Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>C(O)CC(C)C.CO>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][C:3]2[C:2]([NH2:1])=[CH:7][CH:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[N:4]=2)=[CH:17][CH:16]=1
Reactant: Nc1ccc(C(F)(F)F)nc1Cl
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(C)CCO
Product: COc1ccc(CNc2nc(C(F)(F)F)ccc2N)cc1
Temperature: 220 °C

Procedure:
A mixture of the 3-amino-2-chloro-6-(trifluoromethyl)pyridine (416 mg, 2.1 mmol, Matrix), 4-methoxy-benzylamine (294 mg, 2.1 mmol, Aldrich) and sodium bicarbonate (265 mg, 3.2 mmol) in isoamyl alcohol (0.6 mL) was heated at 220° C. in a microwave synthesizer for 30 min. The reaction mixture was then cooled to room temperature, diluted with MeOH (5 mL), filtered and the filtrate was evaporated in vacuo. The residue was purified by preparative HPLC (gradient 0.1% trifluoroacetic acid in acetonitrile) to give the title compound as a yellow oil. MS (ESI, pos. ion) m/z: 298 (M+1)
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[OH:13])[CH2:8][CH2:7]1)C.C(=O)(O)[O-].[Na+]>C(O)C.O>[OH2:3].[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)([OH:13])[CH:9]2[CH2:8][CH2:7][N:6]([CH2:5][C:4]([OH:28])=[O:3])[CH2:11][CH2:10]2)=[CH:19][CH:18]=1.[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]([CH:9]2[CH2:8][CH2:7][N:6]([CH2:5][C:4]([OH:28])=[O:3])[CH2:11][CH2:10]2)([OH:13])[C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)CN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)CN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 16 h
Yield: 53 %

Procedure:
To a stirred solution of 5.0 g (0.013 mole) of 4-[bis(4-fluorophenyl)hydroxymethyl]-1-piperidineacetic acid ethyl ester in 100 mL of 95% ethanol was added a solution of 10.9 g (0.130 mole) of sodium bicarbonate in 150 mL of water and the mixture was heated at reflux for 16 h. The solution was cooled and concentrated under reduced pressure. The residue was partitioned between ethyl ether and water (200 mL each). The layers were separated, and the aqueous layer was further extracted with two 100 mL portions of ethyl ether. The aqueous layer pH was adjusted to 6 with glacial acetic acid, whereupon a solid precipitate began to form. After standing for 16 h, the crystals were collected by filtration, washed with water and recrystallized from 2-propanol to yield 1.7 g (36%) of white solid, mp 198°-200° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:18][CH:17]=3)([CH3:15])[CH2:11][O:12]2)=[CH:7][CH:6]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(Cl)Cl>CO>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:6]3[CH:5]=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:16][CH2:17][CH:29]4[CH2:30][CH2:31][NH:26][CH2:27][CH2:28]4)=[CH:8][CH:7]=3)[C:10]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:20][CH:21]=3)([CH3:15])[CH2:11][O:12]2)=[CH:7][CH:6]=1
Reactant: C1CCNCC1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2)cc1
Solvent: CO
Solvent: ClCCl
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2ccc(OCCCCC3CCNCC3)cc2)cc1
Yield: 150.5 %

Procedure:
To (3RS,4RS)-4-[4-(4-chlorobutyloxy)phenyl]-(7-(methoxymethoxy)-3-(4-(methoxymethoxy)phenyl)-3-methylchroman (393 mg, 0.75 mmol) was added piperidine (738 mg, 7.5 mmol) and the mixture was refluxed for 12 h. After cooling, the mixture was extracted with ethyl acetate, dried over MgSO4, and filtered. The filtrate was evaporated under reduced pressure, and the concentrate thus obtained was subjected to silica gel columnchromatography (CH2Cl2:methanol=20:1) to give 325 mg (yield: 75%) of a colorless oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:10]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].C(N(CC)CC)C.[CH3:25][C:26]([CH3:28])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:2][C:3]1[CH:10]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][N:15]([CH:26]([CH3:28])[CH3:25])[CH2:14][CH2:13]2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: CC(C)=O
Reactant: N#Cc1ccc(OC2CCNCC2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N1CCC(Oc2ccc(C#N)c(Cl)c2)CC1
Reaction time: 0.08 h
Yield: 98.6 %

Procedure:
2-Chloro-4-(4-piperidinyloxy)benzonitrile hydrochloride (D30) (1.5 g) was dissolved in DCM (40 ml) and triethylamine (2.29 ml) was added followed by acetone (0.64 g). The mixture was stirred for 5 min and then sodium triacetoxyborohydride (1.94 g) was added and the reaction stirred at rt under argon overnight. The reaction mixture was then washed with saturated potassium carbonate solution (2×40 ml) and brine (40 ml). The organic layer was dried (MgSO4) and evaporated to give the title compound (D31) as a white solid (1.51 g). MS electrospray (+ion) 279 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>CS(C)=O>[Br:1][C:2]1[C:3]([O:16][C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: Clc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: Clc1ccc(Oc2ncccc2Br)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 3-bromo-2-chloropyridine (10 g, 52 mmol), 4-chlorophenol (6.7 g, 52 mmol), cesium carbonate (34 g, 104 mmol) in 100 mL DMSO was heated to 90° C. with stirring overnight. The reaction mixture was dilution with DCM and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (0-30% EtOAc/hexane) to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.[O:54]1C2C=CC(C(O)=O)=CC=2[O:56][CH2:55]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:28][O:27][C:19]1[CH:18]=[C:17]([NH:16][C:13]2[N:14]=[N:15][C:10]([CH:8]([NH:7][C:5]([C:4]3[CH:29]=[CH:30][C:31]4[O:54][CH2:55][O:56][C:2]=4[CH:3]=3)=[O:6])[CH3:9])=[CH:11][N:12]=2)[CH:22]=[C:21]([O:23][CH3:24])[C:20]=1[O:25][CH3:26]
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccc4c(c3)OCO4)nn2)cc(OC)c1OC
Yield: 100 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (87 mg, 0.28 mmol), 1,3-benzodioxole-5-carboxylic acid (60 mg, 0.37 mmol), diisopropylethylamine (0.13 mL, 0.75 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (140 mg, 0.37 mmol) in dimethylformamide (2 mL) gave N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)-1,3-benzodioxole-5-carboxamide (127 mg, 100%) as a yellow oil. MS m/z 453 (M+1).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[C@H:27]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15]C(OCC2C=CC=CC=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:40].[Li+].[CH2:42]([CH2:45][O:46][CH3:47])OC>O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:47]([O:46][CH2:45][C:42]2[CH:26]=[CH:25][CH:9]=[CH:10][CH:11]=2)=[CH:13][CH:12]=1)[C@@H:25]([OH:40])[CH2:26][C@@H:27]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[C:28]([OH:29])=[O:30])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: COc1ccc(C[C@@H]2C[C@@H]([C@H](Cc3ccc(OCc4ccccc4)cc3)NC(=O)OC(C)(C)C)OC2=O)cc1
Reactant: [OH-]
Reactant: COCCOC
Agent: [Li+]
Solvent: O
Product: COc1ccc(C[C@H](C[C@H](O)[C@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)OC(C)(C)C)C(=O)O)cc1
Reaction time: 25 h

Procedure:
2.6 g (4.89 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-benzyloxy-phenyl)-ethyl]-3(R)-[(p-methoxyphenyl)methyl]dihydrofuran-2-(3H)-one in 50 ml of dimethoxyethane are hydrolysed, under an N2 atmosphere, with 19.6 ml of a 1M lithium hydroxide solution in water. After 25 h at RT, the dimethoxyethane is evaporated off on a RE, and the residue is treated with an ice-cold mixture of 150 ml of sat. NH4Cl solution, 25 ml of 10% citric acid solution and methylene chloride. The aqueous phase is separated off and extracted 2× with methylene chloride. The organic phases are washed with saline, dried with Na2SO4 and evaporated to give the title compound: TLC Rf (B)=0.28; tRet (II)=16.4 min.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1([CH2:8][OH:9])[CH2:7][CH2:6]1.[NH2:10][C@H:11]([C:13](O)=[O:14])[CH3:12]>>[ClH:3].[CH:5]1([CH2:8][O:9][C:13](=[O:14])[C@H:11]([CH3:12])[NH2:10])[CH2:7][CH2:6]1
Reactant: C[C@H](N)C(=O)O
Reactant: O=S(Cl)Cl
Reactant: OCC1CC1
Product: C[C@H](N)C(=O)OCC1CC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Thionyl chloride (1.2 ml, 0.017 M) was added dropwise to a stirred solution of cyclopropyl methanol (6.8 ml, 8.4 mmol) at 0° C. under nitrogen. The mixture was stirred for 30 minutes, then allowed to warm to room temperature. L-Alanine (pre-dried at 60° C. over P2O5 for 4 hrs: 0.75 g, 8.4 mmol) was added and the resulting suspension was heated at reflux overnight (the reaction mixture became a clear, colourless solution). The solvent was removed under reduced pressure to leave an orange/red oil which was repeatedly triturated and coevaporated with diethyl ether, to remove traces of cyclopropyl methanol. Diethyl ether (200 ml) was added and the mixture was stirred for 30 min. The resulting suspension was filtered to give the product as a cream solid (1.29 g, 7.1 mmol, 85%).
Reaction SMILES: C(O)[C:2]([C@@H:4]([OH:12])[C@H:5]([OH:11])[C@@H:6]([OH:10])[C:7](O)=[O:8])=[O:3].[H][H]>[Ni]>[O:3]=[CH:2][C@H:4]([C@@H:5]([C@H:6]([CH2:7][OH:8])[OH:10])[OH:11])[OH:12].[O:3]=[CH:2][C@H:4]([C@@H:5]([C@@H:6]([CH2:7][OH:8])[OH:10])[OH:11])[OH:12]
Reactant: [H][H]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)C(=O)O
Agent: [Ni]
Product: O=C[C@@H](O)[C@H](O)[C@@H](O)CO
Product: O=C[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Hydrogenation of 5-keto-D-gluconic acid to D-gluconic- and L-idonic acids was performed under the following conditions: Hydrogen pressure was 40 bar, reaction temperature 100° C. pH of the feed was adjusted to 5 before reaction. Feed syrup concentration was 400 g/l. The catalyst was Raney-nickel and the catalyst load was 10% wet catalyst per feed dry substance. Decarboxylation of the obtained mixture of D-gluconic acid and L-idonic acid as described in examples 5 and 6 yields L-xylose and D-arabinose, which subsequently are separated by chromatography.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)/[C:17](=[N:21]/[OH:22])/[CH2:16][CH2:15][CH2:14]2)=[CH2:10].[CH:23]([O:26][C:27]1[CH:38]=[CH:37][C:30]([C:31](OC(C)C)=O)=[CH:29][C:28]=1[C:39]([F:42])([F:41])[F:40])([CH3:25])[CH3:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C1(C)C=CC=CC=1>[CH:23]([O:26][C:27]1[CH:38]=[CH:37][C:30]([C:31]2[O:22][N:21]=[C:17]3[C:18]4[C:13]([CH2:14][CH2:15][C:16]=23)=[CH:12][C:11]([CH:9]=[CH2:10])=[CH:20][CH:19]=4)=[CH:29][C:28]=1[C:39]([F:40])([F:41])[F:42])([CH3:25])[CH3:24]
Reactant: C=Cc1ccc2c(c1)CCC/C2=N\O
Reactant: CC(C)OC(=O)c1ccc(OC(C)C)c(C(F)(F)F)c1
Agent: CC(C)[N-]C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Li+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(OC(C)C)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.02 h
Yield: 39.8 %

Procedure:
To the LDA solution at 0° C. was added 6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate 1, 0.212 g, 1.132 mmol) as a solution in THF (1 mL), dropwise over a period of 1 min. After 15 min. isopropyl 4-isopropoxy-3-(trifluoromethyl)benzoate (Preparation 14A, 0.329 g, 1.132 mmol) dissolved in 1 mL of THF was added dropwise over a period of 1 min. at 0° C. and the contents were stirred at 0° C. for 10 min. The reaction mixture was partitioned between 1N hydrochloric acid (5 mL) and ethyl acetate (10 mL)-THF. The 1N hydrochloric acid layer was back extracted with ethyl acetate (10 mL). The combined ethyl acetate layers were dried over sodium sulfate and concentrated under reduced pressure to yield a dark oil. To this oil was added toluene (5 mL). The contents were sonicated for 2 min. and p-toluenesulfonic acid monohydrate (0.431 g, 2.265 mmol) was added at room temperature. The contents were heated at 110° C. for 25 min. The reaction mixture was concentrated and partitioned between dichloromethane (15 mL) and sat. aq. sodium bicarbonate (10 mL). The dichloromethane layer was dried over sodium sulfate, concentrated and subjected to silica gel column chromatography (hexane/ethyl acetate). Product fractions were collected and concentrated to yield 3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole as a semi-solid (180 mg). LC/MS M+1=400.1.
Reaction SMILES: [C:1]([O:25][CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[N:29]([OH:34])[C:28]([CH3:36])([CH3:35])[CH2:27]1)(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH:13]1[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([OH:21])[C:15]([CH3:23])([CH3:22])[CH2:14]1)=[O:11].OO.C(=O)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].[OH-].[Na+]>C1(C)C=CC=CC=1.C(O)(C)(C)C.C(O)(=O)C>[C:1]([O:25][CH:26]1[CH2:27][C:28]([CH3:36])([CH3:35])[N:29]([O:34][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH3:40])[C:30]([CH3:33])([CH3:32])[CH2:31]1)(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH:13]1[CH2:14][C:15]([CH3:22])([CH3:23])[N:16]([O:21][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:17]([CH3:19])([CH3:20])[CH2:18]1)=[O:11]
Reactant: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Reactant: CCCCCCCCC=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: CCCCCCCCON1C(C)(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)CC1(C)C
Temperature: 40 °C
Reaction time: 10 h

Procedure:
10.0 g Bis(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl) sebacate (Prostab 5415, commercial product of Ciba Specialty Chemicals Inc.) are dissolved in 40 ml toluene/tert-butanol (2:1) and 8 g 50% aqueous hydrogen peroxide are added, followed by 18 ml nonanal, 0.1 ml acetic acid and 0.15 g CuCl2. The reaction mixture is stirred for 2 h at 25-25° C. and afterwards for 10 h at 40° C. The mixture is poured into 100 ml 0.1 N NaOH and subsequently extracted with methylene chloride. The organic phase is washed twice with water and then with sat. sodium chloride solution and dried over sodium sulfate. The organic phase is removed in vacuo and the residue subjected to column chromatography on silica gel to afford 5.4 g of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[C:4]([Cl:34])[N:3]=1.Cl.[NH2:36][OH:37].C([O-])(O)=O.[Na+]>>[Cl:34][C:4]1[CH:5]=[C:6](/[C:8](=[N:36]/[OH:37])/[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([OH:32])=[O:31])=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: Cc1ccccc1[C@H](CC(=O)c1cc(Cl)nc(Cl)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1[C@H](C/C(=N\O)c1cc(Cl)nc(Cl)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
In analogy to example 132, step 6, from (R)-4′-(3-(2,6-dichloropyridin-4-yl)-3-oxo-1-o-tolylpropyl)biphenyl-4-carboxylic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as an off-white foam, MS (ESI−): m/z=503.09 ([M−H]−, 1Cl).
Reaction SMILES: N(OCCC(C)C)=O.CS[S:11][CH3:12].[Br:13][C:14]1[CH:20]=[CH:19][C:17](N)=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1>>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([S:11][CH3:12])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: CSSC
Agent: CC(C)CCON=O
Product: CSc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 85 °C
Yield: 97.1 %

Procedure:
A solution of isoamyl nitrite (10.05 mL, 75 mmol) in dimethyl disulfide (49.5 mL, 550 mmol) at 25° C. was slowly treated with 4-bromo-2-nitroaniline (10.85 g, 50 mmol). The reaction was exothermic with gas evolution. The resulting brown reaction mixture was heated to 80-90° C. for 2 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was cooled to 25° C. and then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (300 mL). The organic layer was washed successively with a 1N aqueous hydrochloric acid solution (1×300 mL) and a saturated aqueous sodium chloride solution (1×300 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 6/1 to 5/1 hexanes/ethyl acetate) afforded 4-bromo-1-methylsulfanyl-2-nitro-benzene (12.05 g, 97%) as a brown solid: EI-IRMS m/e calcd for C7H6BrNO2S (M+) 246.9372, found 246.9368.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:14]=[CH:13][C:12]([NH:15][C:16](=[O:38])[NH:17][C:18]2[CH:23]=[CH:22][C:21]([C@H:24]3[O:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)=[CH:20][C:19]=2[CH3:37])=[CH:11][CH:10]=1.[OH-].[Na+]>O.C(#N)C>[Cl:8][C:9]1[N:14]=[CH:13][C:12]([NH:15][C:16]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C@H:24]3[O:29][CH2:28][CH2:27][NH:26][CH2:25]3)=[CH:20][C:19]=2[CH3:37])=[O:38])=[CH:11][CH:10]=1
Reactant: Cc1cc([C@@H]2CN(C(=O)OC(C)(C)C)CCO2)ccc1NC(=O)Nc1ccc(Cl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc([C@@H]2CNCCO2)ccc1NC(=O)Nc1ccc(Cl)nc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 50.8 %

Procedure:
To a stirred solution of trifluoroacetic acid (233 μl) in water (6 ml) was added a solution of (R)-tert-butyl 2-(4-(3-(6-chloropyridin-3-yl)ureido)-3-methylphenyl)morpholine-4-carboxylate (104 mg) in acetonitrile (2 ml). The reaction mixture was then capped and the mixture was shaken at 80° C. for 4 h. The reaction mixture was then cooled to room temperature and poured into 1 M aq. NaOH and the resulting mixture was extracted twice with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis); gradient: heptane/EtOAc/MeOH) to afford (R)-1-(6-chloropyridin-3-yl)-3-(2-methyl-4-(morpholin-2-yl)phenyl)urea (41 mg, 51%) as a white solid. MS (ISP): 349.1 ([{37Cl}M+H]+), 347.1 ([{35Cl}M+H]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([N+:16]([O-])=O)=[CH:11][C:10]=1[Cl:19])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([NH2:16])=[CH:11][C:10]=1[Cl:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)COc1c(Cl)cc(N)cc1Cl

Procedure:
A solution of (4-nitro-2,6-dichloro-phenoxy)-acetic acid tert-butyl ester (1 g) in ethanol (17 mL) and water (8.6 mL) is treated with iron powder (0.861 g) and ammonium chloride (86 mg) and the mixture is heated to reflux for approximately 1 hour. The mixture is then filtered and concentrated under reduced pressure. The resulting oil is partitioned between water and ethyl acetate, and the organic phase is then washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide the desired compound as a pale yellow solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[N:8]=1)(=O)=O.[C:28]([CH2:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)#[N:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.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>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:25])[C:18]=1[N:9]1[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=2[C:7]([C:34]2[CH:35]=[CH:36][C:31]([CH2:30][C:28]#[N:29])=[CH:32][CH:33]=2)=[N:8]1
Reactant: N#CCc1ccc(B(O)O)cc1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nccc2c1c(-c1ccc(CC#N)cc1)nn2-c1c(F)cccc1F
Temperature: 130 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To a solution of 1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (150 mg) obtained in Step C of Example 35 in DMF (4 mL)/water (0.40 mL) were added (4-(cyanomethyl)phenyl)boronic acid (156 mg), tetrakis(triphenylphosphine)palladium(0) (42.4 mg) and potassium carbonate (101 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (107 mg).
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])OC1=O.[F:13][C:14]([F:23])([F:22])[C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([C:14]([F:13])([F:22])[F:23])=[CH:16][CH:17]=1)=[O:11]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccccc1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 115 °C
Reaction time: 16 h

Procedure:
To a solution of 1H-benzo[d][1,3]oxazine-2,4-dione (1.63 g, 10.0 mmol) in anhydrous DMF (20 mL) was added 4-trifluoromethyl-aniline (1.61 g, 10.0 mmol) and the reaction mixture was stirred at 115° C. for 16 hours. It was then cooled to room temperature, diluted with ethyl acetate (150 mL), and the organic phase was washed with water (100 mL), 10% aq. NaOH solution (100 mL), water (150 mL), brine (150 mL), and dried over anhydrous Na2SO4. Solvent was evaporated and the crude compound was purified by the Simpliflash system (20% ethyl acetate in hexanes as eluent) to give 2-amino-N-(4-trifluoromethyl-phenyl)-benzamide as an off-white solid. Yield: 0.2 g (7%).