Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N1CC2C(C[N:12]([CH2:16][C:17]3[S:25][C:24]4[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[N:22][C:21]([Cl:32])=[N:20][C:19]=4[CH:18]=3)[CH2:13]2)C1)=O)(C)(C)C.Cl.[C:34]([O:38][C:39]([N:41]1[CH2:45][CH2:44][C:43]2([CH2:50]CN[CH2:47][CH2:46]2)[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39]([N:41]1[CH2:45][CH2:44][C:43]2([CH2:46][CH2:47][N:12]([CH2:16][C:17]3[S:25][C:24]4[C:23]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)=[N:22][C:21]([Cl:32])=[N:20][C:19]=4[CH:18]=3)[CH2:13][CH2:50]2)[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC2(CCN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2)C1

Procedure:
Prepared according to the method used in the preparation of 5-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 2,8-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester hydrochloride in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a tan solid (104 mg, 71%).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:14][CH:13]=2)[CH:8]=[C:7]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[N:6]=1)(=O)=O.CCN(C(C)C)C(C)C.[NH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=1>C1COCC1>[OH:48][C:45]1[CH:46]=[CH:47][C:42]([CH2:41][NH:40][C:5]2[N:10]=[C:9]([NH:11][C:12]3[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:14][CH:13]=3)[CH:8]=[C:7]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[N:6]=2)=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2cc(OCC(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Reactant: NCc1ccc(O)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1ccc(Nc2cc(OCC(F)(F)F)nc(NCc3ccc(O)cc3)n2)cc1
Yield: 81.6 %

Procedure:
To a solution of tert-butyl 4-((2-(methylsulfonyl)-6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)benzoate (80 mg, 0.18 mmol), and Hunig's Base (0.062 mL, 0.36 mmol) in THF (1 mL) was added 4-(aminomethyl)phenol (44 mg, 0.36 mmol). The resulting mixture was stirred at r.t for 16 hs. The solvent was removed and the crude product was purified by silica gel chromatography using 40-70%-100% EtOAc/Hexanes to give tert-butyl 4-((2-((4-hydroxybenzyl)amino)-6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)benzoate (72 mg, 83%) as white solid.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:32])[C@H:7]([CH3:31])[CH2:8][C@@H:9]1[O:13]C(C)(C)[N:11](C(OC(C)(C)C)=O)[C@H:10]1[CH2:23][C:24]([CH3:30])([CH3:29])[CH2:25][C:26]([OH:28])=O)[CH2:2][CH2:3][CH3:4].[C:33]([CH2:36][CH2:37][CH:38]1[CH2:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[NH:40][CH2:39]1)(=[O:35])[NH2:34]>>[CH2:1]([NH:5][C:6](=[O:32])[C@H:7]([CH3:31])[CH2:8][C@H:9]([OH:13])[C@@H:10]([NH2:11])[CH2:23][C:24]([CH3:29])([CH3:30])[CH2:25][C:26]([N:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:47][CH:38]([CH2:37][CH2:36][C:33](=[O:35])[NH2:34])[CH2:39]1)=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: NC(=O)CCC1CNc2ccccc2C1
Reactant: CCCCNC(=O)[C@H](C)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CC(=O)O
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)CC(C)(C)CC(=O)N1CC(CCC(N)=O)Cc2ccccc21

Procedure:
Starting from 230 mg of 3-[N-tert-butoxycarbonyl-4(S)-(3-carboxy-2,2-dimethylpropyl)-2,2-dimethyl-1,3-oxazolidin-5(S)-yl]-2(R)-methyl-propionic acid (N-butyl)amide and 205 mg of 3(R,S)-(2-carbamoyl)ethyl-1,2,3,4-tetrahydroquinoline, the title compound is obtained via (4O,5N-isopropylidene)-5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(R),7,7-trimethyl-8-[3(R,S)-(2-carbamoyl)ethyl-1,2,3,4-tetrahydroquinolin-1-ylcarbonyl]-octanoic acid (N-butyl)amide (analogously to Example 1a); Rf (X)=0.08; Rf (V)=0.56; Rt (VI)=30.8 min) and 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(R),7,7-trimethyl-8-[3(R,S)-(2-carbamoyl)ethyl-1,2,3,4-tetrahydroquinolin-1-ylcarbonyl]-octanoic acid (N-butyl)amide (Rf (P)=0.32; Rt (VI)=26.8 min; FAB-MS: (M+H)+ =603) in a manner analogous to Example 1) as a diastereomer mixture: Rf (V)=0.21; Rt (VI)=20.3 min; FAB-MS: (M+H)+ =503.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([C@@H:36]([O:38]C(=O)C)[CH3:37])=[O:35]>>[OH:38][C@@H:36]([CH3:37])[C:34]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:35]
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c(OCC2CC2)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A150) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)[C:4]([OH:6])=O.[NH2:19][CH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>>[C:20]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:4](=[O:6])[CH:3]([O:2][CH3:1])[C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=3)[CH:8]=2)=[CH:23][CH:22]=1)#[N:19]
Reactant: COc1ccc2cc(C(OC)C(=O)O)ccc2c1
Reactant: N#Cc1ccc(CN)cc1
Product: COc1ccc2cc(C(OC)C(=O)NCc3ccc(C#N)cc3)ccc2c1

Procedure:
(RS)-Methoxy-(6-methoxy-naphthalen-2-yl)-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-N-(4-cyano-benzyl)-2-methoxy-2-(6-methoxy-naphthalen-2-yl)-acetamide. Off-white foam. MS 361.2 ([M+H]+)
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:17][C:18]1[C:19]([O:21][C:22](=[O:24])[CH:23]=1)=[O:20]>C(=S)=S>[O:16]=[C:12]1[CH2:13][CH2:14][CH2:15][N:11]1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:19](=[O:20])[C:18]([CH3:17])=[CH:23][C:22]([OH:24])=[O:21]
Reactant: CC1=CC(=O)OC1=O
Reactant: O=C1CCCN1c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=CC(=O)O)C(=O)c1ccccc1N1CCCC1=O
Reaction time: 40 h

Procedure:
66.7 g (0.5 mole) of anhydrous aluminum chloride are suspended in 150 ml of carbon disulphide. 32.2 g (0.2 mole) of N-phenyl-pyrrolidin-2-one and 22.4 g (0.2 mole) of methylmaleic anhydride are added, while stirring and cooling. The mixture is heated under reflux until a viscous mass is formed, and this is left to stand at room temperature for 40 hours, the solvent is decanted off and the mixture is decomposed carefully with icewater and concentrated aqueous hydrochloric acid and extracted with methylene cchloride or ethyl acetate. The organic phase is extracted with dilute sodium hydroxide solution, the aqueous phase is clarified by filtration, acidified with acetic acid and extracted and the extract is concentrated. The resulting oil is further reacted directly.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][O:13][C:14]1[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=1>>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: COc1ccccc1N
Product: COc1ccccc1Nc1ccccc1CC(=O)O

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with o-anisidine to yield 2-[(2-methoxyphenyl)amino]phenylacetic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]([OH:13])([CH2:12][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: C1COCCN1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(O)(CN2CCOCC2)CC1
Yield: 64.7 %

Procedure:
1-Oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (100 mg, 0.47 mmol) and morpholine (42 μL, 0.48 mmol, 1.03 eq) were stirred in EtOH at RT overnight. Solvent was removed in vacuo and the residue purified by flash chromatography (silica gel, 4% MeOH/DCM) to give 4-hydroxy-4-morpholin-4-ylmethyl-piperidine-1-carboxylic acid tert-butyl ester as a white solid (91.4 mg, 67%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][C:6]1([OH:16])[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1.I[CH3:18].O>O1CCCC1>[CH3:18][O:16][C:6]1([CH2:5][O:4][CH3:3])[CH2:15][CH2:14][C:9]2([O:10][CH2:11][CH2:12][O:13]2)[CH2:8][CH2:7]1
Reactant: COCC1(O)CCC2(CC1)OCCO2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC1(OC)CCC2(CC1)OCCO2
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 82.27 g sodium hydride (80%) in 2.1 L tetrahydrofuran was slowly added the solution of 208 g (1.03 mol) 8-(methoxymethyl)-1,4-dioxaspiro[4.5]decan-8-ol (prepared according to intermediate example 16f) in 1 L tetrahydrofuran under cooling. After 0.5 hours at 23° C. 143 mL iodomethane were added and the mixture was stirred at 23° C. overnight. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. After filtration and removal of the solvent 227.5 g (max. 100%) of the title compound were obtained that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[N:21]1([CH2:27][C:28]2[CH:29]=[C:30]([NH2:34])[CH:31]=[CH:32][CH:33]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:34][C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([CH2:27][N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[CH:29]=2)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Reactant: Nc1cccc(CN2CCOCC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Clc1nc2c(c(Nc3cccc(CN4CCOCC4)c3)n1)SCC2
Reaction time: 20 h
Yield: 70.6 %

Procedure:
1.25 g 2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidine are placed in 5 ml dimethylformamide, first 1.05 ml diisopropylethylamine, then 0.960 g 3-morpholin-4-ylmethyl-phenylamine (J. Med. Chem. 1990, 33, 327) are added. The reaction mixture is sf 20 hours at 60° C., then after cooling evaporated down. The residue is extracted with dichloromethane and water, the organic phase is dried and evaporated to dryness. The residue is crystallised with petroleum ether/ethyl acetate. 1.28 g of the product are obtained as a powder.
Reaction SMILES: [C:1]([S:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH:16]OS([O-])=O.[K+]>CO>[C:1]([S:5]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Sc1ccc(C(=O)O)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)S(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 156.7 %

Procedure:
4-(tert-Butylthio)benzoic acid (3.18 g, 15.1 mmol) was dissolved in methanol (78.70 mL) followed by the addition of water (7.9 mL) and OXONE (4.65 g, 7.56 mmol). The reaction mixture was stirred at room temperature for 45 minutes before it was filtered using methanol. The solvent was evaporated under reduced pressure. Water (35 mL) was added to the residue and the mixture was basified using solid NaOH and was washed with ethyl acetate (3×50 mL). The aqueous layer was acidified with 1N HCl before it was extracted with ethyl acetate (3×100 mL). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to yield 4-(tert-butylsulfinyl)benzoic acid (2.68 g, 78%) as a white solid. 1H NMR (400 MHz, DMSO) δ 13.29 (s, 1H), 8.12-8.08 (m, 2H), 7.73-7.69 (m, 2H), 1.09 (s, 9H). ESI-MS m/z calc. 226.1, found 227.3 (M+1)+; Retention time: 1.05 minutes (3 min run).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:63][C:64]([CH3:68])([CH3:67])[CH2:65][NH2:66]>C(Cl)Cl>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:66][CH2:65][C:64]([CH3:68])([CH3:67])[CH3:63])=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CC(C)(C)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NCC(C)(C)C)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (40 mg, 0.074 mmol) in methylene chloride (2 mL) were added HBTU (30 mg, 0.079 mmol) and (2,2-dimethylpropyl)amine (0.045 mL, 0.37 mmol). The mixture was stirred at rt overnight. Solvent was removed by rotovap. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (39 mg, 86%). LC-MS m/z 591 (M+H)+.
Reaction SMILES: [CH2:1]([CH:4]([CH2:15][CH2:16][CH3:17])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11])[CH2:2][CH3:3].[C:18](#[N:20])[CH3:19]>>[OH:11][CH:10]([C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([O:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:15][CH2:16][CH3:17])[CH:8]=1)[CH2:19][C:18]#[N:20]
Reactant: CCCC(CCC)COc1cccc(C=O)c1
Reactant: CC#N
Product: CCCC(CCC)COc1cccc(C(O)CC#N)c1

Procedure:
Reaction of 3-(2-propylpentyloxy)benzaldehyde with acetonitrile was conducted following the method used for Example 20. Purification by flash chromatography (20% EtOAc-hexanes) gave 3-hydroxy-3-(3-(2-propylpentyloxy)phenyl)propanenitrile as a clear oil. Yield (1.05 g, 59%): 1H NMR (DMSO-d6) δ 7.21 (t, J=8.0 Hz, 1H), 6.92-6.95 (m, 2H), 6.81 (ddd, J=8.0, 2.4, 0.8 Hz, 1H), 5/87 (br s, 1H), 4.82 (t, J=6.4 Hz, 1H), 3.81 (d, J=5.6 Hz, 1H), 2.86 (dd, J=16.8, 5.0 Hz, 1H), 2.77 (dd, J=17.2, 6.8 Hz, 1H), 1.74 (quint., J=5.6 Hz, 1H), 1.26-1.40 (m, 8H), 0.84-0.87 (m, 6H).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[CH2:23][NH2:24].CCOC(C)=O>CS(C)=O>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[CH2:23][NH:24][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N:3]=1
Reactant: Cc1ccc2nc(Cl)cnc2c1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(CNc2cnc3cc(C)ccc3n2)c(OC)c1
Yield: 95.8 %

Procedure:
2-Chloro-6-methylquinoxaline (0.51 g, 2.86 mmol), prepared according to J. Chem. Soc. 1948, 1310-1313, and (2,4-dimethoxyphenyl)methanamine (1.29 mL, 8.57 mmol) were microwaved in DMSO (2.5 mL) for 30 min at 150° C. This was diluted into 150 mL EtOAc and extracted three times with 100 mL brine. The crude product was purified by flash chromatography on a 90 g silica gel cartridge with 20 to 60% EtOAc in hexane, 50 min, at 40 mL/min to afford N-(2,4-dimethoxybenzyl)-6-methylquinoxalin-2-amine (848 mg, 2.74 mmol, 96% yield).
Reaction SMILES: [Cl:1][CH:2]=[CH:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1.C1C(C(OO)=[O:18])=CC=CC=1>C(Cl)(Cl)Cl>[Cl:1][CH:2]=[CH:3][CH2:4][C:5]1[CH:10]2[O:18][CH:9]2[CH:8]=[CH:7][CH:6]=1
Reactant: ClC=CCc1ccccc1
Reactant: O=C(OO)c1ccccc1
Solvent: ClC(Cl)Cl
Product: ClC=CCC1=CC=CC2OC12
Reaction time: 8 h
Yield: 33 %

Procedure:
(a) To 6.1 g of m-chloroallylbenzene was added 85 ml of chloroform solution containing perbenzoic acid and the mixture was allowed to stand at room temperature overnight. This solution was washed with sodium hydroxide solution, 20% Mohr's salt solution and then water, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain the residue, which was distilled under reduced pressure to give 2.2 g (yield 33%) of m-chloroallylbenzene oxide having a boiling point of 117° C/7 mmHg.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[OH-].[Li+]>C1COCC1.O>[C:32]([O:31][C:29]([NH:28][CH2:27][CH2:26][CH2:25][NH:24][C:20]1[N:19]=[C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:36])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)[CH:23]=[CH:22][N:21]=1)=[O:30])([CH3:34])([CH3:35])[CH3:33]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc(NCCCNC(=O)OC(C)(C)C)n3)cc(C)c21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2ccnc(NCCCNC(=O)OC(C)(C)C)n2)cc2c1C(CC(=O)O)OB2O
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
A solution of {6-[2-(3-tert-butoxycarbonylamino-propylamino)-pyrimidin-4-yloxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid ethyl ester (0.39 g, 0.78 mmol) in THF (10 mL) was treated with lithium hydroxide (0.089 g, 3.90 mmol) in water (2 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour, then at room temperature for 1 hour. The mixture was quenched with 2N HCl to pH 2 then concentrated in vacuo. The residue was diluted with brine and extracted with ethyl acetate. The organic extracts were dried (Na2SO4), filtered and concentrated to give {6-[2-(3-tert-butoxycarbonylamino-propylamino)-pyrimidin-4-yloxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid as a yellow solid (0.27 g, 74%) after lyophilization. 1H NMR (400 MHz, CD3OD) δ8.09 (d, J=6.25 Hz, 1H), 7.22 (s, 1H), 7.10 (s, 1H), 6.32 (m, 1H), 5.67 (d, J=6.25 Hz, 1H), 3.28-3.14 (br m, 2H), 3.17 (dd, J=15.24, 2.35 Hz, 1H), 3.10-2.90 (m, 2H), 2.38 (s, 3H), 2.36-2.25 (m, 1H), 1.70-1.50 (m, 2H), 1.41 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26]>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:25](=[O:26])[C:24]4[CH:28]=[CH:29][CH:30]=[C:22]([O:21][C:20]([F:19])([F:31])[F:32])[CH:23]=4)[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1cccc(OC(F)(F)F)c1
Yield: 64 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 3-(trifluoromethoxy)benzoyl chloride to afford the title compound as an off-white solid (36 mg, 64%). 1H-NMR (δ, ppm, DMSO-d6): 6.50 (d, 1H, HPy,5, J=6.0 Hz), 6.93 (d, 1H, Harom, J=7.0 Hz), 7.44 (ps t, 1H, Harom, J=8.0 Hz), 7.62 (s, 1H, Harom), 7.64-7.69 (m, 3H, Harom), 7.81 (d, 1H, HPy,6, J=6.0 Hz), 7.88 (s, 1H, Harom), 7.99 (d, 1H, Harom, J=8.0 Hz), 10.47 (s, 1H, NHamide), 11.20 (s, 1H, NHPy3), 11.39 (s, 1H, NHPy2). 13C-NMR (δ, ppm, DMSO-d6): 106.61, 110.86, 113.78, 114.72, 116.36, 120.05, 121.07, 124.17, 126.80, 130.23, 130.64, 136.83, 140.47, 141.35, 144.55, 147.17, 148.28, 154.21, 154.76, 164.03. HRMS (EI): m/z [M+H] calcd for C20H14F3N4O4: 431.0967; found: 431.0968.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([CH:14]=O)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[Br-].[CH2:19]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:20]1(/[CH:19]=[CH:14]/[C:12]2[NH:11][N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=3)[CH:13]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1cc(-c2ccc(C(F)(F)F)cc2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc(/C=C/c3ccccc3)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 40.1 %

Procedure:
3-[4-(Trifluoromethyl)phenyl]-1H-pyrazole-5-carbaldehyde (1.20 g, 5.00 mmol) was dissolved in N,N-dimethylformamide (10 mL), benzyltriphenylphosphonium bromide (3.25 g, 7.50 mmol) and potassium carbonate (2.76 g, 20.0 mmol) were added, and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1-1:2) to give the title compound (630 mg, yield 40%) as colorless crystals. MS: m/z 315 (MH+), 1H NMR (CDCl3) δ: 6.79 (1H, s), 6.99 (1H, d, J=16.5 Hz), 7.10 (1H, d, J=16.5 Hz), 7.28-7.39 (3H, m), 7.41-7.47 (2H, m), 7.64 (2H, d, J=8.5 Hz), 7.87 (2H, d, J=8.0 Hz), 10.90 (1H, s).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][N:15]2[CH3:20])=[O:10].Cl.N1C=CC=CC=1>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][N:15]2[CH3:20])=[O:10]
Reactant: COc1ccccc1C(=O)c1cccc2c1ccn2C
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1ccc2c(C(=O)c3ccccc3O)cccc21
Yield: 60.7 %

Procedure:
Using the procedure of Step C of Example 3, 29.9 g of the product of Step C and 300 g of pyridine hydrochloride were reacted to obtain using methylene chloride as eluant for the chromatography 17.2 g of the expected product melting at 80° C. which was used as is for the following step.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][C:24](=[O:26])[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].CC(C)=O>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][CH:24]([OH:26])[CH3:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)COC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: CC(O)COC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1
Reaction time: 7 h
Yield: 60.5 %

Procedure:
To a solution of {2S,4R)-1-benzyloxycarbonyl-2-(2-oxopropyl)oxymethyl-4-methanesulfonyloxypyrrolidine (12 g) in ethanol (120 ml) was added by portions sodium borohydride (2.4 g) at 0° C. After 7 hours, to the reaction mixture was added dropwise acetone (20 ml) carefully at 0° C. and the solvent was evaporated in vacuo. To the resultant residue were added ethyl acetate (200 ml) and water (100 ml), the organic layer was separated, washed with brine (100 ml) and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (500 ml) eluting with 5% methanol in dichloromethane (V/V) gave (2S,4R)-1-benzyloxycarbonyl-2-(2-hydroxypropyl)oxymethyl-4-methanesulfonyloxypyrrolidine (7.3 g).