Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[CH:7]=[C:6]([NH2:8])[O:5][N:4]=1.Cl[C:12]([O:14][C:15]([CH3:17])=[CH2:16])=[O:13].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>>[F:1][C:2]([F:10])([F:9])[C:3]1[CH:7]=[C:6]([NH:8][C:12](=[O:13])[O:14][C:15]([CH3:17])=[CH2:16])[O:5][N:4]=1
Reactant: Nc1cc(C(F)(F)F)no1
Reactant: C=C(C)OC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: C=C(C)OC(=O)Nc1cc(C(F)(F)F)no1
Yield: 38.2 %

Procedure:
Using general method G, 3-(trifluoromethyl)isoxazol-5-amine (1.38 g, 9.1 mmol) and isopropenyl chloroformate (1.1 g, 9.1 mmol) in presence of LiHMDS (1.0M, 18 mL, 18.2 mmol) were combined to afford prop-1-en-2-yl 3-(trifluoromethyl)isoxazol-5-ylcarbamate (0.82 g, 38% yield).). 1H NMR (400 MHz, DMSO-d6): δ 12.3 (s, 1H), 6.48 (s, 1H), 4.83 (m, 1H), 4.80 (m, 1H), 1.93 (s, 3H); MS (ESI) m/z: 237.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:9]2[C:5]([CH:6]=[C:7]([C:16](=[S:18])[NH2:17])[NH:8]2)=[CH:4][C:3]=1[O:19][C:20]1[CH:21]=[N:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=1.[C:30]([O:35][CH2:36][CH3:37])(=[O:34])[C:31]#[C:32][CH3:33].O1CCCC1.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[F:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:9]2[C:5]([CH:6]=[C:7]([C:16]3[S:18][CH:32]([CH2:31][C:30]([O:35][CH2:36][CH3:37])=[O:34])[CH2:33][N:17]=3)[NH:8]2)=[CH:4][C:3]=1[O:19][C:20]1[CH:21]=[N:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: COCCOc1c(F)c(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=S)[nH]c12
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)c(F)c(OCCOC)c3[nH]2)S1
Temperature: 40 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To a stirred solution of 6-fluoro-7-(2-methoxyethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carbothioamide (0.58 g), ethyl 2-butynoate (0.31 mL), tetrahydrofuran (10 mL) and toluene (15 mL) was added tributylphosphine (0.40 mL) at room temperature under argon atmosphere. After stirring at 40° C. for 3 h, the reaction mixture was concentrated to give a light brown oil, which was purified by silica gel chromatography (ethyl acetate:hexane=35:65 to 100:0, volume ratio) to give the title compound (525 mg, 72%) as a pale yellow oil. MS 552 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:16][CH:15]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)Cc1ccccc1Br
Product: COc1ccc(Nc2ccccc2CC(=O)O)cc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with p-anisidine to yield 2-[(4-methoxyphenyl)amino]phenylacetic acid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]=[C:4]([CH2:8][C:9](=O)[CH3:10])[CH2:3]1.Cl.[CH2:13]([O:16][NH2:17])[CH:14]=[CH2:15]>C(O)C>[CH2:13]([O:16][N:17]=[C:8]([C:4]1[CH2:3][N:2]([CH3:1])[CH2:7][CH2:6][CH:5]=1)[CH2:9][CH3:10])[CH:14]=[CH2:15]
Reactant: C=CCON
Reactant: CC(=O)CC1=CCCN(C)C1
Agent: Cl
Solvent: CCO
Product: C=CCON=C(CC)C1=CCCN(C)C1
Yield: 52.8 %

Procedure:
1-(1,2,5,6-Tetrahydro-1-methyl-3-pyridinyl)propanone (3.06 g, 20 mmol, prepared as described in Example 8 above) was reacted with 3.27 g (30 mmol) of O-2-propenylhydroxylamine hydrochloride in 20 ml of ethanol to prepare 2.2 g (53%) of the title compound, isolated as the ethanedioate salt, mp 117°-120° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH:12]([CH2:30][CH3:31])[C:13]([NH:15][C:16]([CH3:29])([CH3:28])[C:17]#[C:18][CH:19]([O:24][SiH](C)C)C(C)(C)C)=[O:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC.C(OCC)(=O)C>O1CCCC1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH:12]([CH2:30][CH3:31])[C:13]([NH:15][C:16]([CH3:28])([CH3:29])[C:17]#[C:18][CH2:19][OH:24])=[O:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCC(Oc1ccc2ncccc2c1)C(=O)NC(C)(C)C#CC(O[SiH](C)C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCC(Oc1ccc2ncccc2c1)C(=O)NC(C)(C)C#CCO
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 69.8 %

Procedure:
2-(6-Quinolinyloxy)-N-(1-tert.butyldimethylsilyloxy-4-methylpent-2-yn-4-yl)butyramide (0.58 g) in tetrahydrofuran (10 ml) was stirred at 3–5° C. and a solution of tetra n-butylammonium fluoride (2.64 ml of 1M solution in tetrahydrofuran) was added dropwise over 5 minutes. On completion of addition, the mixture was stirred for 0.5 hour at 0° C., 0.75 hour at ambient temperature then stored for 18 hours. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate and aqueous ammonium chloride. The organic phase was separated, washed with aqueous ammonium chloride, brine, dried over magnesium sulphate and evaporated under reduced pressure to give a gum that was fractionated by chromatography (silica; hexane/ethyl acetate, 1:2 by volume) to give the required product as a colourless glass (0.30 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:11])[CH3:10].[C:12]1([C:18]#[CH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:12]1([C:18]#[C:19][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9](=[O:11])[CH3:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)Cc1ccccc1Br
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(=O)Cc1ccccc1C#Cc1ccccc1
Yield: 59 %

Procedure:
To a 3-necked, round bottom flask under nitrogen was added 4.0 g (18.8 mmole) of 2-bromophenyl-2-propanone in 40 ml of triethylamine, 2.5 ml (22.5 mmole) of phenylacetylene, 0.3 g (2 mole %) of bis-(triphenylphosphine) palladium dichloride and 0.14 g (4 mole %) of cuprous iodide. After refluxing for three hours another 0.5 ml (4.5 mmole) of phenylacetylene, 0.6 g (4 mole %) of bis (triphenylphosphine) palladium dichloride and 0.3 g (8 mole %) of cuprous iodide were added. Reflux was continued another 11/2 hours before 1.0 ml (9.0 mmole) of phenylacetylene and 10 ml of triethylamine were added. After an additional 21/2 hours at reflux the reaction was partitioned between ether and water, washed with brine, dried over MgSO4 and evaporated in vacuo to yield 55 g of crude reaction product. The mixture was flash chromatographed eluting with 1:19 ethyl acetate:hexane to give 2.6 g (59%) of 2-(phenylethynyl)phenyl-2-propanone as a dark oil.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[CH2:11][CH:10]([O:12][CH2:13][CH:14]([OH:29])[CH2:15][O:16][C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[C:20]([C:26]([NH2:28])=O)[NH:21]4)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1.N1C=CC=CC=1>[C:30]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][CH:10]([O:12][CH2:13][CH:14]([OH:29])[CH2:15][O:16][C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[C:20]([C:26]#[N:28])[NH:21]4)[CH2:9]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NC(=O)c1cc2c(OCC(O)COC3CN(C(c4ccccc4)c4ccccc4)C3)cccc2[nH]1
Solvent: C1COCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: N#Cc1cc2c(OCC(O)COC3CN(C(c4ccccc4)c4ccccc4)C3)cccc2[nH]1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
10.0 g of 4-(3-(1-diphenylmethylazetidin-3-oxy)-2-hydroxypropoxy)-1H-indole-2-carboxamide are dissolved in a mixture of 112 ml of dioxane and 10 g of pyridine and 10 ml of trifluoroacetic anhydride in 10 ml of dioxane are added at 10° C. After standing for two hours at room temperature, the mixture is stirred into ice water. The mixture is extracted using methylene chloride, washed first with dilute NaOH, then with water, and the organic phase is dried over sodium sulphate and concentrated. The residue is purified by column chromatography on silica gel (eluent: chloroform).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[N:13]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>Cl.O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][NH2:13])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Br)cc1C(F)(F)F
Temperature: -10 °C
Reaction time: 3 h

Procedure:
A suspension of 25.6 g (0.11 mol) 4-bromo-2-(trifluoromethyl)-aniline in 125 ml of conc. hydrochloric acid is cooled to −10° C. and a solution of 7.7 g (0.11 mol) sodium nitrite in 125 ml of water is added. The reaction mixture is stirred for 3 hours at −10 to −5° C., then a solution of 103 g (0.46 mol) tin-(II)-chloride-dihydrate in 125 ml of conc. hydrochloric acid is added dropwise. The mixture is stirred for 1 hour at −5° C. The precipitate formed is suction filtered and washed with water. The aqueous mother liquor is extracted with petroleum ether, then made basic with sodium hydroxide. The precipitate formed is extracted with diethyl ether. The organic phase is dried and evaporated to dryness. Yield: 12.9 g
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[F:23][C:24]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27]>>[F:23][C:24]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:25]=1[CH2:26][NH:27][C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=2[F:21])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5]
Reactant: NCc1ccc(F)cc1F
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O
Product: Cn1c(-c2c(F)cccc2F)nc(C(=O)NCc2ccc(F)cc2F)c(O)c1=O

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 2,4-difluorobenzylamine (72 mg, 0.5 mmol). The title product was obtained as an off-white solid (36.2 mg, 89% yield). 1HNMR (500 MHz, CDCl3) δ: 12.13 (1H, s), 7.87 (1H, br s), 7.06 (2H, dd, J=8.54, 7.33 Hz), 6.86–6.81 (2H, m), 6.75–6.69 (2H, m), 4.56 (2H, d, J=6.41 Hz), 3.42 (3H, s). HRMS (ESI) calcd for C19H12F4N3O3 (M−H): 406.0815; found: 406.0812.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[O:13]=[C:14]1[N:18]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[NH:15]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:22]3[CH2:21][CH2:20][CH:19]([N:18]4[C:17]5[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=5[NH:15][C:14]4=[O:13])[CH2:24][CH2:23]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1[nH]c2ccccc2n1C1CCN(Cc2cn3cc(Cl)ccc3n2)CC1
Temperature: 45 °C
Reaction time: 20 h
Yield: 34.8 %

Procedure:
A mixture of 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 4, Step 1: 0.186 g), 4-(2-keto-1-benzimidazolinyl)piperidine (Aldrich; 0.201 g), triethylamine (0.094 g), and dichloromethane (4 mL) is stirred at 45° C. for 20 h, after which time the mixture is cooled. Dichloromethane and aqueous sodium bicarbonate are added and the solids collected and dried. Additional material is obtained by concentration of the organic layer. Crystallization from methanol/dichloromethane/hexane gives 0.123 g of the title compound; mp 210-211 (decomp)°C; IR (mineral oil) 1695, 1486, 1338, 736, 1074 cm-1. 1H NMR (DMSOd6) δ1.63, 2.19, 2.38, 3.08, 3.66, 4.12, 6.96, 7.23, 7.54, 7.87, 8.80, 10.84.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=[O:21])=[CH:16][CH:15]=2)=[CH:12][CH:11]=[N:10]1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28]([CH2:31]C#N)=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]3=[N:20][O:21][C:31]([C:28]4[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:34])[F:35])=[CH:30][CH:29]=4)=[C:16]3[CH:15]=2)=[CH:12][CH:11]=[N:10]1
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccc(F)cc2F)cc1
Product: Fc1ccc(-n2nccc2-c2ccc3noc(-c4ccc(C(F)(F)F)cc4)c3c2)c(F)c1

Procedure:
The title compound, light yellow solid (18 mg, 12%), MS (ISP) m/z=442.2 [(M+H)+], mp 159° C., was prepared in accordance with the general method of example 1 from 1-(2,4-difluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate I) (100 mg, 353 μmol) and commercially available 2-(4-trifluoromethyl-phenyl)-acetonitrile.
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][C@H:11]1[CH2:15][N:14]([C:16]([C@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]([F:27])([F:26])[F:25])[CH2:20][CH2:19]2)=[O:17])[C@@H:13]([CH2:28][O:29][C:30]2[C:31]([C:36](O)=[O:37])=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:39]1[CH:43]=[CH:42][C:41]([NH2:44])=[N:40]1.Cl.Cl.N1CCC[C@@H]1COC1C(C(N)=O)=NC=CC=1>>[CH2:1]([O:8][CH2:9][O:10][C@H:11]1[CH2:15][N:14]([C:16]([C@H:18]2[CH2:19][CH2:20][C@H:21]([C:24]([F:25])([F:26])[F:27])[CH2:22][CH2:23]2)=[O:17])[C@@H:13]([CH2:28][O:29][C:30]2[C:31]([C:36]([NH:44][C:41]3[CH:42]=[CH:43][O:39][N:40]=3)=[O:37])=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ncccc1OC[C@H]1C[C@@H](OCOCc2ccccc2)CN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: Nc1ccon1
Agent: Cl
Agent: NC(=O)c1ncccc1OC[C@H]1CCCN1
Product: O=C(Nc1ccon1)c1ncccc1OC[C@H]1C[C@@H](OCOCc2ccccc2)CN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 4 of EXAMPLE 1 using 3-(((2R,4R)-4-(benzyloxymethoxy)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid (EXAMPLE 79 Step 6) and isoxazol-3-amine instead of cis-4-(trifluoromethyl)cyclohexanecarboxylic acid and (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([C@@:9]1([CH2:42][OH:43])[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C@@H:12]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:11]([C@@H:29]([CH2:39][CH3:40])[CH2:30][N:31]([CH3:38])[S:32]([CH:35]2[CH2:37][CH2:36]2)(=[O:34])=[O:33])[C:10]1=[O:41])[CH:7]=[CH2:8].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:43][CH2:42][C@:9]1([CH2:6][CH:7]=[CH2:8])[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C@@H:12]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:11]([C@@H:29]([CH2:39][CH3:40])[CH2:30][N:31]([CH3:38])[S:32]([CH:35]2[CH2:37][CH2:36]2)(=[O:33])=[O:34])[C:10]1=[O:41])(=[O:4])=[O:3]
Reactant: C=CC[C@@]1(CO)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C2CC2)C1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC[C@@]1(COS(C)(=O)=O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C2CC2)C1=O
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (0.200 ml, 2.59 mmol) was added to a solution of N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(hydroxymethyl)-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide (1.0 g, 1.725 mmol) and triethylamine (0.480 ml, 3.45 mmol) in DCM. The reaction was stirred for 2 hours. The reaction mixture was diluted with DCM and washed with HCl (1N) and satd NaCl and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as an oil. The product was purified by chromatography through a RediSep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.) (12 g), eluting with a gradient of 0% to 80% EtOAc in hexane, to provide the title compound as an oil. Mass Spectrum (ESI) m/z=657.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])=[C:6]([CH2:8]O)[CH:7]=1.FC(OC1C=CC(F)=CC=1C[Br:50])(F)C1C=CC(C2C=CC(C(F)(F)F)=CC=2)=CC=1>>[Br:50][CH2:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19]
Reactant: Fc1ccc(OC(F)(F)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)c(CBr)c1
Reactant: OCc1cc(F)ccc1OCc1ccccc1C(F)(F)F
Product: Fc1ccc(OCc2ccccc2C(F)(F)F)c(CBr)c1
Yield: 80 %

Procedure:
The title compound is prepared in 80% yield from (5-fluoro-2-{[2-(trifluoromethyl)benzyl]oxy}-phenyl)methanol (Example 48A) in analogy to 2-(bromomethyl)-4-fluorophenyl difluoro[4′-(trifluoromethyl)biphenyl-4-yl]methyl ether (Example 41A).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:24][CH:25]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]1>>[C:32]([O:31][C:29]([N:27]1[CH2:28][CH:25]([NH:24][C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][O:10][CH:11]=3)=[CH:23][CH:22]=2)=[O:21])[CH2:26]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Product: CC(C)(C)OC(=O)N1CC(NC(=O)c2ccc(OCc3conc3-c3ccc(Cl)cc3)nc2)C1
Yield: 68 %

Procedure:
As described for example 346b, 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid (200 mg, 0.6 mmol) was converted, using 3-amino-1-N-Boc-azetidine instead of ethanolamine, to the title compound (200 mg, 68%) which was obtained as a colourless gum. MS: m/e=483.1 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1sc2nc(-c3cnccn3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3cnccn3)nc(NCc3ccc(F)cc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(4-fluorobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][CH2:8][N:9]([CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)[C:10]1[S:11][CH:12]=[C:13]([C:15](O)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>>[CH:15]([C:13]1[N:14]=[C:10]([N:9]([CH:29]2[CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:8][CH2:7][C:6]([OH:34])=[O:5])[S:11][CH:12]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)CCN(c1nc(C(O)(c2ccccc2)c2ccccc2)cs1)C1CCCC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCN(c1nc(C(c2ccccc2)c2ccccc2)cs1)C1CCCC1
Yield: 40.4 %

Procedure:
The above alcohol (131 mg, 0.274 mmol), TFA (2.0 mL) and Et3SiH (0.23 mL) were combined according to general procedure O. After aqueous workup the residue was purified by silica gel chromatography (gradient, hexane→1/1 EtOAc-hexane). After concentration and trituration from hexane, 3-[(4-Benzhydryl-thiazol-2-yl)-cyclopentyl-amino]-propionic acid (45 mg, 40%) was obtained. LCMS m/z: 408 (M+1). The HCl salt was also prepared, using general procedure G2, by the addition of 4 M HCl in dioxane.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([NH:10][C:11](=[O:29])[NH:12][C:13]3[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)=[O:18])=[CH:15][CH:14]=3)[CH:7]=[CH:6][C:5]=12.[Cl:30]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:30][C:3]1[N:4]2[CH:9]=[C:8]([NH:10][C:11]([NH:12][C:13]3[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)=[O:18])=[CH:15][CH:14]=3)=[O:29])[CH:7]=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(Nc1ccc(C(=O)NCC2CCCCO2)cc1)Nc1ccc2nccn2c1
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(C(=O)NCC2CCCCO2)cc1)Nc1ccc2ncc(Cl)n2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-(3-imidazo[1,2-a]pyridin-6-ylureido)-N-((tetrahydro-2H-pyran-2-yl)methyl)benzamide (0.016 g, 0.041 mmol) in chloroform (0.813 ml) was treated with N-chlorosuccinimide (5.70 mg, 0.043 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under a stream of nitrogen and purified using normal phase chromatography to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.11 (s, 1H), 9.02 (s, 1H), 8.89-8.85 (m, 1H), 8.35 (t, J=5.8 Hz, 1H), 7.85-7.79 (m, 2H), 7.69-7.60 (m, 2H), 7.58-7.52 (m, 2H), 7.19 (dd, J=9.5, 2.0 Hz, 1H), 3.91-3.83 (m, 1H), 3.46-3.19 (m, 4H), 1.80-1.73 (m, 1H), 1.66-1.57 (m, 1H), 1.49-1.36 (m, 3H), 1.26-1.09 (m, 1H); MS (ESI(+)) m/e 428 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[BH4-].[Na+]>>[OH:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Agent: [BH4-]
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3O)nc1
Yield: 68.8 %

Procedure:
Using a method similar to intermediate 13, using 6-(1-Oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 500 mg, 1.86 mmol) and NaBH4 (105 mg, 2.79 mmol) gives 6-(1-Hydroxy-indan-5-yloxy)-nicotinamide (346 mg) as a white solid. Mass spectrum (ion spray): m/z=271 (M+1); 1HNMR (DMSO-d6): 8.58 (s, 1H), 8.22 (d, 1H), 8.00 (s, 1H), 7.45 (s, 1H), 7.34 (d, 1H), 7.03 (d, 1H), 6.97 (s, 1H), 6.93 (d, 1H), 5.03 (t, 1H), 2.93-2.86 (m, 1H), 2.73-2.66 (m, 1H), 2.38-2.30 (m, 1H), 1.84-1.72 (m, 1H), 1.33 (s, 1H). Convert 6-(1-Hydroxy-indan-5-yloxy)-nicotinamide to the title compound using a method similar to intermediate 13. Due to instability, use this material without purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[O:6][C:7]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)(=[O:4])=[O:3].[Br:16]N1C(=O)CCC1=O>C(#N)C>[Br:16][C:10]1[C:8]2[CH:9]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[O:6][C:7]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc2cc(S(C)(=O)=O)oc12
Solvent: CC#N
Product: COc1ccc(Br)c2cc(S(C)(=O)=O)oc12
Yield: 109.2 %

Procedure:
Prepared from 2-methanesulfonyl-7-methoxybenzofuran (0.50 g) and N-bromosuccinimide (0.39 g) in acetonitrile (30 ml). Purification by flash chromatography on silica eluting with 50% ethyl acetate in hexane gave the title compound as a white solid (0.73 g).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:22])[C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[F:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N+:18]([C:16]1[CH:17]=[C:12]([C:11]2[O:22][C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=3[N:10]=2)[C:13]([F:21])=[CH:14][CH:15]=1)([O-:20])=[O:19]
Reactant: COc1ccc(O)c(NC(=O)c2cc([N+](=O)[O-])ccc2F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COc1ccc2oc(-c3cc([N+](=O)[O-])ccc3F)nc2c1

Procedure:
Prepared by the method of Example 15b), from N-(2-hydroxy-5-methoxyphenyl)-2-fluoro-5-nitro benzamide (1.23 g, 4.0 mmol) and p-toluenesulfonic acid monohydrate (1.67 g, 8.8 mmol) the subtitle compound was obtained (700 mg, 53%). MS 289.1 m/z (M+H)+.