Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].F[C:7]1[C:8]([S:13]([NH2:16])(=[O:15])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=1>O1CCCC1>[CH2:1]([NH:5][C:7]1[C:8]([S:13]([NH2:16])(=[O:15])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NS(=O)(=O)c1ncccc1F
Reactant: CCCCN
Solvent: C1CCOC1
Product: CCCCNc1cccnc1S(N)(=O)=O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
49.6 ml of n-butylamine are added to a mixture of 8.81 g of 3-fluoropyridin-2-ylsulfonamide in 10 ml of tetrahydrofuran (THF). After the reaction mixture has been stirred for 18 hours at a temperature of 60° C., the reaction mixture is evaporated, the oily residue is triturated with 100 ml of ice/water, the mixture is filtered, and the filtrate is washed first with a little cold water and subsequently with n-hexane. After drying at a temperature of 45° C. in vacuo, 8.8 g of 3-n-butylaminopyridin-2-ylsulfonamide (intermediate No. 2.001) of a melting point of 100°-101° C. are obtained.
Reaction SMILES: [OH:1][C@H:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].[Cl:9][C:10]1[CH:15]=[CH:14][C:13](O)=[CH:12][C:11]=1[CH3:17]>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([O:1][C@@H:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4])=[CH:12][C:11]=1[CH3:17]
Reactant: Cc1cc(O)ccc1Cl
Reactant: CC[C@@H](O)C(=O)OC
Product: CC[C@H](Oc1ccc(Cl)c(C)c1)C(=O)OC

Procedure:
The title compound was prepared following the same protocol as described in Step 1, Example 42, using the (R)-methyl 2-hydroxybutanoate instead of the (S)-methyl 2-hydroxypropanoate and the 4-chloro-3-methylphenol instead of the m-cresol.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH:4]=[CH:5][C:6]1[O:7][C:8]([CH3:16])=[C:9]([C:11]([O:13]CC)=[O:12])[N:10]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH:4]=[CH:5][C:6]1[O:7][C:8]([CH3:16])=[C:9]([C:11]([OH:13])=[O:12])[N:10]=1
Reactant: CCOC(=O)c1nc(C=Cc2ccccc2Cl)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(C=Cc2ccccc2Cl)nc1C(=O)O
Temperature: 100 °C

Procedure:
Ethyl 2-(2-chlorostyryl)-5-methyl-4-oxazolecarboxylate (6.0 g) was added to a mixture of ethanol (42 ml) and 2N sodium hydroxide (21 ml) and the whole mixture was heated on a water bath at 100° C. for dissolution. New crystals (sodium salt) immediately precipitated out. They were dissolved by addition of water and the solution was acidified with acetic acid to give 2-(2-chlorostyryl)-5-methyl-4-oxazolecarboxylic acid as crystals; yield 5.2 g (96.3%). Recrystallization from acetic acid-water gave colorless needles. melting at 223°-224° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:13]([O:23][CH3:24])[CH:12]=3)=[C:8]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][C:35]([O:37]C)=[O:36])=[CH:27][CH:26]=3)[S:7][C:6]=2[CH:39]=1.[OH-].[Li+].Cl>C1COCC1.CO.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:13]([O:23][CH3:24])[CH:12]=3)=[C:8]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:29][CH:30]=3)[S:7][C:6]=2[CH:39]=1
Reactant: COC(=O)CCCOc1ccc(-c2sc3cc(O)ccc3c2Cc2ccc(CN3CCCC3)c(OC)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(Cc2c(-c3ccc(OCCCC(=O)O)cc3)sc3cc(O)ccc23)ccc1CN1CCCC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
6-Hydroxy-3-[3-methoxy-4-(1-pyrrolidinylmethyl)benzyl]-2-[4-[4-methoxy-4-oxobutoxy]phenyl]benzo[b]thiophene (147 mg) was dissolved in THF:MeOH:H2O (3:1:1, 3.0 mL), treated with lithium hydroxide monhydrate (12 mg) in one portion, and allowed to stir at ambient temperature for 4 days. The reaction mixture was neutralized with dilute HCl and concentrated in vacuo. The residue was dissolved in methanol. The solution was transfered to a clean vial and solvent was removed with a stream of nitrogen to give the product as an off-white solid. (100 mg).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.CC(C)([O-])C.[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O.C1(C)C=CC=CC=1>[CH2:17]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([Br:1])=[N:3]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Brc1n[nH]c2ccccc12
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1nn(Cc2ccccc2)c2ccccc12
Yield: 50 %

Procedure:
3-bromo-1H-indazole (90.4 g, 0.459 mol, 1.0 eq.) and toluene (450 mL) were placed in a 1 litre flask fitted with a mechanical stirrer under an atmosphere of nitrogen. Then potassium t-butoxide (t-BuOK, 54.2 g, 0.483 mol, 1.05 eq.) was added at room temperature over about half an hour and benzyl bromide (86.3 g, 0.505 mol, 1.1 eq.) was added over approximately 1.5 hours. The mixture was left stirred at the same temperature until the reaction was complete (checked by TLC, approximately 3 hours). Then 0.1 M HCl (45 mL) and water (90 mL) were added and the resulting phases were separated. The organic phase was washed with water, and the solvent was evaporated off at reduced pressure in order to obtain a red oily residue. The product was then precipitated through the addition of n-heptane, filtered and dried under vacuum at room temperature. Yield: 65.9 g of beige solid (yield 50%).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17](F)[C:16]=1[F:25].Cl>C1COCC1>[F:25][C:16]1[C:15]([F:14])=[CH:20][CH:19]=[C:18]([N+:21]([O-:23])=[O:22])[C:17]=1[O:13][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: Oc1cccc2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(F)c1Oc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
Sodium hydride (60% oil dispersion) (2.77 g, 69.4 mmol) was added to a solution of 1-naphthol (10.00 g, 69.4 mmol) in THF (200 mL) while cooling in an ice bath. The mixture was stirred at 0° C. for 30 min and 1,2,3-trifluoro-4-nitrobenzene (12.28 g, 69.4 mmol) was added and the mixture was allowed to warm to room temperature. After 2 hrs, the reaction mixture was poured into a mixture of ice and 10% aqueous HCl and was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was evaporated. The residue was purified by flash chromatography (hexane:ethyl acetate) to give the title compound (14.5 g, 69.4%). 1H NMR (400 MHz, chloroform-d) 6d ppm 8.31-8.45 (m, 1H), 7.82-7.99 (m, 2H), 7.54-7.66 (m, 3H), 7.30 (t, 1H), 7.17-7.26 (m, 1H), 6.61 (d, 1H).
Reaction SMILES: O.[F:2][C:3]1[C:21]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:20][C:6]([O:7][C:8]2[C:9]([S:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:10][CH:11]=[CH:12][CH:13]=2)=[C:5]([N+:35]([O-])=O)[CH:4]=1>C(O)(=O)C.[Fe]>[NH2:35][C:5]1[CH:4]=[C:3]([F:2])[C:21]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:30])([F:32])[F:31])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:20][C:6]=1[O:7][C:8]1[C:9]([S:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)CSc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)CSc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a mixture of 0.5 g of iron powder, 1.5 ml of acetic acid, and 0.15 ml of water was added dropwise a solution of 0.41 g of 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-2-(methoxycarbonyl)methylthiopyridine in 1 ml of acetic acid, while the temperature of the reaction mixture was kept at 35° C. or lower. After completion of the dropwise addition, the reaction mixture was stirred for 2 hours and then filtered through Celite. The filtrate was diluted with ethyl acetate. The mixture was neutralized with saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.36 g of 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methylthiopyridine.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1CC[CH2:5][N:4]1[CH2:8][C:9]1[S:13][CH:12]=[C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([C:23]([NH2:25])=[O:24])[CH:22]=2)[NH:19][CH:18]=[C:17]3[CH:26]2[CH2:31][CH2:30][N:29]([S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[CH2:28][CH2:27]2)[CH:10]=1.N1CCC[C@@H]1CO>>[OH:1][CH2:2][CH2:3][N:4]([CH2:8][C:9]1[S:13][CH:12]=[C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([C:23]([NH2:25])=[O:24])[CH:22]=2)[NH:19][CH:18]=[C:17]3[CH:26]2[CH2:31][CH2:30][N:29]([S:32]([CH:35]([CH3:37])[CH3:36])(=[O:33])=[O:34])[CH2:28][CH2:27]2)[CH:10]=1)[CH3:5]
Reactant: CC(C)S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCC[C@@H]5CO)c4)cc23)CC1
Agent: OC[C@H]1CCCN1
Product: CC(C)S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)CCO)c4)cc23)CC1
Yield: 51.9 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[(2R)-2-(hydroxymethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide, substituting 2-(methylamino)ethanol (90.13 mg, 1.20 mmol) for (2R)-2-pyrrolidinylmethanol to afford 8 mg of the title compound (51.9%),
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[C:16]([O:20][C:21]([N:23]1[CH2:30][CH:29]2[O:31][CH:25]([CH2:26][NH:27][CH2:28]2)[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:16]([O:20][C:21]([N:23]1[CH2:24][CH:25]2[O:31][CH:29]([CH2:28][N:27]([CH2:2][CH2:3][NH:4][S:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=3)(=[O:7])=[O:6])[CH2:26]2)[CH2:30]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: N#Cc1ccc(S(=O)(=O)NCCBr)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CN(CCNS(=O)(=O)c3ccc(C#N)cc3)CC(C1)O2
Temperature: 60 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
A suspension of N-(2-bromoethyl)-4-cyanobenzenesulfonamide (5 g, 0.017 mol; see step (i) above), 9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (3.96 g, 0.0173 mol; see WO 01/28992) and potassium carbonate (3.6 g, 0.025 mol) in acetonitrile (50 mL) was stirred at 60° C. overnight. The reaction mixture was filtered and the solvent concentrated under reduced pressure to yield the crude product, which was purified by column chromatography (using methanol in chloroform as the eluent) to yield (5 g) of the sub-title compound as pale yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:16][C:17]#[N:18])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Br:15])=[CH:10][CH:9]=2)=[O:5])C.O[Li].O>C1COCC1.O>[Br:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:16][C:17]#[N:18])[C:6]([C:4]([OH:5])=[O:3])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1CC#N
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: N#CCn1c(C(=O)O)cc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 86 %

Procedure:
To a solution of 1.0 eq. of 5-Bromo-1-cyanomethyl-1H-indole-2-carboxylic acid ethyl ester (prepared according to U.S. Pat. No. 5,854,245) in a mixture of THF/H2O ((9/1) was added LiOH.H2O (1.0 eq.) and the reaction mixture stirred 6 h at RT, acidified to pH 2 and then partially concentrated until precipitation of the crude product which was filtered off and washed with Et2O and then dried to give the desired product as a beige solid (86%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([N:18]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)=[O:20])[CH2:14][CH2:13]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.N12CCN(CC1)CC2.[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[CH:44][CH:43]=1>ClCCl.C(Cl)(Cl)Cl>[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([S:48]([NH:1][CH2:2][CH2:3][C:4]2([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]([C:26]4[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=4)[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)=[O:20])[CH2:14][CH2:13]3)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)(=[O:50])=[O:49])=[CH:44][CH:43]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCN)CCCCC3)CC2)cc1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCNS(=O)(=O)c4ccc(Cl)cc4)CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of N-[1-[2-[1-(2-aminoethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide (synthesized in Example 18) (199 mg) in dichloromethane (3 mL) were added 1,4-diazabicyclo[2.2.2]octane (100 mg) and p-chlorobenzenesulfonyl chloride (100 mg) successively. The solution was stirred at room temperature for 2 hours. The reaction solution was diluted with chloroform, washed in turn with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was purified by chromatography [NH silica gel, hexane-ethyl acetate (7:3)] to give the title compound (181 mg).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[CH3:18][O:19][C:20]1[CH:46]=[CH:45][C:23]([CH2:24][N:25]2[C:29]([C:30]3[CH:35]=[CH:34][C:33](B4OC(C)(C)C(C)(C)O4)=[CH:32][CH:31]=3)=[N:28][N:27]=[N:26]2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(C1C=CC(C2C3C(=CC=CC=3)N(S(C3C=CC=CC=3C(F)(F)F)(=O)=O)N=2)=CC=1)(O)C(F)(F)F.O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][N:25]2[C:29]([C:30]3[CH:35]=[CH:34][C:33]([C:2]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[NH:4][N:3]=4)=[CH:32][CH:31]=3)=[N:28][N:27]=[N:26]2)=[CH:45][CH:46]=1
Reactant: COc1ccc(Cn2nnnc2-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Reactant: CC(C)(C)OC(=O)n1nc(Br)c2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(c1ccccc1C(F)(F)F)n1nc(-c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)c2ccccc21
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Cn2nnnc2-c2ccc(-c3n[nH]c4ccccc34)cc2)cc1
Temperature: 25 °C

Procedure:
Tert-butyl 3-bromo-1H-indazole-1-carboxylate (5.0 g, 16.8 mmol) and a mixture of the regio-isomers of 1-(4-methoxybenzyl)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-tetrazole (Example 19, step ii) (7.92 g, 20.2 mmol) were dissolved in 100 ml of a 1 to 1 mixture of 1,4-dioxane and water under a nitrogen atmosphere. Sodium carbonate (5.35 g, 50.5 mmol) was added and the system was purged with nitrogen. Then Pd(PPh3)4 (486 mg, 0.42 mmol) was added and the reaction mixture was heated overnight at reflux temperature under a nitrogen atmosphere. After cooling to room temperature the mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate. After filtration the solvent was removed under reduced pressure. The residue was purified on SiO2 using 20 to 30% ethyl acetate in hexane as the eluent to give 3-(4-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)phenyl)-1H-indazole as a mixture of two regioisomers in a 2 to 1 ratio (2.8 g) as a white solid.
Reaction SMILES: [O:1]([CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:17](C(C1C=CC=CC=1)CO)[C:18]1C=CC=CC=1>>[OH:17][CH2:18][C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:1][CH2:8][CH:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:10]
Reactant: OCC(Oc1ccccc1)c1ccccc1
Reactant: OC(COc1ccccc1)c1ccccc1
Product: OCc1ccccc1OCC(O)c1ccccc1

Procedure:
2-phenoxy-1-phenylethanol or 2-phenoxy-2-phenyl ethanol
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]([OH:17])=O)[S:8][C:7]=3[C:6]=2[CH:18]=1.C(Cl)(=O)C(Cl)=O.C(=O)([O-])O.[Na+].[Cl:30][C:31]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:32]=1[NH:33][CH3:34]>ClCCl.CN(C=O)C.C(#N)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]([N:33]([C:32]4[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:31]=4[Cl:30])[CH3:34])=[O:17])[S:8][C:7]=3[C:6]=2[CH:18]=1
Reactant: CNc1ccc(Cl)cc1Cl
Reactant: O=C(O)c1cc2c(s1)-c1cc(Br)ccc1OCC2
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CN(C(=O)c1cc2c(s1)-c1cc(Br)ccc1OCC2)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 9-bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-2-carboxylic acid (911 mg) in dichloromethane (20 mL) and DMF (1 drop) was added oxalyl chloride (0.42 mL) and the reaction stirred at room temperature for 3 h. The solvent was then reduced in vacuo and the residue redissolved in acetonitrile. Sodium hydrogen carbonate (259 mg) and 2,4-dichloro-N-methylaniline (546 mg) were added and the reaction stirred at room temperature for 16 h. Water (20 mL) was added and the product extracted into ethyl acetate (2×20 mL). The organics were dried (MgSO4), reduced in vacuo and purified on silica to give 356. NMR: (CDCl3): 2.95-2.98 (2 H, m), 3.29 (3 H, s, Me), 4.13-4.16 (2 H, m), 6.72 (1 H, s, Ar), 6.78 (1 H, d, J 8.6, Ar), 7.16 (1 H, dd, J 8.6 and 2.3, Ar), 7.22 (1 H, d, J 8.5, Ar), 7.29 (1 H, dd, J 8.4 and 2.2, Ar) and 7.48-7.52 (1 H, m, Ar)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:4]([O:20][CH3:21])[CH:3]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:26](Cl)=[O:27]>>[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1)[C:26]([N:14]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[O:20][CH3:21])[CH2:15][C:16]([F:18])([F:17])[F:19])=[O:27]
Reactant: COc1cc(F)ccc1-c1ccncc1NCC(F)(F)F
Reactant: O=C(Cl)c1cc(F)cc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-(2,2,2-trifluoro-ethyl)-amine (example 133, intermediate a) and 3-fluoro-5-(trifluoromethyl)benzoic acid chloride (CAS RN 171243-30-4). The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50), followed by preparative HPLC using a gradient of methanol:water (10:50 to 95:5). Colorless solid (22%). MS (ESI): m/z=491.099 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[CH3:12][OH:13]>C[O-].[Na+]>[CH3:12][O:13][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: CO
Reactant: O=C(O)c1cccc(CBr)c1
Agent: C[O-]
Agent: [Na+]
Product: COCc1cccc(C(=O)O)c1
Reaction time: 0.12 h
Yield: 92 %

Procedure:
12 g (55.75 millimoles) of 3-bromomethyl-benzoic acid are dissolved in 10 ml of anhydrous methanol and to the solution 22.30 ml of sodium methylate (concentration 5 millimoles/ml) are added dropwise at room temperature. The reaction mixture is stirred for 5-10 minutes, the methanol is removed in vacuo. The residue is dissolved in 10 ml of ethyl acetate, to the solution 2 ml of water are added and the pH of the mixture is adjusted to 2-3 with a 2N sodium hydrogen sulfate solution at 0° C. The layers are separated, the organic phase is dried, filtered and the solvent is distilled off in vacuo. Thus 8.55 g of the title compound are obtained, yield 92,3%.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][N:6]1C(OC)=O.Br>>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][NH:6]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1c(F)cccc1F
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](Cc3c(F)cccc3F)C2)o[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.2 %

Procedure:
(2R,4S)-methyl 2-(2,6-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (370 mg, 1.05 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 8 mL, 45.68 mmol) and the mixture stirred at room temperature for 24 h. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx III, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(2,6-difluorobenzyl)piperidin-4-yl)isoxazol-3(2H)-one (254 mg, 82%). 1H NMR (600 MHz, cd3od) δ 1.47 (q, 1H), 1.67 (qd, 1H), 2.02 (dd, 2H), 2.78-3.02 (m, 4H), 3.16-3.24 (m, 1H), 3.27-3.33 (m, 1H), 5.49 (s, 1H), 6.98 (t, 2H), 7.27-7.37 (m, 1H). HRMS Calculated for [C15H16F2N2O2+H]+: 295.1258. Found: 295.1248
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](N)=[N:8][CH:7]=[N:6][C:5]=2[O:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[ClH:18].O1CCOCC1.N(OCCC(C)C)=O>C(Cl)(Cl)Cl.O>[Br:1][C:2]1[C:10]2[C:9]([Cl:18])=[N:8][CH:7]=[N:6][C:5]=2[O:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ncnc2oc(-c3ccccc3)c(Br)c12
Reactant: Cl
Agent: CC(C)CCON=O
Solvent: C1COCCO1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Clc1ncnc2oc(-c3ccccc3)c(Br)c12
Reaction time: 3 h
Yield: 55.5 %

Procedure:
Put 54 g (186 mmol) 5-bromo-6-phenylfuro[2,3-d]pyrimidine-4-amine in 135 ml chloroform, add 70 ml 4 N hydrogen chloride in dioxan (280 mmol) and heat to reflux. Add 50 ml (372 mmol) isoamyl nitrite dropwise (evolution of gas). At the end of addition, stir for 3 h under reflux, before adding the cooled reaction mixture to water and extracting it with dichloromethane. Wash the organic phase with satd. sodium hydrogencarbonate solution, dry over sodium sulphate and concentrate by vacuum evaporation. Purify the raw product by chromatography on silica gel (eluent: dichloromethane). For further purification, mix the product in methanol, filter with suction, and dry at high vacuum. 32 g of the target product (55.5% of theor.) is obtained.