dry tetrahydrofuran and mixture stirred at room temperature for 15 minutes and then treated by double ended needle with the solution of alkynylzinc prepared above. The mixture was stirred at room temperature for 20 hours and then quenched with ice and 30 ml of 3N hydrogen chloride. The mixture was extracted with 3×75 ml ether and ether extracts were combined and washed successively with saturated NaHCO3 and saturated NaCl and then dried (MgSO4). Solvent was removed in vacuo and the residue further purified by flash chromatography (silica; 10% ethyl acetate in hexane) to give the title compound as a yellow solid.