Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].F[C:10]1[CH:15]=[CH:14][C:13]([S+:16]([C:23]2[CH:28]=[CH:27]C=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1.[OH-].[Na+].[CH3:31][C:32]1([CH3:44])[CH2:37][O:36][C:35]2([CH2:42][CH2:41][CH2:40][CH2:39][CH:38]2S)[O:34][CH2:33]1>ClCCl>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[CH3:31][C:32]1([CH3:44])[CH2:37][O:36][C:35]2([CH2:42][CH2:41][CH2:40][CH2:39][CH:38]2[S:3]([C:2]2[CH:27]=[CH:28][C:23]([S+:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]3[CH:12]=[CH:11][CH:10]=[CH:15][CH:14]=3)=[CH:24][CH:25]=2)(=[O:6])=[O:4])[O:34][CH2:33]1
Reactant: Fc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Reactant: CC1(C)COC2(CCCCC2S)OC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC1(C)COC2(CCCCC2S(=O)(=O)c2ccc([S+](c3ccccc3)c3ccccc3)cc2)OC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 125.3 %

Procedure:
26.7 g of 4-fluorophenyl diphenylsulfonium trifluoromethanesulfonate was dissolved in 200 g of dichloromethane in a reaction flask, in which the atmosphere was replaced with nitrogen. 200 g of 10 wt % sodium hydroxide aqueous solution and 14.6 g of 3,3-dimethyl-1,5-dioxaspiro[5.5]undecane-7-thiol were added. The mixture was stirred at 30 minutes for room temperature and transferred to a separatory funnel, shaken, and allowed to stand still. The water layer was removed. After the addition of 300 ml of distilled water, the mixture was further shaken and allowed to stand still. The water layer was removed. The resulting dichloromethane solution was dried with anhydrous magnesium sulfate and filtered. After evaporating dichloromethane from the dried solution, the residual liquid was dried under reduced pressure to obtain 25.6 g of [4-(3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-7-ylsulfonyl)phenyl]diphenylsulfonium trifluoromethanesulfonate.
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[NH:4][C:2]1=S.[Br:12]Br>>[Br:12][C:2]1[NH:1][C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=1
Reactant: BrBr
Reactant: O=c1[nH]c(=S)[nH]c2nc[nH]c12
Product: O=c1[nH]c(Br)nc2nc[nH]c12

Procedure:
This compound is prepared from 2-thioxanthine** through oxidation of the mercapto group by bromine and in situ displacement by hydrobromine. For reference on the oxidation and displacement, see Beaman, A. G.; Gerster, J. F.; Robins, R. K, J. Org. Chem, 1962, 27, 986.1.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:12][CH2:13][CH2:14][NH2:15])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>C(Cl)Cl>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:12][CH2:13][CH2:14][NH:15][C:23]([C:19]3[O:18][CH:22]=[CH:21][CH:20]=3)=[O:24])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCCn1cnc(-c2ccccc2)c1
Reactant: O=C(Cl)c1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCCn1cnc(-c2ccccc2)c1)c1ccco1

Procedure:
A mixture of 2.0 g. of 4-phenyl-1H-imidazole-1-propanamine, 50 ml. of methylenechloride and 10 ml. of 1N sodium hydroxide was stirred and 2.0 ml. of 2-furoyl chloride was added. The mixture was stirred for eighteen hours, methylene chloride was added and the layers were separated. The organic layer was washed with water, dried over magnesium sulfate and concentrated. The residue was washed onto a filter with diethyl ether, giving the desired product, m.p. 120°-122° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([N:15]3[CH2:18][CH:17]([OH:19])[CH2:16]3)=[O:14])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:21]1[CH:22]=[CH:23][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[N:25][CH:26]=1>>[CH:1]1([N:6]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([N:15]3[CH2:18][CH:17]([O:19][C:21]4[CH:22]=[CH:23][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[N:25][CH:26]=4)[CH2:16]3)=[O:14])[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(O)c1ccc(F)cn1
Reactant: O=C(N1CCCN(C2CCCC2)CC1)N1CC(O)C1
Product: CC(C)(O)c1ccc(OC2CN(C(=O)N3CCCN(C4CCCC4)CC3)C2)cn1

Procedure:
In a similar fashion (Route 20, GP I), 1-[(4-cyclopentyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-ol (100 mg, 0.41 mmol) and 2-(5-fluoropyridin-2-yl)propan-2-ol (90 mg, 0.41 mmol) were used to give the title compound. Crude material (38 mg) after workup gave the title compound as colourless oil (19.3 mg) after purification by preparative HPLC.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]1[O:22][CH:23]=[CH:24][N:25]=1.[CH3:26][O:27][C:28]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][N:31]=1)=[O:29]>>[CH3:26][O:27][C:28]([C:30]1[CH:38]=[CH:37][C:33]([C:34](=[O:35])[NH:1][CH2:2][C:3]2[C:12](=[O:13])[C:11]3[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=3)[N:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:4]=2[C:21]2[O:22][CH:23]=[CH:24][N:25]=2)=[CH:32][N:31]=1)=[O:29]
Reactant: NCc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: COC(=O)c1ccc(C(=O)O)cn1
Product: COC(=O)c1ccc(C(=O)NCc2c(-c3ncco3)n(-c3ccccc3)c3cc(Cl)ccc3c2=O)cn1

Procedure:
5-[(7-Chloro-2-oxazol-2-yl-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-carbamoyl]-pyridine-2-carboxylic acid methyl ester was prepared starting from intermediate A and 6-(methoxycarbonyl)nicotinic acid. MS calcd. for C27H20ClN4O5 [(M+H)+] 515.1, obsd. 515.0.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:18][CH2:19][CH2:20][CH2:21]I.CCCCCCC>C(#N)C>[Cl:18][CH2:19][CH2:20][CH2:21][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:1][CH2:2][C:3]1=[O:11]
Reactant: O=C1CSc2ccccc2N1
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCCCCCC
Product: O=C1CSc2ccccc2N1CCCCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2H-1,4-benzothiazine-3(4H)-one (1.0 g, 6.05 mmol) and Cs2CO3 (2.96 g, 9.08 mmol) were dissolved in dry acetonitrile (20 mL) under nitrogen atmosphere and stirred at rt for 30 min. 3-chloro-1-iodopropane (1.37 g, 6.66 mmol) dissolved in acetonitrile (4 mL) was added via a syringe. The reaction mixture was stirred at rt for 18 hours and concentrated in vacuo. Water (150 mL) was added and the reaction mixture was extracted with ethyl acetate (3×150 mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo to give 1.45 g of crude. The crude product was subjected to CC[eluent:Heptane:EtOAC(4:1)] to give the pure title compound as a slightly yellow oil. Yield 1.37 g, 90.2%. Rr 0.24 [Heptane:EtOAC(4:1)], 1H NMR (CDCl3): δ 2.14 (m, 2H), 3.38 (s, 2H), 3.36 (t, 2H), 4.17 (t, 2H), 7.03 (t, 1H), 7.18 (d, 1H), 7.26 (t, 1H), 7.37 (d, 1H). 13C NMR (CDCl3): δ 30.61, 31.81, 42.48, 42.66, 117.87, 123.78, 124.29, 127.52, 127.52, 128.78, 139.40, 165.51
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][O:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9]([S:23][CH3:24])[N:8]=1.C1C=C(Cl)C=C(C(OO)=[O:38])C=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][O:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:18]=[CH:19][CH:20]=[CH:21][N:22]=2)=[O:14])=[CH:11][N:10]=[C:9]([S:23]([CH3:24])=[O:38])[N:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(COc2nc(SC)ncc2C(=O)NCc2ncccn2)cc1Cl
Solvent: ClCCl
Product: COc1ccc(COc2nc(S(C)=O)ncc2C(=O)NCc2ncccn2)cc1Cl
Yield: 96.2 %

Procedure:
4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide (250 mg, 0.58 mmol) were dissolved in 20 mL of dichloromethane, m-CPBA (110 mg, 0.64 mmol) was added and reacted at room temperature for 12 h, washed with water after the reaction is complete, extracted with dichloromethane, the organic layer was dried, dried by rotation to obtain yellow solid 250 mg, yield 97%, this product was directly used in the next reaction without purification.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH:1]1([N:6]2[C:10]3=[N:11][C:29]([C:28]4[CH:31]=[CH:32][CH:33]=[C:26]([O:25][CH2:24][CH2:23][N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)[CH:27]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: O=Cc1cccc(OCCN2CCOCC2)c1
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3cccc(OCCN4CCOCC4)c3)nc(=O)c1-2
Temperature: 160 °C

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.05 g, 4.73 mmol), 3-[2-(4-morpholinyl)ethoxy]benzaldehyde (1.67 g) and xylenes (7 ml) was heated to 160° C. overnight. Additional aldehyde (0.4 g) was added and the mixture was heated at 160° C. until the reaction was complete. The reaction mixture was cooled to room temperature and a solid formed which was collected by filtration and washed with ether. The filtrate was concentrated to dryness and the residue was combined with the solid and was purified by column chromatography on silica gel eluting with ethyl acetate/ethanol (60/40). The solid product thus obtained was washed with ether, recrystallized from ethyl acetate and then washed with ether again to afford 1-cyclopentyl-3-ethyl-6-[3-[2-(4-morpholinyl)ethoxy]phenyl]-pyrazolo[3,4-d]pyrimidin-4-one, m.p. 173°-176° C.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[C:9]1[CH3:29])(C)(C)C.Br[CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1>>[Cl:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:6]([OH:5])=[O:30])[C:9]([CH3:29])=[C:10]2[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:28])[N:20]([CH2:32][CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[N:19]=1
Reactant: Clc1ccc(OCCBr)cc1
Reactant: Cc1c(-c2n[nH]c(=O)c3ccccc23)c2cc(Cl)ccc2n1CC(=O)OC(C)(C)C
Product: Cc1c(-c2nn(CCOc3ccc(Cl)cc3)c(=O)c3ccccc23)c2cc(Cl)ccc2n1CC(=O)O

Procedure:
The title compound was prepared from the product of example 16, step c) and 1-(2-bromo-ethoxy)-4-chloro-benzene using the procedure described in example 14. MS: ESI (negative): 520, 522 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.[O:12]=[C:13]([C:19](OCC)=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[NH4+].[NH4+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[O:9][CH2:8][CH2:7][N:6]3[C:19](=[O:20])[C:13]([OH:12])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([CH:11]=1)=[C:5]23
Reactant: Clc1ccc2c(c1)OCCN2
Reactant: CCOC(=O)C(=O)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCOC(=O)C1(O)C(=O)N2CCOc3cc(Cl)cc1c32
Temperature: 0 °C
Yield: 77.3 %

Procedure:
7-Chloro-3,4-dihydro-2H-1,4-benzoxazine (Japan Kokai JP No. 61-152984, U.S. Pat. No. 4,593,092) (19.77 g. 0.116 mol) was dissolved in 74 ml of acetic acid and to which diethyl ketomalonate 20.2 g (0.116 mol) was added dropwise at a room temperature. Then after refluxing for 20 minutes, the mixture was stand for overnight. After pouring into 500 ml of ice, ammonium carbonate was added to the solution. The resultant crystalline solid was collected by filtration, washed with water and dried to yield pale orange powders quantitatively. Recrystallization from ethanol afforded 26.67 g (77.3%) of the title compound as pale yellow prisms, mp 186°-187° C.
Reaction SMILES: [Li+].[OH-].[CH3:3][C:4]1[S:5][CH:6]=[C:7]([C:9]2[S:13][C:12]([C:14]([O:16]C)=[O:15])=[CH:11][CH:10]=2)[N:8]=1.Cl>O1CCOCC1>[CH3:3][C:4]1[S:5][CH:6]=[C:7]([C:9]2[S:13][C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=2)[N:8]=1
Reactant: COC(=O)c1ccc(-c2csc(C)n2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nc(-c2ccc(C(=O)O)s2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
Aqueous LiOH (1N, 1.5 mL) is added to a solution of methyl 5-(2-methylthiazol-4-yl)thiophene-2-carboxylate (81 mg, 0.34 mmol) in dioxane (1 mL). The reaction is stirred at room temperature for 2 hours. Aqueous HCl (1N, 4 mL) is added and the resultant precipitate is collected by filtration, washed with water, and dried to give the desired product (53 mg, 69%). 1H NMR (300 MHz, DMSO) δ 8.03, 7.69,7.59, 2.70.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:20]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[CH2:21]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](O)=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1[O:39][NH2:40].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[F:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][N:22]1[CH2:23][CH2:24][C@@H:20]([N:8]([C:9]2[CH:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[C:17](=[O:18])[NH:40][O:39][CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38][O:33]3)=[CH:13][N:14]=2)[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH2:21]1
Reactant: NOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)O)cn1)[C@@H]1CCN(Cc2cccc(F)c2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)NOC2CCCCO2)cn1)[C@@H]1CCN(Cc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
To a solution of (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylic acid (2.25 g, crude) in DMF (23 mL) was added was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (776 mg), HOBt (1.03 g), and EDCI (1.19 g) and the resulting mixture was stirred at ambient temperature for 3 hours. The reaction mixture was diluted with water and extracted with AcOEt. The organic phase was washed with sat NH4Cl aq solution, sat NaHCO3 aq solution, and brine, and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography eluted with AcOEt to give tert-butyl [(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate (2.51 mg) as pale yellow form.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)Cl>[C:29]([NH:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (140 mg, 0.42 mmol) in DCM (10 ml), were sequentially added triethylamine (175 μl, 1.26 mmol) and acetyl chloride (35.8 μl, 0.50 mmol). The reaction was stirred at RT for 2 hours, and then the solvent was evaporated. The residue was taken up with little EtOAc, and the insoluble was filtered off. The organic phase was evaporated to dryness achieving (R)-quinuclidin-3-yl 2-acetamido-2-phenylacetate (127 mg; quantitative yield).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[OH:25][CH2:26][CH2:27][SH:28]>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([NH:7][C:5]2[S:6][C:2]([S:28][CH2:27][CH2:26][OH:25])=[CH:3][N:4]=2)=[O:9])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Reactant: OCCS
Product: Cc1ccc(NC(=O)Nc2ncc(SCCO)s2)c(C(=O)C2CCCC2)c1
Yield: 28.1 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[5-(2-hydroxy-ethylsulfanyl)-thiazol-2-yl]-urea (114 mg, 28%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 2-hydroxy-ethanethiol (158 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:17][C:18]1[C:19]([CH:34]2[CH2:36][CH2:35]2)=[N:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[N:22][CH:23]=1>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:17][C:18]2[C:19]([CH:34]3[CH2:36][CH2:35]3)=[N:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=3)=[N:22][CH:23]=2)=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(O)cc1C
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Product: CCOC(=O)CCc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1C

Procedure:
In analogy to the procedures described in examples 8A] and 31B], 3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester was reacted with 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) to give 3-{4-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenyl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]([C:14]([F:17])([F:16])[F:15])=[N:11][NH:12][CH:13]=2)O1.Cl[C:20]1[C:29]([N:30]([CH:32]([CH3:34])[CH3:33])[CH3:31])=[N:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:35]([O:37][CH3:38])=[O:36])[CH:26]=2)[N:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH:32]([N:30]([CH3:31])[C:29]1[C:20]([C:9]2[C:10]([C:14]([F:15])([F:16])[F:17])=[N:11][NH:12][CH:13]=2)=[N:21][C:22]2[C:27]([N:28]=1)=[CH:26][C:25]([C:35]([O:37][CH3:38])=[O:36])=[CH:24][CH:23]=2)([CH3:34])[CH3:33]
Reactant: CC1(C)OB(c2c[nH]nc2C(F)(F)F)OC1(C)C
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc2nc(-c3c[nH]nc3C(F)(F)F)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (536.0 mg, 2.05 mmol) in DME (5 mL) and water (0.5 mL) was added methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (200.0 mg, 0.68 mmol), sodium carbonate (217.0 mg, 2.05 mmol) and Pd(PPh3)4 (39 mg, 0.03 mmol) with stirring for 0.5 h at 90° C. in an oil bath with an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to get a residue, which was purified by a silica gel column with 2%-10% ethyl acetate in petroleum to afford methyl 3-(isopropyl(methyl)amino)-2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)quinoxaline-6-carboxylate as a light yellow solid (80 mg, 30%).
Reaction SMILES: [CH:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:8]([CH:10]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O>>[CH:1](=[O:7])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:8][CH3:10]
Reactant: CCCCCC=O
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCCCC/C=C/C=O

Procedure:
from 20 g of hexanal and 42.6 g of formylmethylenetriphenylphosphorane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].[H][H]>[Pd].C(O)(C)C>[C:4]([O:11][CH:8]1[CH2:9][CH2:10][CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:12])[CH2:6][CH2:7]1)(=[O:3])[CH2:5][CH3:6]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [Pd]
Solvent: CC(C)O
Product: CCOC(=O)C1CCC(OC(=O)CC)CC1
Reaction time: 4 h

Procedure:
289 Grams of ethyl-p-hydroxybenzoate and 4 grams of 5% palladium on carbon are charged to a 1-liter magnetically stirred autoclave. The material is hydrogenated at 125°-140° C. and 50 psig hydrogen pressure. Hydrogenation is continued until the uptake is approximately 70% of theory. GLC analysis indicates that the reaction mass is now 71% ketone and 7.6% alcohol. The reaction product is cooled, diluted with isopropyl alcohol, filters. The isopropyl alcohol is removed by stripping and the remainder is distilled through a short column. 286 Grams of the resulting distillate is admixed with 75 grams of propionicanhydride at 100° C. for a period of four hours. The resulting material is washed until neutral and distilled through an eight plate vigreux column yielding the following fractions:
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[C:16]([O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[C:15]([O:22][CH3:23])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10].[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[C:24]([NH:6][C:7]1[C:16]([O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[C:15]([O:22][CH3:23])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(OC)c(OCC2CC2)c1N
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OC)c(OCC2CC2)c1NC(C)=O
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
Sulfuric acid (1 mL) was added dropwise to a solution of methyl 2-amino-3-(cyclopropylmethoxy)-4-methoxybenzoate (98%, 187 g, 0.73 mol) and acetic anhydride (372 g, 3.65 mol). The reaction was warmed at 30° C. overnight, quenched with water/ice (1.5 L), and then stirred vigorously for 30 min. The resulting solids were collected by filtration and dried in an oven to give 140 g of methyl 2-acetamido-3-(cyclopropylmethoxy)-4-methoxybenzoate as a white solid. MS (ESI): 293.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C(C)(C)C)=[CH:4][C:3]=1[C:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[N:20]2)=[O:16].Cl.[OH-].[Na+]>CC(O)=O>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[N:20]3)=[O:16])[CH:4]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1
Temperature: 110 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a solution of N-(4-fluoro-3-(quinoxaline-6-carbonyl)phenyl)pivalamide (4.7 g, 13.5 mmol, 1.0 eq.) in HOAc (60 mL) was added cone. HCl (30 mL). The mixture was stirred at 110° C. for 4 h, then poured onto ice. The mixture was basified to pH=10 by the addition of 1N NaOH aqueous solution and extracted with DCM (100 mL×3). The combined organic layers were dried over Na2SO4 and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=1/2, v/v) to afford (5-amino-2-fluorophenyl)(quinoxalin-6-yl)methanone (3.5 g, 99%) which was used in the next step without further purification.
Reaction SMILES: CN1CCCC1=O.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH2:18][CH:19]([CH2:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:20]([OH:22])=O)(=[O:17])=[O:16])=[CH:11][CH:10]=1.Cl.CN(C)CCCN=C=NCC.Cl.[NH2:47][OH:48]>C(OCC)(=O)C>[OH:48][NH:47][C:20](=[O:22])[CH:19]([CH2:18][S:15]([C:12]1[CH:11]=[CH:10][C:9]([CH3:8])=[CH:14][CH:13]=1)(=[O:17])=[O:16])[CH2:23][S:24]([C:27]1[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=1)(=[O:26])=[O:25]
Reactant: NO
Reactant: Cc1ccc(S(=O)(=O)CC(CS(=O)(=O)c2ccc(C)cc2)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccc(S(=O)(=O)CC(CS(=O)(=O)c2ccc(C)cc2)C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-methylpyrrolidinone (20 mL) cooled in an ice bath, is added 2-[(4-methylbenzenesulfonyl)methyl]-3-(4-methylbenzenesulfonyl)-propionoic acid (4.4 g, 11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.2 g, 22 mmol), and hydroxylamine hydrochloride (1.5 g, 22 mmol). After stirring overnight at ambient temperature, the mixture is transferred to ethyl acetate and extracted with aqueous 10% hydrochloric acid, distilled water, aqueous sodium bicarbonate, brine, and dried over anhydrous sodium sulfate. The organic phase is concentrated in vacuo and triturated from hexane to afford the title compound as a white solid.