Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:3]1.[C:15]([NH:25][CH2:26][C:27](O)=[O:28])([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C)C=O>[C:19]1([CH2:18][O:17][C:15](=[O:16])[NH:25][CH2:26][C:27]([NH:1][N:2]2[CH:6]=[CH:5][C:4]([C:7](=[O:8])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:3]2)=[O:28])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: Nn1ccc(C(=O)c2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(CNC(=O)OCc1ccccc1)Nn1ccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (1-amino-1H-pyrrol-3-yl)phenylmethanone (5.96 g) and N-carbobenzyloxyglycine (6.69 g) in 70 ml of anhydrous DCM and 30 ml of anhydrous dimethylformamide was added DCC (7.22 g). The reaction mixture was stirred at room temperature for 4 hours and filtered. The filter cake was washed with ethyl acetate, and the combined filtrates were evaporated in vacuo. The residual oil was purified by preparative HPLC (silica gel, DCM/ethyl acetate 3:1). Evaporation of the desired fractions afforded a colorless oil, which was crystallized from DCM/ethyl ether yielding the product as colorless crystals (5.96 g), m.p. 144°-145° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12](O)=[O:13])[CH:7]=[CH:8][CH:9]=1.C(Cl)(=O)C(Cl)=O.[NH3:23]>C1COCC1.CN(C)C=O>[F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]([NH2:23])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)C=Cc1cccc(OC(F)(F)F)c1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)C=Cc1cccc(OC(F)(F)F)c1
Reaction time: 3 h
Yield: 45 %

Procedure:
To a suspension of 3-(3-trifluoromethoxy-phenyl)-acrylic acid (2.21 g, 9.53 mmol) in THF (15 ml) and N,N-dimethyl formamide (0.2 ml) a solution oxalyl chloride (2.42 g, 19.06 mmol) was added dropwise at 0° C. within 45 min. Stirring was continued at 0–5° C. for 30 min. and 3 h at room temperature thereafter. The resulting solution was cooled to 0–5° C. again and then added within 15 min. to 12 ml of a 25% aqueous ammonia solution. After stirring for 30 min. the precipitated amide was collected, washed with water and dried at 40° C. in vacuo yielding 0.99 g (45%) 3-(3-trifluoromethoxy-phenyl)-acrylamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=4[F:26])[CH2:14][CH2:13]3)[N:10]=2)[CH:7]=1.[OH-].[Na+].C([OH:33])(C)(C)C>OO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:25]=[CH:24][C:21]([C:22]([NH2:23])=[O:33])=[CH:20][C:19]=4[F:26])[CH2:14][CH2:13]3)[N:10]=2)[CH:7]=1
Reactant: N#Cc1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)c(F)c1
Reactant: CC(C)(C)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)c(F)c1
Temperature: 90 °C

Procedure:
A mixture of 4-[4-[(6-chloroimidazo[1,2-a]pyridin-2-yl)methyl]-1-piperazinyl]-3-fluorobenzonitrile (Example 38; 0.298 g), pulverized NaOH (0.159 g), tert-butanol (3 mL), and 5 drops of 30% hydrogen peroxide in water is heated at 90° C. for 5.5 h. The mixture is then concentrated under reduced pressure and the resulting solids are slurried in water, collected by filtration, and washed and dried under reduced pressure. The solids are then crystallized from dichloromethane/methanol to give 0.180 g of material, which is chromatographed on silica gel using methanol/dichloromethane (4/96). After combining and concentrating the appropriate fractions, the residue is crystallized from ethyl acetate/dichloromethane/methanol to give 0.084 g of the title compound; mp 253-255° C.; MS m/z 387, 389; IR (mineral oil) 1435, 1620, 1678, 1225, 1505 cm-1 ; 1H NMR (CDCl3 +CD3OD) δ2.77, 3.38, 3.80, 6.94, 7.19, 7.53, 7.62, 8.23.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[OH:16])[C:9]([O:11][CH3:12])=[O:10])(=O)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.Cl.[NH2:24][OH:25]>C(O)C>[OH:16][C:15]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1/[C:1](=[N:24]/[OH:25])/[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cc(C(=O)OC)ccc1O
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCC/C(=N\O)c1cc(C(=O)OC)ccc1O

Procedure:
A stirred solution of methyl 3-butyryl-4-hydroxybenzoate, pyridine (3.7 mL, 46 mmol), and hydroxylamine hydrochloride (3.55 g, 51 mmol) in ethanol (30 mL) was heated reflux for 2 h. The mixture was concentrated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with 1 N hydrochloric acid, saturated sodium bicarbonate, dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford a crude oil. Purification by flash column chromatography (silica, 10:1 hexanes/ethyl acetate) provided methyl 4-hydroxy-3-[(1E)-N-hydroxybutanimidoyl]benzoate (170 mg): 1H NMR (500 MHz, CD3OD): δ 8.30–8.28 (m, 1H), 7.85–7.82 (m, 1H), 6.92–6.89 (m, 1H), 3.88 (s, 3H), 2.87–2.84 (m, 2H), 1.67–1.60 (m, 2H), 1.05–1.00 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[Cl:24][C:25]1[C:26]([NH:40][CH3:41])=[N:27][CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:30]=1>>[Cl:24][C:25]1[CH:30]=[C:29]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:28]=[N:27][C:26]=1[NH:40][CH3:41]
Reactant: CNc1ncc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CNc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1Cl

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 0.107 mmol) and [3-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-methyl-amine (stage 146.1.1) to give the title compound as a yellow foam. (HPLC: tR 2.53 min (Method A); M+H=485 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.91 (s, 1H), 8.24-8.21 (m, 1H), 8.15 (s, 1H), 8.06-8.01 (m, 1H), 7.92-7.87 (m, 1H), 7.62-7.57 (m, 1H), 7.40-7.37 (m, 1H), 6.81-6.76 (m, 1H), 3.95 (s, 3H), 3.57 (s, 3H), 2.89 (d, 3H), 1.95 (s, 3H))
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:23]=[C:22]3[C:14]([N:15]4[C:20](=[CH:21]3)[C:19](=[O:24])[NH:18][CH2:17][CH2:16]4)=[N:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].FC(F)(F)S(O[CH2:31][C:32]([F:35])([F:34])[F:33])(=O)=O.[H-].[Na+]>>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([O:10][C:11]2[CH:23]=[C:22]3[C:14]([N:15]4[C:20](=[CH:21]3)[C:19](=[O:24])[N:18]([CH2:31][C:32]([F:35])([F:34])[F:33])[CH2:17][CH2:16]4)=[N:13][CH:12]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2cnc3c(c2)cc2n3CCNC2=O)CC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2cnc3c(c2)cc2n3CCN(CC(F)(F)F)C2=O)CC1
Yield: 42 %

Procedure:
The title compound was synthesized in analogy to example 17, from 7-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one (example 84), 2,2,2-trifluoroethyl trifluoromethanesulfonate and sodium hydride, to give the desired product as a colorless solid (42%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[CH2:16][CH2:17][CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=2)[NH:21][CH:20]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=3)[NH:21][CH:20]=2)[CH2:11][CH2:10]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: Fc1ccc2[nH]cc(CCCCl)c2c1
Product: Fc1ccc2[nH]cc(CCCN3CCN(c4cccc(Cl)c4Cl)CC3)c2c1

Procedure:
from 1-(2,3-dichlorophenyl)piperazine and 3-(3-chloropropyl)-5-fluoro-1H-indole. Mp 147–148° C. 1H NMR (DMSO-d6): 1.75–1.85 (m, 2H); 2.30–2.45 (t, 2H); 2.45–2.60 (m, 2H); 2.70 (t, 2H); 3.00 (b s, 4H); 3.35 (b s, 2H); 6.85–6.95 (m, 1H); 7.05–7.15 (m, 1H); 7.20 (s, 1H); 7.20–7.35 (m, 4H); 10.85 (b s, 1H). Ms m/z: 406 (MH+).
Reaction SMILES: [CH3:1][S:2]([N:5]=[C:6](SC)[S:7][CH3:8])(=[O:4])=[O:3].[CH3:11][NH2:12]>C(O)C>[CH3:11][NH:12][C:6](=[N:5][S:2]([CH3:1])(=[O:4])=[O:3])[S:7][CH3:8]
Reactant: CN
Reactant: CSC(=NS(C)(=O)=O)SC
Solvent: CCO
Product: CNC(=NS(C)(=O)=O)SC
Temperature: 53 °C
Reaction time: 8 h

Procedure:
A mixture of N-methylsulphonyl-bis(methylthio)methanimine (188 g) and ethanol (760 ml) was stirred and warmed to 53° C. and the resulting solution was treated dropwise at 45° C. with a solution of methylamine in ethanol (33% w/w; 115 ml) during 2 hours. The solution was then stirred at room temperature for 7 hours and allowed to stand overnight. The solution was concentrated in vacuo to low volume and crystallised from cold ethanol, to give N-methyl-N'-methylsulphonyl-S-methylisothiourea (162 g), m.p. 88°-91° C.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-][CH2:10][CH3:11].[Na+]>C1COCC1>[C:2]1([CH:10]=[CH:11][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[O-]
Reactant: O=Cc1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 50 mg (0.47 mmol) benzaldehyde and 100 mg (0.047 mmol) Rink amide resin bound compound 1 in 5 mL THF, 12 μL 2M sodium ethoxide was added. It was shaken at room temperature for 2 hours. The resulting Resin bound compound 2 was collected in a 3 mL filtering column and washed with water (3×2 mL), DMF (2×2 mL) and methylene chloride (3×2 mL). After drying under vacuum, 5 mg Resin bound compound 2 was treated with 1.5 mL 5% trifluoroacetic acid in methylene chloride for 20 minutes. The solid was filtered off and washed with 1 mL methylene chloride, combined methylene chloride solution was concentrated and dried under vacuum to give 0.5 mg product 3. MS m/z252 (M+ +1). ##STR55##
Reaction SMILES: CN([SiH3])[Si:3]([CH3:6])(C)[CH3:4].[F:8][C:9]([F:22])([F:21])[S:10]([O:13]S(C(F)(F)F)(=O)=O)(=[O:12])=[O:11]>>[F:8][C:9]([F:22])([F:21])[S:10]([O:13][SiH:3]([CH3:6])[CH3:4])(=[O:12])=[O:11]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CN([SiH3])[Si](C)(C)C
Product: C[SiH](C)OS(=O)(=O)C(F)(F)F

Procedure:
Additionally, for example when mixing tetramethyldisilazane as the silicon compound B and trifluoromethanesulfonic anhydride as the acid B, the trifluoromethanesulfonic anhydride is rapidly reacted to form dimethylsilyl trifluoromethanesulfonate as the acid A.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]([CH3:20])[CH2:15][C:16](=[O:19])[NH:17][N:18]=2)=[CH:9][CH:8]=1)=[O:5].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)CC>[CH2:21]([NH:28][CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]([CH3:20])[CH2:15][C:16](=[O:19])[NH:17][N:18]=2)=[CH:9][CH:8]=1)=[O:5])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC1CC(=O)NN=C1c1ccc(NC(=O)CCBr)cc1
Reactant: NCc1ccccc1
Solvent: CCCO
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)CCNCc2ccccc2)cc1
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A suspension of 6-[4-(3-bromopropionamido)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (120 g, 0.355 mol) and benzylamine (152 g, 1.47 mol) in n-propanol (800 ml) was stirred under reflux for 16 hours. The reaction mixture was filtered whilst hot and white solid was collected, which was washed with ether to remove excess benzylamine. The crude material was boiled with ethanol (300 ml) for 2 hours; the mixture was cooled and filtered. The resulting white solid was washed with ether and dried to give 6-[4-(3-benzylaminopropionamido)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (114 g, 88%) as the hydrobromide salt m.p. 279°-285° C.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:19])[N:4]([CH2:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])[C:5](SC)=[N:6][N:7]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1>>[C:13]([C:12]1[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=1[CH2:10][N:4]1[C:3](=[O:19])[C:2]([CH3:1])=[N:7][N:6]=[C:5]1[N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]1)#[N:14]
Reactant: CSc1nnc(C)c(=O)n1Cc1ccccc1C#N
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Product: Cc1nnc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2ccccc2C#N)c1=O
Temperature: 130 °C
Reaction time: 0.08 h

Procedure:
The mixture of 2-((6-methyl-3-(methylthio)-5-oxo-1,2,4-triazin-4(5H)-yl)methyl)benzonitrile (6, 68 mg, 0.25 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (60 mg, 0.30 mmol) was ground for 5 min and then heated in a tube under nitrogen atmosphere at 130° C. for 13 h. The mixture was separated by silica gel column, and eluted with 2:1 to 1:1 petroleum ether-ethyl acetate and then with 1:1:2 petroleum ether-dichloromethane-ethyl acetate to give (R)-tert-butyl 1-(4-(2-cyanobenzyl)-6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)piperidin-3-ylcarbamate (7). MS: m/z, 425 (100%, M+1), 447(40%, M+23).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:12])[C:10]=1O)[C:5]([OH:7])=[O:6].[CH3:13][Si](C=[N+]=[N-])(C)C.S([O-])([O-])(=O)=O.[Mg+2]>CCOCC.CO>[CH3:13][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([CH3:1])[CH:10]=[C:9]([CH3:12])[CH:8]=1
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3,5-dimethyl-4-hydroxybenzoic acid (1.0 g) in ether (5 mL) and methanol(5 mL) was treated with excess trimethylsilyldiazomethane. After stirring 30 min at room temperature the reaction was treated with magnesium sulfate, filtered and concentrated to a brown solid. The title compound was obtained by purification on silica gel to give a colorless solid (670 mg). NMR (CDCl3); δ 7.75 (s,2H), 3.85 (s,3H), 2.30 (s,6H).
Reaction SMILES: [NH2:1][C:2](=[O:36])[CH:3]([CH3:35])[O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([CH2:19][NH:20]C(=O)OC(C)(C)C)=[C:8]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[F:34].Cl>O1CCOCC1>[NH2:20][CH2:19][C:9]1[C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])=[N:11][C:12]2[C:7]([C:8]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[F:34])=[CH:6][C:5]([O:4][CH:3]([CH3:35])[C:2]([NH2:1])=[O:36])=[CH:14][CH:13]=2
Reactant: CC(C)Cc1nc2ccc(OC(C)C(N)=O)cc2c(-c2ccccc2F)c1CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Cc1nc2ccc(OC(C)C(N)=O)cc2c(-c2ccccc2F)c1CN
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
To tert-butyl [6-(2-amino-1-methyl-2-oxoethoxy)-4-(2-fluorophenyl)-2-isobutylquinolin-3-yl]methylcarbamate (0.12 g, 0.24 mmol) was added 4N solution of hydrogen chloride in 1,4-dioxane (5 ml) and the mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned between ethyl acetate-isopropanol (4:1, 125 ml) and 10% aqueous potassium carbonate solution (100 ml). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.070 g, yield 73%) as a colorless powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1)([O-])=O>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2c1OCCO2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)cc2c1OCCO2
Reaction time: 18 h
Yield: 99.9 %

Procedure:
Methyl 7-nitro-2,3-dihydro-1,4-benzodioxine-5-carboxylate (5.6 g, 23.4 mmol) and palladium on carbon (250 mg, 30 wt. %) were suspended in ethyl acetate (200 mL). The reaction vessel was evacuated and then immediately filled with hydrogen gas. This deoxygenation process was repeated three times at atmospheric pressure. The black suspension was stirred under a hydrogen atmosphere for 18 h, at which time it was filtered through a bed of Celite and rinsed with ethyl acetate. The filtrate was concentrated, and the residue was triturated with diethyl ether to give 4.89 g (100%) of methyl 7-amino-2,3-dihydro-1,4-benzodioxine-5-carboxylate as an off-white powder: 1H NMR (400 MHz, CDCl3): 6.74 (d, J=2.8 Hz, 1H), 6.40 (d, J=2.8 Hz, 1H), 4.26-4.25 (m, 4H), 3.86 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[C:12]([CH3:23])[C:11]=2[O:24][CH3:25])=[C:6]([F:26])[CH:5]=[CH:4][C:3]=1[OH:27].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CC(C)=O.O>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[C:12]([CH3:23])[C:11]=2[O:24][CH3:25])=[C:6]([F:26])[CH:5]=[CH:4][C:3]=1[O:27][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: CCOC(=O)CBr
Reactant: COc1c(C)cc(-c2cccc(F)c2)cc1CNc1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)cc(C)c2OC)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.1 %

Procedure:
To a stirred solution of 2,4-difluoro-3-[[5-(3-fluorophenyl)-2-methoxy-3-methyl-phenyl]methylamino]phenol (47 mg, 0.13 mmol, 1.0 eq) in acetone (5 mL) was added Cs2CO3 (61.5 mg, 0.19 mmol, 1.5 eq). The resulting mixture was stirred for 30 min at room temperature then ethyl bromoacetate (25.2 mg, 0.15 mmol, 1.2 eq) was added. The resulting mixture was stirred for 1 h then diluted with water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc, 1:0 to 20:1) to give the title compound as an oil (64 mg, 86%).
Reaction SMILES: [S:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13](O)=[O:14])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>CCOCC>[S:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[CH2:13][OH:14])([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2CO)cc1
Yield: 53.1 %

Procedure:
A solution of 1-tosyl-L-proline (17.8 g) prepared in Reference Example 38 in anhydrous ether (80 ml) was dropwise added to a suspension of lithium aluminum hydride (3.76 g) in anhydrous ether (80 ml) over 30 minutes with ice-cooling. After stirring the reaction liquid at room temperature for one hour, 100 ml of ethyl acetate was added thereto and the resulting mixture was stirred for additional 16 hours. The insolubles formed was filtered off through a Celite layer, the organic phase obtained was washed with water and dried over anhydrous magnesium sulfate. The organic phase was concentrated, then the resulting residue was subjected to silica gel column chromatography and eluted with chloroform/ethyl acetate (98/2) to give 8.96 g (yield 53.1%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH2:23]([NH:25][CH2:26][CH2:27][OH:28])[CH3:24]>>[Br:1][C:2]1[C:3]([N:25]([CH2:23][CH3:24])[CH2:26][CH2:27][OH:28])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: CCNCCO
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(Br)c1
Product: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1Br

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 33.1 using 5-bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Stage 169.2) and 2-ethylamino-ethanol to afford an off-white crystalline solid. (Reaction Time was 10 h). HPLC (Condition 4) tR=6.1 min, UPLC-MS (Condition 3) tR=1.21 min, m/z=466.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[C:38]([CH:43]3[CH2:45][CH2:44]3)[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[C:38]([CH:43]3[CH2:44][CH2:45]3)[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C2CC2)n1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cc(C2CC2)n1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(2-cyclopropyl-6-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K36) (264 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (309 mg, 73%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[CH3:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([OH:30])[CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.[OH-].[Na+]>>[CH3:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][S:10]([C:3]4[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=4[F:1])(=[O:12])=[O:11])[CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1
Reactant: CN1CCC(c2c[nH]c3ccc(O)cc23)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1F
Agent: [Na+]
Agent: [OH-]
Product: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)c4ccc(F)c(F)c4F)cc23)CC1
Yield: 105.8 %

Procedure:
By a method similar to Example 31, using 2,3,4-trifluorobenzenesulfonyl chloride (280 mg, 1.2 mmol) and 3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole (231 mg, 1.0 mmol) and 0.2 N sodium hydroxide (5.5 mL, 1.1 mmol) gave 449 mg of a purple foam. The crude product was purified by radial chromatography (silica gel, 2000 micron rotor, 100/10 methylene chloride/methanol then 100/10/0.5 methylene chloride/methanol/ammonium hydroxide) to give 418 mg (98%) of homogeneous product. The product was crystallized from ethyl acetate/hexanes to give 280 mg of the title compound as a white powder: mp=160-162° C.; MS(m/e): 424 (M+); Calculated for C20H19F3N2O3S: C, 56.60; H, 4.51; N, 6.60. Found: C, 56.53; H, 4.78; N, 6.51.