Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.C([C@H]1COC(=O)N1[C:16](=[O:32])[C@@H:17]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]1([CH3:23])[CH2:22][CH2:21][CH2:20][CH2:19]1)C1C=CC=CC=1.O.[OH-].[Li+].S([O-])([O-])=[O:37].[Na+].[Na+].C(=O)([O-])O.[Na+].Cl>O1CCCC1.O>[C:27]([O:26][C:25]([NH:24][C@@H:17]([C:18]1([CH3:23])[CH2:19][CH2:20][CH2:21][CH2:22]1)[C:16]([OH:32])=[O:37])=[O:31])([CH3:28])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C1(C)CCCC1
Reactant: O=S([O-])[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: OO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1(C)CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
Aqueous hydrogen peroxide solution (30% 1.15 mL) was added to a stirred solution of Boc-protected intermediate (135) (1.02 g, 2.45 mmol) in a mixture of tetrahydrofuran (30 mL) and water (9 mL) at 0° C. Lithium hydroxide monohydrate (128 mg, 3.04 mmol) was added then the mixture was stirred at 0° C. for 1 h, then overnight at ambient temperature. A further aliquot of hydrogen peroxide solution (30% 0.575 mL) was added followed by lithium hydroxide monohydrate (64 mg and stirring continued at ambient temperature for 3 h. A solution of sodium sulphite (1.87 g) in water (10 mL) was then added followed by aqueous sodium hydrogen carbonate solution (30 mL). The mixture was stirred for 5 minutes then the volume reduced by half in vacuo (≧25 mbar, external water bath 25° C.). Water (50 mL) was added then the pH adjusted to ≦2 using 5M hydrochloric acid. The aqueous phase was, extracted with dichloromethane (4×50 mL), then the combined organic layers were dried (Na2SO4), filtered and reduced in vacuo to leave a pale yellow oil. The oil was partitioned between a solution of sodium carbonate (1.4 g) in water (50 mL) and diethyl ether (20 mL). The aqueous layer was re-extracted with diethyl ether (3×20 mL) then the pH adjusted to ≦2 using 5M hydrochloric acid. The acidified aqueous layer was then extracted with diethyl ether (3×20 mL) then the combined organic layers dried (MgSO4), filtered and reduced in vacuo to leave acid (136) as a colourless gum (Yield 475 mg, 76%). Analytical HPLC, Rt=16.74 min., HPLC-MS 156.1 [M−Boc+2H]+, 220.1 [M+2H−tBu]+, 537.3 [2M+Na]+; [α]D21 +27.2° (c=2.576, CHCl3). δH (500 MHz, CDCl3) 0.90 (3H, s, CH3C), 1.35-1.45+1.61-1.81 (8H, m, 4×CH2), 1.45 (9H, s, (CH3)3C), 4.18 (1H, d, J=9.2, NCH), 5.12 (1H, d, J=8.95, NH), 8.7-10.0 (1H, b, COOK); δC (125 MHz, CDCl3) 22.26/22.41/22.66 (CH3C), 23.85/24.08/24.32/24.61/25.91+36.88/36.94 (4×CH2), 28.30 ((CH3)3C), 45.03/45.61 (CH3C), 60.84 (NHCH), 79.98 ((CH3)3C), 155.76/156.46 (NHC═O), 177.04 (CHC═O).
Reaction SMILES: [CH2:1]([CH:3]1[C:9](=[O:10])[NH:8][C:7]2=[C:11]3[C:16](=[N:17][C:18]4=[CH:19][CH:20]=[CH:21][C:5](=[C:6]24)[O:4]1)[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH3:2].[CH3:22]C(C)([O-])C.[K+].CI>O1CCCC1>[CH2:1]([CH:3]1[C:9](=[O:10])[N:8]([CH3:22])[C:7]2=[C:11]3[C:16](=[N:17][C:18]4=[CH:19][CH:20]=[CH:21][C:5](=[C:6]24)[O:4]1)[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH3:2]
Reactant: CCC1Oc2cccc3nc4c(c(c23)NC1=O)CCCC4
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CCC1Oc2cccc3nc4c(c(c23)N(C)C1=O)CCCC4
Reaction time: 0.33 h
Yield: 68.4 %

Procedure:
To a suspension of 3-ethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (5.0 g) in dry tetrahydrofuran (150 ml) was added potassium t-butoxide (3.0 g), with stirring. After 20 mins, methyl iodide (1.66) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, diluted with saturated potassium carbonate solution, and extracted with 2-butanone. The organic extracts were dried over anhydrous magnesium sulfate and concentrated. The residue was adhered to silica (methanol) and flash chromatographed (50% ethyl acetate/hexane). The appropriate fractions were concentrated and the residue was triturated with diethyl ether to give 3.59 g (68%) of 3-ethyl-1,3,9,10,11,12-hexahydro-1-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.
Reaction SMILES: [Na].[CH2:2]1[O:12][C:11]2[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][C:4]=2[O:3]1.[Br:13][CH2:14][C:15]([CH3:19])=[CH:16][CH2:17]Br>COCCOC>[Br:13][CH2:14][C:15]([CH3:19])=[CH:16][CH2:17][O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:11]2[O:12][CH2:2][O:3][C:4]=2[CH:5]=1
Reactant: OCc1ccc2c(c1)OCO2
Reactant: CC(=CCBr)CBr
Agent: [Na]
Solvent: COCCOC
Product: CC(=CCOCc1ccc2c(c1)OCO2)CBr
Reaction time: 0.25 h

Procedure:
8.7 g (0.05 mol) of sodium salt of the 3,4-methylendioxybenzylalcohol are added at 0° during the course of 15 minutes and while stirring to 12.5 g (0.055 mol) of 1,4-dibromo-2-methyl-2-butene which is dissolved in 100 cc of 1,2-dimethoxyethane. The mixture is stirred at 20°-25° for 16 hours and at 50° for 15 minutes. The solvent is then distilled off at reduced pressure and 100 cc amounts of water and ether are added to the residue. The aqueous phase is separated in a separatory funnel, the ether phase is extracted with saturated salt solution, is dried with sodium sulphate and evaporated. The residue is chromatographed on silica gel with hexane/ethyl acetate 9:1, whereby the 5-[(4-bromo-3-methyl-2-butenyloxy)-methyl]-1,3-benzodioxol is obtained as uniform colourless oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH2:5][CH2:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH:9]([O:12][CH2:13][CH2:14][OH:15])[C:10]=2[N:11]=1.C(P(CCCC)CCCC)CCC.[CH2:33]([O:35][C:36](=[O:49])[CH:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1)[CH3:34].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1C=CC=CC=1.O>[CH2:33]([O:35][C:36](=[O:49])[CH:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:15][CH2:14][CH2:13][O:12][CH:9]2[C:8]3[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=3[CH2:6][CH2:5][C:4]3[O:3][C:2]([CH3:1])=[N:11][C:10]2=3)=[CH:41][CH:40]=1)[CH3:34]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: Cc1nc2c(o1)CCc1ccccc1C2OCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCOC2c3ccccc3CCc3oc(C)nc32)cc1)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 39.1 %

Procedure:
Under a nitrogen atmosphere, 2-(2-methyl-9,10-dihydro-4H-1-oxa-3-aza-benzo[f]azulen-4-yloxy)-ethanol (400 mg, 1.6 mmol), tributylphosphine (480 mg, 2.4 mmol) and 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (380 mg, 1.6 mmol) were successively dissolved in dry benzene (10 mL). Solid azodicarboxylic dipiperidine (ADDP) (480 mg, 2.4 mmol) was added under stirring at 0° C. to the solution. After 10 min, the reaction mixture was brought to room temperature and the stirring was continued for 16 h. The mixture was added water and the product extracted with ethyl acetate. The combined organic phases was dried (MgSO4), and concentrated in vacuo. The residue was purified chromatography eluting with petroleum ether/ethyl acetate (1:1) to give 300 mg (40%) of the title compound: 1H NMR (300 MHz, CDCl3) δ1.15 (t, 3H). 1.20 (t, 3H), 22.38 (s, 3H), 2.60-2.85 (m, 2H), 2.90-3.05 (m, 3H), 3.25-3.38 (m,1H), 3.52-3.65 (m, 1H), 3.65-3.75 (m, 1H). 3.75-3.90 (m, 2H), 3.95 (t, 1H), 4.05 (t, 2H), 4.15 (q, 2H), 5.25 (s, 1H), 6.75 (d, 2H), 7.10 (d, 2H), 7.13-7.30 (m, 4H).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:34][Mg]Br.O>O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]([OH:33])[CH3:34])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (200 mg) in tetrahydrofuran (5 mL) was added methylmagnesium bromide (3M diethyl ether solution, 450 μL) at 0° C., and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (83.0 mg, yield 40%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate. MS: 481 (MH+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.[CH:22]([N:25]([CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[C:32]([O:39][CH3:40])[CH:31]=1)[CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(N(CC)CC)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:17][CH2:18][N:19]([C:34](=[O:35])[C:33]3[CH:37]=[CH:38][C:30]([CH2:29][N:25]([CH:26]([CH3:27])[CH3:28])[CH:22]([CH3:24])[CH3:23])=[CH:31][C:32]=3[O:39][CH3:40])[CH2:20][CH2:21]1)(=[O:14])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1cc(CN(C(C)C)C(C)C)ccc1C(=O)O
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(CN(C(C)C)C(C)C)ccc1C(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.6 %

Procedure:
To a solution of 1-(6-chloronaphthalene-2-sulfonyl)piperazine hydrochloride(100 mg), 4-diisopropylaminomethyl-2-methoxybenzoic acid (77 mg), triethylamine (35 mg) and HOBt (43 mg) in DMF (10 ml) was added WSC hydrochloride (61 mg) under ice-cooling, and the solution was stirred at room temperature for 4 hours and concentrated. To the residue were added ethyl acetate and sodium bicarbonate solution. The organic layer was separated, washed with water and extracted with 1 N hydrochloric acid. The extract was made alkaline with sodium hydroxide solution and extracted with dichloromethane. The extract was dried and concentrated and the residue was crystallized with ether to give colorless crystals of the title compound (99 mg).
Reaction SMILES: BrCCO[Si](C(C)(C)C)(C)C.Cl[CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.[CH3:22][C:23]1[CH:27]=[C:26]([N:28]2[CH2:32][CH2:31][NH:30][C:29]2=[O:33])[S:25][C:24]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([CH2:13][N:30]2[CH2:31][CH2:32][N:28]([C:26]3[S:25][C:24]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:23]([CH3:22])[CH:27]=3)[C:29]2=[O:33])=[CH:15][CH:16]=1)#[N:19]
Reactant: CCOC(=O)c1sc(N2CCNC2=O)cc1C
Reactant: N#Cc1ccc(CCl)cc1
Agent: CC(C)(C)[Si](C)(C)OCCBr
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc(C#N)cc3)C2=O)cc1C
Yield: 86 %

Procedure:
Following the procedure as described in Example 50, making variations as required to replace (2-bromoethoxy)(tert-butyl)dimethylsilane with 4-(chloromethyl)benzonitrile to react with ethyl 3-methyl-5-(2-oxoimidazolidin-1-yl)thiophene-2-carboxylate, the title compound was obtained as a cream solid in 86% yield: 1H NMR (300 MHz, CDCl3) δ 7.66 (d, J=8.1 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 6.18 (s, 1H), 4.53 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.89-3.81 (m, 2H), 3.52-3.43 (m, 2H), 2.50 (s, 3H), 1.34 (t, J=7.1 Hz, 3H); MS (ES+) m/z 370.2 (M+1).
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[C:6]([F:16])[CH:5]=1.O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(O)(=O)C>[Br:1][C:11]1[S:10][C:9]([CH2:8][C:7]2[CH:14]=[CH:15][C:4]([Br:3])=[CH:5][C:6]=2[F:16])=[CH:13][CH:12]=1
Reactant: BrBr
Reactant: Fc1cc(Br)ccc1Cc1cccs1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Fc1cc(Br)ccc1Cc1ccc(Br)s1
Reaction time: 2 h
Yield: 72 %

Procedure:
A solution of bromine (0.44 ml) in acetic acid (5 ml) was added during 10 minutes to a stirred solution of (4-bromo-2-fluorobenzyl)thiophene (2.33 g) in acetic acid (10 ml). The solution was stirred for 2 hours, then poured into a mixture of water (50 ml) and a 20% w/v solution of sodium metabisulphite (20 ml). The mixture was extracted with ether (2×50 ml), the combined extracts washed with water and saturated brine, and then dried (MgSO4). The solvent was removed by evaporation to give 2-bromo-5-(4-bromo-2-fluorobenzyl)thiophene as an oil; in 72% yield; NMR: 4.04(s,2H), 6.55(d,1H), 6.85(d,1H), 7.07(t,1H), 7.14-7.30(m,2H); m/e, (chemical ionisation) 348(M+); which was used without further purification.
Reaction SMILES: [OH:1][CH:2]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:5]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:4]=2[CH2:3]1.N1C=CC=CC=1.[C:30](OC(=O)C)(=[O:32])[CH3:31].[OH-].[Na+]>O.C(Cl)Cl.CO>[OH:1][CH:2]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13]2[CH2:18][CH2:17][N:16]([C:30](=[O:32])[CH3:31])[CH2:15][CH2:14]2)[C:5]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:4]=2[CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: OC1Cc2cc(Cl)ccc2C(=C2CCNCC2)c2ncccc21
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N1CCC(=C2c3ccc(Cl)cc3CC(O)c3cccnc32)CC1

Procedure:
To a mixture of 32.6 mg (0.10 mmole) of 5-hydroxy-8-chloro-11-(4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine and 9.7 )1 (0.12 mmole) of pyridine in a solution of 2 mL of methanol and 1 mL of CH2Cl2 at 0° C. and under a nitrogen atmosphere was added 11.3 )1 (0.12 mmole) of acetic anhydride. After 30 min. the mixture was poured into water which was subsequently adjusted to pH of about 9 with aqueous sodium hydroxide. The mixture was extracted 2× with CH2Cl2. The organic portions were combined, washed once with brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield 31.2 mg of the title compound as a glass.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[OH:34])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1.[H-].[Na+].[Cl:46][C:47]1[CH:52]=[C:51](Cl)[N:50]=[CH:49][N:48]=1.O>CN(C)C=O.C(OCC)(=O)C>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[O:34][C:51]1[CH:52]=[C:47]([Cl:46])[N:48]=[CH:49][N:50]=1)[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2O)nc1
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2Oc2cc(Cl)ncn2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (300 mg) is dissolved in N,N-dimethylformamide (5 ml) and thereto are added sodium hydride (60%) (29 mg) and 4,6-dichloro-pyrimidine (107 mg) under ice-cooling, and the mixture is stirred for 30 minutes, and the reaction solution is cooled to room temperature, and thereto is added 4,6-dichloro-pyrimidine (107 mg), and the mixture is stirred for 30 minutes. To the reaction solution are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=49:1→17:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(6-chloro-pyrimidin-4-yloxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (244 mg). MS (m/z): 738/740 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:32][CH3:33])=[C:4]([C@H:9]([CH2:30][CH3:31])[CH2:10][C@:11]([OH:29])([C:25]([F:28])([F:27])[F:26])C=NC2C=CC=C3C=2C=CC(=O)N3)[CH:5]=[CH:6][C:7]=1[F:8].B(Br)(Br)Br.[C:38]([O-])(O)=[O:39].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([O:32][CH3:33])=[C:4]([CH:9]([CH2:30][CH3:31])[CH2:10][C:11]([OH:29])([C:25]([F:27])([F:26])[F:28])[CH:38]=[O:39])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C([O-])O
Reactant: CC[C@H](C[C@@](O)(C=Nc1cccc2[nH]c(=O)ccc12)C(F)(F)F)c1ccc(F)c(Cl)c1OC
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: ClCCl
Product: CCC(CC(O)(C=O)C(F)(F)F)c1ccc(F)c(Cl)c1OC
Temperature: -30 °C

Procedure:
300 mg (0.88 mmol) of (2R,4R)-4-(3-chloro-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal and 140 mg (0.88 mmol) of 5-aminoquinolin-2(1H)-one are dissolved in 19 ml of toluene and the solution is admixed with 0.55 ml (1.75 mmol) of titanium tert-butoxide and 0.1 ml of acetic acid. The reaction mixture is heated at 100° C. for 2 hours, cooled, poured into water and stirred vigorously. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo to give 539 mg of (5-{[(2R,4R)-4-(3-chloro-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}quinolin-2(1H)-one as a crude product. The imine is dissolved in 44 ml of CH2Cl2 and the solution is cooled to −30° C. 8.9 ml (8.9 mmol) of a 1M BBr3 solution in dichloromethane are added slowly dropwise over 15 minutes and the mixture is allowed to warm to room temperature over 22 hours. The reaction solution is poured onto a mixture of saturated NaHCO3 solution and ice. It is extracted repeatedly with ethyl acetate and the extracts are washed with saturated NaCl solution and dried over Na2SO4. Purification by column chromatography on silica gel (hexane/ethyl acetate 0-100%) yields 134 mg of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:20]=1[NH2:21]>>[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: Nc1cc(O)ccc1Cl
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Product: Oc1ccc(Cl)c(Nc2cc(C(F)(F)F)nc(-c3cnccn3)n2)c1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (40 mg, 0.154 mmol) and 2-chloro-5-hydroxyaniline (33 mg, 0.231 mmol) similar to Example 190 and was isolated as a solid (6 mg). 1H NMR (CDCl3): 9.72 (d, J=1.5 Hz, 1H), 8.78 (dd, J=5.7, 1.5 Hz, 1H), 8.73 (d, J=1.2 Hz, 1H), 7.33 (d, J=8.7 Hz, 1H), 7.05 (s, 1H), 7.04 (d, J=8.7 Hz, 1H), 6.73 (dd, J=8.7, 2.7 Hz, 1H), 6.29 (d, J=2.7 Hz, 1H), 6.19 (dd, J=8.4, 2.7 Hz, 1H).
Reaction SMILES: [C:1]([NH:5][N:6]=[C:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:20]Cl>CCCCC>[C:1]([N:5]=[N:6][C:7]1([Cl:20])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCl
Reactant: CC(C)(C)NN=C1CCCCC1
Solvent: CCN(CC)CC
Solvent: CCCCC
Product: CC(C)(C)N=NC1(Cl)CCCCC1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 252 grams (1.5 moles) of cyclohexanone t-butylhydrazone and 160 grams (1.5 moles) of triethylamine in 1200 ml pentane in a 3 liter 4 neck flask equipped with a mechanical stirrer, thermometer and gas inlet tube, was added 107 grams (1.5 moles) of chlorine gas, holding the temperature at -10° to 0° C. After the chlorine addition was complete, the reaction mixture was stirred an additional 15 minutes and the insoluble triethylamine hydrochloride filtered off. The filter cake was washed with an additional 300 ml pentane and the filtrate stripped of pentane under reduced pressure. The yield of 1-t-butylazo-1-chlorocyclohexane was 266 grams (87.5% crude yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:13]2[CH2:27][CH2:26][C:16]3([O:21][CH2:20][C:19](=[O:22])[N:18]([CH:23]4[CH2:25][CH2:24]4)[CH2:17]3)[CH2:15][CH2:14]2)[C:9]([O:11][CH3:12])=[O:10])=[C:4]([F:28])[CH:3]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].Br[C:53]1[CH:62]=[C:61]2[C:56]([CH:57]=[C:58]([O:63][CH3:64])[CH:59]=[N:60]2)=[CH:55][CH:54]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:23]1([N:18]2[CH2:17][C:16]3([CH2:26][CH2:27][N:13]([CH:8]([C:5]4[CH:6]=[CH:7][C:2]([C:53]5[CH:62]=[C:61]6[C:56]([CH:57]=[C:58]([O:63][CH3:64])[CH:59]=[N:60]6)=[CH:55][CH:54]=5)=[CH:3][C:4]=4[F:28])[C:9]([O:11][CH3:12])=[O:10])[CH2:14][CH2:15]3)[O:21][CH2:20][C:19]2=[O:22])[CH2:25][CH2:24]1
Reactant: COC(=O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Reactant: COc1cnc2cc(Br)ccc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)C(c1ccc(-c2ccc3cc(OC)cnc3c2)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 80 °C
Reaction time: 8 h
Yield: 28.1 %

Procedure:
A solution of methyl 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetate (0.626 mmol) in 1,4-dioxane (2.5 mL) was treated with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.751 mmol), potassium acetate (0.939 mmol), and PdCl2(dppf)-CH2Cl2 adduct (0.031 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture stirred in an oil bath at 80° C. overnight. The reaction mixture was cooled to room temperature and was treated with 7-bromo-3-methoxyquinoline (0.626 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.031 mmol), and 2M aq potassium carbonate (1.878 mmol). The solution was degassed with a stream of nitrogen for 3 min, at which point the reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120° C. for 15 min. The resulting black mixture was diluted with water (100 mL) and was extracted three times with chloroform. The combined organic layers were treated with Silicycle Si-thiol (50 mg), dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by reverse phase HPLC (20-65% acetonitrile/water with 0.1% NH4OH) followed by chiral HPLC (Chiralpak IA column, methanol:acetonitrile-1:1) and lyophilization from water (w/25% acetonitrile) afforded the title compound as a white solid (94 mg, 26%). MS(ES)+ m/e 534.2 [M+H]+, >99% ee, αD=+58 deg (c=0.05, methanol:acetonitrile 1:1).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]=[C:12]([SH:14])[NH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:16][C:17](=O)[CH3:18].CCOCC.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([S:8][C:9]1[N:13]=[C:12]2[S:14][CH:16]=[C:17]([CH3:18])[N:11]2[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CCl
Reactant: Sc1nc(SCc2ccccc2)n[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: Cc1csc2nc(SCc3ccccc3)nn12
Yield: 92.3 %

Procedure:
The product of stage (a) (22.3 g) and chloroacetone (9.6 g) were heated in ethanol (120 ml) under reflux for 22 hours. The solution was then reduced under vacuum, and the residue was stirred with a mixture of ether and aqueous sodium bicarbonate. The ether solution was separated, washed with water, dried over magnesium sulphate, and reduced under vacuum to give 24.1 g of the desired product as an orange oil.