Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH3:28])[CH2:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][CH:17]3O)[N:9]=1)[CH3:2].[NH2:29][CH2:30][CH2:31][OH:32]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH3:28])[CH2:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][CH:17]3[NH:29][CH2:30][CH2:31][OH:32])[N:9]=1)[CH3:2]
Reactant: NCCO
Reactant: CCOc1ccc(Cc2nc(-c3cccc4c3CCC4O)no2)cc1OCC
Product: CCOc1ccc(Cc2nc(-c3cccc4c3CCC4NCCO)no2)cc1OCC

Procedure:
Prepared using General Procedure 14 using 4-(5-(3,4-diethoxybenzyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ol 60 and 2-aminoethanol.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[F:16][C:17]([F:41])([F:40])[CH2:18][NH:19][C:20]([C:22]1([CH2:35][CH2:36][CH2:37][CH2:38]Br)[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21]>>[F:16][C:17]([F:40])([F:41])[CH2:18][NH:19][C:20]([C:22]1([CH2:35][CH2:36][CH2:37][CH2:38][N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: Cl
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc(Cl)cc3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-(4-chloro-phenyl)-piperazine dihydrochloride and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [SH:1]CCC(OC)=O.[H-].[Na+].[Cl:10][C:11]1[C:12]([C:27]([NH2:29])=[O:28])=[C:13]2[N:18]([C:19]=1[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:17][CH2:16][C:15](Cl)=[CH:14]2.Cl>CN(C)C=O.O>[Cl:10][C:11]1[C:12]([C:27]([NH2:29])=[O:28])=[C:13]2[N:18]([C:19]=1[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:17][CH2:16][C:15]([SH:1])=[CH:14]2
Reactant: COC(=O)CCS
Reactant: NC(=O)c1c(Cl)c(-c2cccnc2)n2c1C=C(Cl)CC2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1c(Cl)c(-c2cccnc2)n2c1C=C(S)CC2
Temperature: 68 °C
Yield: 36 %

Procedure:
2.4 g of methyl 3-mercaptopropionate are dissolved in 100 cm3 of dimethylformamide. 0.8 g of sodium hydride is added in small fractions, and then 3.08 g of 2,7-dichloro-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxamide in 80 cm3 of dimethylformamide are poured in. The mixture is heated at 68° C. for 2 hours 30 minutes, and then poured into 25 cm3 of hydrochloric acid (4 N). The mixture is concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 60° C. The yellow residue obtained is taken up in 280 cm3 of water and 10 cm3 of hydrochloric acid (2 N), and then filtered and washed with twice 5 cm3 of water. 1.1 g of 2-chloro-3-pyridin-3-yl-7-mercapto-5,6-dihydroindolizine-1-carboxamide are thus obtained in the form of a yellow powder melting at 232° C.
Reaction SMILES: Cl.[CH:2]12[NH:11][CH:6]([CH2:7][C:8](=[O:10])[CH2:9]1)[CH2:5][O:4][CH2:3]2.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22])([O-:14])=[O:13]>C(Cl)Cl>[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:11]1[CH:6]2[CH2:7][C:8](=[O:10])[CH2:9][CH:2]1[CH2:3][O:4][CH2:5]2)(=[O:23])=[O:22])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: O=C1CC2COCC(C1)N2
Agent: Cl
Solvent: ClCCl
Product: O=C1CC2COCC(C1)N2S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 75 %

Procedure:
A solution of 3-oxa-9-azabicyclo[3.3.1]nonan-7-one hydrochloride (CAS 1126795-00-3, 2.82 g), TEA (6.12 g, 60 mmol, 3.0 eq) and 2-Nitro-benzenesulfonyl chloride (8.84 g, 40 mmol, 2.0 eq) in DCM (100 mL) was stirred at room temperature for 10 h. Then the solvent was removed in vacuo, the residue was purified by silica gel (EA/PE=1:3) to give 9-(2-nitrophenyl)sulfonyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-one 107b as a white solid, 4.90 g, yield: 75%. MS: calc'd (MH+) 327, measured (MH+) 327.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:10]=1[CH:11]=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:8][C:9]1[C:10]2[CH:11]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[O:17][C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: O=Cc1c(O)cccc1Cl
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)cccc2o1
Temperature: 25 °C

Procedure:
Ethyl chloroacetate (8.0 mL, 1.3 eq.) was added to a mixture of 2-chloro-6-hydroxy-benzaldehyde (Example 1a), 9.0 g, 57 mmol) and potassium carbonate (16.0 g, 114 mmol) in DMF (100 mL) at rt. The reaction mixture was heated at +120° C. for 1.5 h, cooled to room temperature and filtered through a short bed of Celite. The filtrate was acidified to pH 2 with 5 M HCl and the solution was extracted with dichloromethane (2×100 mL). The combined organic extracts was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography by using hexane/ethyl acetate (9/1) as eluent to give the title compound. Yield: 10 g (77%). 1H NMR (400 MHz, CDCl3) δ ppm 1.44 (t, 3H) 4.56 (q, 2H) 7.29-7.32 (m, 1H) 7.35-7.40 (m, 1H) 7.49-7.52 (m, 1H) 7.60 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)[C:19](=[O:33])[CH2:18]2)=[C:13]([CH3:34])[N:12]([CH2:35][C:36]2C(F)=[CH:40][CH:39]=[CH:38][C:37]=2[F:43])[C:11]1=[O:44])(C)(C)C.[F:52][C:53]([F:58])([F:57])[C:54](O)=O.C([O-])(O)=O.[Na+]>ClCCl>[NH2:7][C@H:8]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)[C:19](=[O:33])[CH2:18]2)=[C:13]([CH3:34])[N:12]([CH2:35][C:36]2[C:54]([C:53]([F:58])([F:57])[F:52])=[CH:40][CH:39]=[CH:38][C:37]=2[F:43])[C:11]1=[O:44]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1c(N2CCN(Cc3cccc([N+](=O)[O-])c3)C(=O)C2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(N2CCN(Cc3cccc([N+](=O)[O-])c3)C(=O)C2)c(=O)n(C[C@H](N)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
To a solution of ((R)-2-{3-(2,6-difluoro-benzyl)-4-methyl-5-[4-(3-nitro-benzyl)-3-oxo-piperazin-1-yl]-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl}-1-phenyl-ethyl)-carbamic acid tert-butyl ester (28 mg, 0.0371 mmol) in 1 mL of dichloromethane was added trifluoroacetic acid (0.1 ml, 1.29 mmol) under ice cooling, followed by stirring at room temperature for 2 hrs. The solution was neutralized with sat. NaHCO3, extracted with dichloromethane and concentrated in a vacuum. The residue was purified by column chromatography eluting with a dichloromethane/methanol (20/1) eluent to afford 11 mg of compound 9-1 (45%). 1H NMR (300 MHz, CDCl3) δ 2.42 (3H, s), 2.81 (1H, m), 3.12 (1H, m), 3.30-3.49 (2H, m), 3.72 (1H, m), 4.02-4.22 (3H, m), 4.33 (1H, dd), 4.55 (1H, m), 4.91 (1H, m), 5.23 (2H, dd), 6.92 (2H, t), 7.20-7.37 (6H, m), 7.53 (1H, t), 7.65 (1H, d), 8.13 (1H, s), 8.15 (1H, m).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[C:22]6[CH:28]=[CH:27][NH:26][C:23]6=[N:24][CH:25]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8]2=[O:30])[C:4]([CH3:31])=[N:3]1.[H-].[Na+].I[CH3:35]>CN(C=O)C.CO>[CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[C:22]6[CH:28]=[CH:27][N:26]([CH3:35])[C:23]6=[N:24][CH:25]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8]2=[O:30])[C:4]([CH3:31])=[N:3]1
Reactant: CI
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc5[nH]ccc5c4)cc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc5c(ccn5C)c4)cc3c21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of a new batch of 1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 36, 45.4 mg, 0.111 mmol) in 1.5 ml anhydrous DMF was treated with 55% NaH in oil (6.0 mg, 0.138 mmol). The reaction mixture was stirred for 20 min at rt, then was added iodomethane (0.009 ml, 138 mmol). The reaction mixture was stirred for 1.5 h at rt. The RM was diluted with MeOH+3 drops TFA and purified directly by Prep.HPLC (H2O (0.1% TFA)/CH3CN 95:5 to 60:40). The fractions containing products were collected together and basified with NaHCO3 (0.3 g), before being concentrated. The resulting suspension was filtered and the cake was washed with water, before being dried under high vacuum to give the title compound as a white solid. (HPLC: tR 2.62 min (Method A); M+H=424 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.96 (s, 1H), 8.38-8.36 (m, 1H), 8.18-8.16 (m, 1H), 8.13-8.09 (m, 1H), 8.06-8.04 (m, 1H), 7.99-7.95 (m, 1H), 7.60-7.58 (m, 1H), 7.57-7.55 (m, 1H), 6.54-6.51 (m, 1H), 3.93 (s, 3H), 3.85 (s, 3H), 3.58 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [C:1](=[O:25])([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:2][CH:3](Cl)[CH3:4].[C:26]([NH:29][C:30]1[C:31]([I:46])=[C:32]([N:41]([CH3:45])[C:42](=[O:44])[CH3:43])[C:33]([I:40])=[C:34]([C:37]([O-:39])=[O:38])[C:35]=1[I:36])(=[O:28])[CH3:27].[K+].[I-].[K+]>CN(C)C=O>[C:26]([NH:29][C:30]1[C:31]([I:46])=[C:32]([N:41]([CH3:45])[C:42](=[O:44])[CH3:43])[C:33]([I:40])=[C:34]([C:37]([O:39][CH:3]([O:2][C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:25])[CH3:4])=[O:38])[C:35]=1[I:36])(=[O:28])[CH3:27]
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)OC(C)Cl
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOC(=O)OC(C)OC(=O)c1c(I)c(NC(C)=O)c(I)c(N(C)C(C)=O)c1I
Temperature: 50 °C
Reaction time: 18 h

Procedure:
1-Chloroethyl octadecyl carbonate (7.54 g, 20 mmol) was added at room temperature to a solution of potassium 5-acetamido-3-(N-methylacetamido)-2,4,6-triiodobenzenecarboxylate (15.99 g, 24 mmol) and potassium iodide (0.33 g, 2 mmol) in dry N,N-dimethylformamide. After stirring at 50° C. for 18 hours the solvent was removed at reduced pressure. The residue was suspended in chloroform (200 ml) and washed three times with a saturated sodium bicarbonate solution and finally twice with water. After drying with magnesium sulphate the solvent was removed at reduced pressure. Yield: 18.6 g. The product was further purified by flash chromatography (Silicagel 60, chloroform/acetonitrile 85:15). 1H NMR (DMSO-d6): δ 0.852(CH2CH3), 1.236(CH2), 1.639(CHCH3),1.657(COOCH2CH2), 1.670(N(CH3)COCH3), 2.051(NCOCH3),2.965(NCH3), 4.154(COOCH2), 6.971 (CHCH3),10.103 (NH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[F:15].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:26][O:27][C:28]1[CH:43]=[CH:42][C:31]([CH2:32][O:33][CH2:34][C@@H:35]2[C@@H:40]3[C@H:36]2[CH2:37][O:38][C:39]3=[O:41])=[CH:30][CH:29]=1.Cl>C1COCC1.CCOC(C)=O>[F:15][C:3]1[CH:4]=[C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:6]=[CH:7][C:2]=1[NH:1][C:37]([C@@H:36]1[C@@H:35]([CH2:34][O:33][CH2:32][C:31]2[CH:42]=[CH:43][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)[C@@H:40]1[CH2:39][OH:41])=[O:38]
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Reactant: COc1ccc(COC[C@H]2[C@@H]3COC(=O)[C@H]23)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(COC[C@H]2[C@H](CO)[C@@H]2C(=O)Nc2ccc(-n3ccccc3=O)cc2F)cc1
Temperature: 78 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of 850 mg (3.4 mmol) of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (prepared according to C. F. Bigge et al., patent application WO 2003045912) in 80 ml of THF was cooled to −78° C., treated dropwise with 4.8 ml of a 1M lithium bis(trimethylsilyl)amide-solution in THF and stirred for 30 min at 78° C. To this solution were added 839 mg (4.8 mmol) of (1R,5S,6S) 6-(4-methoxy-benzyloxymethyl)-3-oxa-bicyclo[3.1.0]hexan-2-one dissolved in 5 ml of THF. Stirring was continued at −78° C. for 1 hr and then for 3 hrs at RT. Pouring of the mixture into a 2M aqueous solution of HCl, extraction with AcOEt, drying of the combined organic phases over Na2SO4, filtration and evaporation of the solvent gave 1.2 g (77%) of (1S,2S,3S) 2-hydroxymethyl-3-(4-methoxy-benzyloxymethyl)-cyclopropanecarboxylic acid [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. Yellow semisolid. 453 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8](=[O:11])[C:9]#[CH:10])=[CH:4][CH:3]=1.C(=O)C.C(CN)O>>[F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C@@H:8]([OH:11])[C:9]#[CH:10])=[CH:4][CH:3]=1
Reactant: C#CC(=O)COc1ccc(F)cc1
Agent: CC=O
Solvent: NCCO
Product: C#C[C@H](O)COc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.7 %

Procedure:
A solution of R-Alpine-Borane® (0.5 M in THF, 930 mL, 465 mmol) was evaporated to dryness under vacuum to get about 150 g of a thick syrup. 4-(4-Fluorophenoxy)-1-butyn-3-one (27.6 g, 155 mmol) was added and when an exothermic reaction was observed, the reaction mixture was cooled with an ice/water bath, then allowed to warm to ambient temperature. After two days, the reaction mixture was cooled to 0° C. and acetaldehyde (26 mL, 465 mmol) was added to quench the excess reagent. After stirring at ambient temperature for 2 hours the reaction mixture was placed under vacuum and stirred first at 0° C. for one hours, then at 65° C. for 2 hours. The reaction mixture was cooled to ambient temperature and ether (300 mL) was added under nitrogen. Ethanolamine (30 mL, 465 mmol) was added drop-wise at 0° C. and the resulting reaction mixture was stored in the freezer overnight. The resulting precipitate was removed by filtration and washed with cold ether. The combined filtrates were concentrated under vacuum. The crude product was purified by flash chromatography on a 2.5 L column of silica gel with 10-25% ethyl acetate in hexane as eluant to obtain 27 g of (3S)-4-(4-fluorophenoxy)-3-hydroxy-1-butyne, a compound of formula (BB), in quantitative yield; 1H NMR (CDCl3) δ 2.56 (s, 1H), 4.10 (m, 2H), 4.78 (m, 1H), 6.85 (m, 2H), 7.0 (m, 2H). This material was determined to be about 64% ee based on chiral HPLC of its 3,5-dinitrobenzoyl ester (see below).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[F:15][C:16]1[CH:17]=[C:18]([CH:28]([NH:30][C:31]([C:33]2[N:34]=[C:35](Cl)[O:36][CH:37]=2)=[O:32])[CH3:29])[CH:19]=[C:20]([F:27])[C:21]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:27][C:20]1[CH:19]=[C:18]([CH:28]([NH:30][C:31]([C:33]2[N:34]=[C:35]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]=3[F:1])[O:36][CH:37]=2)=[O:32])[CH3:29])[CH:17]=[C:16]([F:15])[C:21]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1coc(-c2cccc(C(F)(F)F)c2F)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 31.8 %

Procedure:
2-Fluoro-3-trifluoromethylbenzeneboronic acid (54 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylaminophenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (21 mg, 32%) after purification by flash chromatography on silica gel (% EtOAc in hexane=12%˜80%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C@@H:5]1[CH2:9][CH:8]([OH:10])[CH2:7][N:6]1C(OCC1C=CC=CC=1)=O)[CH3:2].[ClH:22]>C(O)C.[Pd]>[ClH:22].[CH2:1]([O:3][C:4](=[O:21])[C@@H:5]1[CH2:9][CH:8]([OH:10])[CH2:7][NH:6]1)[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(O)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC(O)CN1
Reaction time: 3 h

Procedure:
To a solution of N-Cbz-4-hydroxy-L-proline ethyl ester (3.29 g) in 40 ml ethanol was added 6 ml of ethanol saturated with gaseous HCl followed by 10% palladium on carbon (0.50 g). The mixture was hydrogenated on a Parr Hydrogenator at 30-40 psi for 3 hours. The solution was filtered over celite and concentrated in vacuo to provide 2.09 g of the crystalline product.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][CH2:28][C:29]([NH:33][S:34]([C:37]1[S:38][C:39]([Cl:43])=[C:40]([NH2:42])[CH:41]=1)(=[O:36])=[O:35])([CH2:31][OH:32])[CH3:30]>>[Cl:43][C:39]1[S:38][C:37]([S:34](=[O:36])(=[O:35])[NH:33][C:29]([CH2:28][OH:27])([CH3:30])[CH2:31][OH:32])=[CH:41][C:40]=1[NH:42][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:13]
Reactant: CC(CO)(CO)NS(=O)(=O)c1cc(N)c(Cl)s1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(CO)(CO)NS(=O)(=O)c1cc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(Cl)s1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (example B.7) according to general procedure II. Yellow solid. MS (ISP) 656.0 [(M−H)−]; mp 201° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9][C:8]([C:19]([O:21][CH3:22])=[O:20])=[CH:7][C:6]=2[CH:23]=1.Cl.[OH-].[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][C:8]([C:19]([O:21][CH3:22])=[O:20])=[CH:7][C:6]=2[CH:23]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COC(=O)C1=Cc2cc(Br)ccc2NCC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
In ethyl acetate (50 ml) was dissolved methyl 7-bromo-1-(t-butoxycarbonyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.5 g). To the solution was added 6N hydrochloric acid (2 ml), and the mixture was heated to stir at 80° C. for 2 hours, neutralized with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give methyl 7-bromo-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.0 g) as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[C:12](Cl)(=[O:20])[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:12](=[O:20])[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:7]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 62.6 %

Procedure:
To a solution of 8.0 g of 2-amino-4,6-dimethoxypyrimidine in 50 ml of tetrahydrofuran are added 4.0 g of phenyl chlorocarbonate and 0.1 g of 4-dimethylaminopyridine, followed by stirring for 17 hours at room temperature. The mixture is allowed to stand overnight and filtered to remove insoluble product and the filtrate is purified by silica gel chromatography (eluent: dichloromethane) to give 4.4 g of the title compound. mp. 118°-119° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](=[N:5][NH:6][C:7]1[CH:8]=[N:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[NH2:4].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=O)=[CH:21][CH:20]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O1CCOCC1>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:23]([C:22]3[CH:26]=[CH:27][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)=[N:4][C:3]([C:2]([F:1])([F:15])[F:16])=[N:5]2)=[CH:8][N:9]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(NN=C(N)C(F)(F)F)cn1
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COc1ccc(-c2nc(C(F)(F)F)nn2-c2ccc(OC)nc2)cc1
Reaction time: 8 h
Yield: 19.1 %

Procedure:
A mixture of 2,2,2-trifluoro-N′-(6-methoxypyridin-3-yl)ethanehydrazonamide (0.2 g, 0.854 mmol), 4-methoxybenzoyl chloride (175 mg, 1.02 mmol), pyridine (0.083 mL, 1.02 mmol), and 4-dimethylaminopyridine (125 mg, 1.02 mmol) in dioxane (2 mL) was refluxed with stirring overnight. After cooling, the solvent was removed under reduced pressure. ethyl acetate-tetrahydrofuran (9:1) and water was poured into the residue and the organic layer was separated, washed with 0.1 N hydrochloric acid, water, and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 2-methoxy-5-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]pyridine (57 mg, 19.1% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[H-].[Na+].I[CH3:17]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:17])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: CI
Reactant: O=[N+]([O-])c1cc(Br)cc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ncc2c([N+](=O)[O-])cc(Br)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 36.7 %

Procedure:
6-Bromo-4-nitro-1H-indazole (available from Sinova, 1.05 g, 4.13 mmol) was dissolved in THF (20 ml) and cooled to 0° C. under nitrogen. 60% Sodium hydride in mineral oil (191 mg, 7.57 mmol) was added portion-wise allowing the evolution of gas to subside before adding the next portion. This was left under nitrogen, stirring at 0° C. for 15 mins. Iodomethane (0.298 ml, 4.78 mmol) in THF (5 ml) was added dropwise to the reaction, washing through with further THF (5 ml). The reaction was then allowed to warm to room temperature. The reaction was stirred for 5 h then partitioned between ethyl acetate and water, washing the water with ethyl acetate (x3). The combined organics were washed with brine, dried over magnesium sulphate, filtered and evaporated to dryness. The residue was purified by silica chromatography using a gradient of 0-25% ethyl acetate in cyclohexane, to give the title compound (388 mg).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:10]([N:12]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]1)=[O:11])=O)(C)(C)C.[ClH:26].O1CCOCC1>>[ClH:26].[NH2:8][C@H:9]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:10]([N:12]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC(O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](Cc1ccccc1)C(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-2-(N-t-butoxycarbonylamino)-1-(4-hydroxy-piperidin-1-yl)-3-phenyl-propan-1-one (12.5 mmol) was dissolved in 4M HCl-dioxane at 0° C. and the resulting suspension stirred at 25° C. for 1 hour. The mixture was concentrated and the residue triturated with ether. Yield, 3.44 g, 97%.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:4].[OH-].[Na+]>CCO>[CH3:13][S:10]([C:7]1[O:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=1)(=[O:12])=[O:11]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(=O)O)o1
Temperature: 80 °C

Procedure:
To a solution of 5-methanesulfonyl-furan-2-carboxylic acid methyl ester (2.94 g, 14.4 mmol) in EtOH (100 mL) was added a 2 N aqueous solution of sodium hydroxide (40 mL, 80 mmol). The mixture was warmed at 80° C. for 4 hours and then concentrated in vacuo to remove ethanol. The mixture was then acidified with 1 N aqueous HCl and extracted with ethyl acetate (4×30 mL). The combined organic layers were washed with brine (2×100 mL), dried over sodium sulfate, filtered and concentrated to afford 5-methanesulfonyl-furan-2-carboxylic acid.