Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[N:17][C:18]([NH:20][C:21]3[CH:30]=[C:29]4[C:24]([C:25]5([CH2:32][CH2:31]5)[CH2:26][NH:27][CH2:28]4)=[CH:23][CH:22]=3)=[N:19][C:12]=2[N:11]2[CH:33]=[CH:34][N:35]=[C:10]12.C(N(C(C)C)CC)(C)C.[C:45](OC(=O)C)(=[O:47])[CH3:46]>CN(C)C=O.C(OCC)(=O)C>[C:45]([N:27]1[CH2:26][C:25]2([CH2:31][CH2:32]2)[C:24]2[C:29](=[CH:30][C:21]([NH:20][C:18]3[N:17]=[CH:16][C:13]4[C:14](=[O:15])[N:9]([C:3]5[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=5[Cl:8])[C:10]5[N:11]([CH:33]=[CH:34][N:35]=5)[C:12]=4[N:19]=3)=[CH:22][CH:23]=2)[CH2:28]1)(=[O:47])[CH3:46]
Reactant: O=c1c2cnc(Nc3ccc4c(c3)CNCC43CC3)nc2n2ccnc2n1-c1c(Cl)cccc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1Cc2cc(Nc3ncc4c(=O)n(-c5c(Cl)cccc5Cl)c5nccn5c4n3)ccc2C2(CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 109B (200 mg, 0.397 mmol) in 5 mL N,N-dimethylformamide was added diisopropylethylamine (0.346 ml, 1.983 mmol) followed by acetic anhydride (0.041 ml, 0.436 mmol). The reaction mixture was stirred at room temperature overnight, then diluted with ethyl acetate. The organics were washed with saturated aqueous NaHCO3, water, and brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by chromatography was performed with an Analogix 280 with an SF 25-40 column, 0% to 4% methanol/dichloromethane gradient over 30 minutes to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 1.02 (d, J=8.14 Hz, 4H) 2.10 (d, J=21.70 Hz, 3H) 3.46-3.64 (m, 2H) 4.75 (s, 2H) 6.75-7.04 (m, 1H) 7.12 (s, 1H) 7.44-7.90 (m, 6H) 9.16 (s, 1H) 10.80 (s, 1H). MS (ESI+) m/z 546.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][P:4]([NH:23][CH:24]1[CH2:29][S:28][C@H:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:26]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:25]1=[O:42])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1C(=O)C2=CC=CC=C2C1=O)=[O:5])[CH3:2].O.NN>O1CCOCC1.C1(C)C=CC=CC=1>[NH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][P:4]([NH:23][CH:24]1[CH2:29][S:28][C@H:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:26]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:25]1=[O:42])([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)CN1C(=O)C(NP(=O)(CCCCCCN2C(=O)c3ccccc3C2=O)OCC)CS[C@@H]1c1ccccc1
Agent: NN
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CN1C(=O)C(NP(=O)(CCCCCCN)OCC)CS[C@@H]1c1ccccc1
Temperature: 25 °C

Procedure:
A solution of (R)-dihydro-5-[[ethoxy(6-phthalimidohexyl)phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester in dioxane is treated with hydrazine hydrate and stirred at room temperature under argon. After the reaction is completed, the mixture is diluted with toluene and the solvents decanted. The residue is triturated with methylene chloride and filtered. The combined filtrate is evaporated to dryness to give (R)-dihydro-5-[[(6-aminohexyl)ethoxyphosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15]([CH:17]=[C:18]1[CH2:21][N:20]([C:22]2[C:36]([F:37])=[CH:35][C:25]([C:26]([NH:28][C@@H:29]([CH3:34])[C:30]([F:33])([F:32])[F:31])=[O:27])=[C:24]([F:38])[CH:23]=2)[CH2:19]1)#[N:16].N12CCCN=C1CCCCC2>C(#N)C>[C:15]([CH2:17][C:18]1([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:21][N:20]([C:22]2[C:36]([F:37])=[CH:35][C:25]([C:26]([NH:28][C@@H:29]([CH3:34])[C:30]([F:33])([F:31])[F:32])=[O:27])=[C:24]([F:38])[CH:23]=2)[CH2:19]1)#[N:16]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: C[C@H](NC(=O)c1cc(F)c(N2CC(=CC#N)C2)cc1F)C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@H](NC(=O)c1cc(F)c(N2CC(CC#N)(n3cc(B4OC(C)(C)C(C)(C)O4)cn3)C2)cc1F)C(F)(F)F
Temperature: 50 °C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.00 g, 5.15 mmol), 4-[3-(cyanomethylene)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide (1.78 g, 5.15 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.31 mL, 2.1 mmol) in acetonitrile (20.2 mL) was heated at 50° C. overnight. After cooling, the solvent was removed under reduced pressure. The residue was used in the next step without further purification. LCMS cacld. for C24H28BF5N5O3 (M+1)+: m/z=540.2. Found: 540.1.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:15][CH:16]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:23][CH2:24][C:25]([O:27]C)=[O:26].[OH-].[Na+]>C1COCC1.CO.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:15][CH:16]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:23][CH2:24][C:25]([OH:27])=[O:26]
Reactant: COC(=O)COc1ccc2cc(-c3csc(-c4ccccc4)n3)ccc2c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)COc1ccc2cc(-c3csc(-c4ccccc4)n3)ccc2c1Br
Yield: 92.8 %

Procedure:
A mixture of methyl {[1-bromo-6-(2-phenyl-1,3-thiazol-4-yl)-2-naphthyl]oxy}acetate (217 mg, 0.477 mmol), prepared in the previous step, and 1 N NaOH (716 μL, 0.716 mmol) in 20 mL of THF plus 20 mL of methanol plus 10 mL of water was refluxed under nitrogen for 2.25 h. The reaction was filtered, acidified by the addition of 3 mL of 1 N HCl and then concentrated under reduced pressure. The solid that formed was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (195 mg, 92%) as a white solid, mp 222-230° C. Elemental Analysis for C21H14BrNO3S+0.15H2O Calc'd: C, 56.94; H, 3.25; N, 3.16. Found: C, 57.19; H, 3.18; N, 3.04.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH:10]([OH:16])[CH2:9]1)C1C=CC=CC=1.O.NN>C(O)C.[C].[Pd]>[OH:16][CH:10]1[CH:11]([CH2:14][OH:15])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: OCC1CCN(Cc2ccccc2)CC1O
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: OCC1CCNCC1O
Yield: 107.2 %

Procedure:
To a solution of 1-benzyl-3-hydroxy-4-hydroxymethylpiperidine (7.1 g) and hydrazine monohydrate (1.56 ml) in ethanol was added 10% palladium carbon (3 g), and the resulting mixture was stirred at refluxing temperature for 5 hr. 10% Palladium carbon was filtered off and the solvent was evaporated under reduced pressure to give 4.51 g of 3-hydroxy-4-hydroxymethylpiperidine.
Reaction SMILES: [C:1]([O:5][C:6]([O:8]C(OC(C)(C)C)=O)=O)([CH3:4])([CH3:3])[CH3:2].[CH3:16][NH:17][NH2:18].[OH-].[Na+]>O1CCCC1.O>[C:1]([O:5][C:6]([N:17]([CH3:16])[NH2:18])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CNN
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(N)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
Di-t-butyl-dicarbonate (10.91 g, 50 mmole) was added to a solution of methyl hydrazine (2.3 g, 50 mmole) in 100 ml of tetrahydrofuran and 100 ml of water. The pH of the mixture was maintained at 8-9 with 2N sodium hydroxide, and the solution stirred overnight at this pH. The organic solvent was removed in vacuo and the aqueous residue was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and distilled in vacuo to give the title compound as an oil, 3.68 g.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26].[NH2:27][CH:28]1[CH2:32][CH2:31][N:30](CC2C=CC=CC=2)[CH2:29]1.C(N(CC)CC)C>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: NC1CCN(Cc2ccccc2)C1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NC4CCNC4)c(Cl)c32)c(F)cc1F
Temperature: 25 °C
Reaction time: 26 h
Yield: 49.1 %

Procedure:
1-(6-Amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (200 mg), 3-amino-1-benzylpyrrolidine (97 mg) and triethylamine (160 mg) were added to pyridine (600 mg), and the mixture was stirred for 26 hours at room temperature and f or 15 hours at 60° C. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (3 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Acetic acid (2 ml) and 10% palladium-carbon (25 mg) were added to the resultant residue to conduct hydrogenation for 20 hours at 45° C. and for 21 hours at room temperature. After the catalyst was separated by filtration and washed with acetic acid, the filtrate and washings were concentrated under reduced pressure. A process of adding ethanol (3 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Ethanol (2 ml) was added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (115 mg) as a pale brown powder.
Reaction SMILES: [CH3:1][C:2]1N=[C:6]2[NH:8][C:9](=[O:11])[O:10][C:5]2=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:20]=[C:21]([CH2:25]O)[CH:22]=[CH:23][CH:24]=2)=[N:17][CH:18]=1.[C:27]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[N:8]([CH2:25][C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:16]4[N:15]=[CH:14][C:13]([CH3:12])=[CH:18][N:17]=4)[CH:20]=3)[C:6]=2[CH:27]=1
Reactant: Cc1ccc2oc(=O)[nH]c2n1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1cnc(-c2cccc(CO)c2)nc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cnc(-c2cccc(Cn3c(=O)oc4ccc(C)cc43)c2)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
112 mg (0.75 mmol) of 5-methyl-3H-oxazolo[4,5-b]pyridin-2-one, 180 mg (0.90 mmol) of [3-(5-methylpyrimidin-2-yl)phenyl]methanol and 238 mg (0.90 mmol) of triphenylphosphine are suspended in 5 ml of THF, and the mixture is stirred for 30 min. The mixture is subsequently cooled to 0° C., and 186 μl (0.90 mmol) of diisopropyl azodicarboxylate are added. The reaction mixture is stirred at room temperature for 2 h. The reaction mixture is diluted with 20 ml of dichloromethane, washed with 2×20 ml of water, dried over sodium sulfate and evaporated. The residue is purified by column chromatography on silica gel; yield: 101 mg of “A45”; ESI: 332 (M+H); Rt=4.91 min (method C);
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH:6]([NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1[NH2:18])[CH2:7][CH2:8][CH3:9])[CH3:2].C1N=CN([C:25](N2C=NC=C2)=[O:26])C=1>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH:6]([N:10]1[C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:25]1=[O:26])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCC(CC(=O)OCC)Nc1cc(C)ccc1N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccc(C)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
To a solution of 3-(2-Amino-5-methyl-phenylamino)-hexanoic acid ethyl ester (1.4 g, 5.3 mmol) in THF (20 mL) was added CDI (1.0 g, 6.4 mmol). The reaction mixture was stirred at room temperature for 16 h. When the reaction was complete, the reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over Na2SO4 and concentrated to afford 1.3 g of the desired product as dark brown solid. The resulting residue was used for the next reaction without further purification. LCMS (ESMS): m/z 291.40 (M+H+).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[CH2:15][CH2:14][CH2:13]3)[N:4]=[CH:3]1.[Cl:21][C:22]1[S:26][C:25]([CH:27]=O)=[CH:24][CH:23]=1>[OH-].[K+].CCO>[ClH:21].[Cl:21][C:22]1[S:26][C:25]([CH:27]=[C:15]2[CH2:14][CH2:13][C:12]3[C:17](=[CH:18][CH:19]=[C:10]([O:9][CH2:8][CH2:7][C:5]4[N:4]=[CH:3][NH:2][CH:6]=4)[CH:11]=3)[C:16]2=[O:20])=[CH:24][CH:23]=1
Reactant: O=Cc1ccc(Cl)s1
Reactant: O=C1CCCc2cc(OCCc3c[nH]cn3)ccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccc(Cl)s2)CCc2cc(OCCc3c[nH]cn3)ccc21
Yield: 114.3 %

Procedure:
According to the method of Example 34, 6-[2-(1H-imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one, monohydrochloride (0.313 g, 1.07 mmol) was reacted with 5-chloro-2-thiophene carboxaldehyde (0.165 g, 1.13 mmol) in 5 mL of 4% KOH in EtOH overnight to afford 0.272 g (60%) of the title compound as a dull yellow powder, mp dec. >210° C.: CI-MS m/e 385, 387 (M+—Cl).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[Cl:16][CH2:17][C:18](Cl)=[O:19]>>[Cl:16][CH2:17][C:18]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: O=C(Cl)CCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)CCl)CC1

Procedure:
The title compound 604 mg (89%) was obtained in a manner similar to the Manufacturing Example 3 by use of tert-butyl trans-4-aminocyclo-hexylcarbamate and chloroacetyl chloride, instead of the compound obtained in the Manufacturing Example 2 and acetyl chloride, respectively.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[C:19]2[C:14](=[C:15]([C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([CH3:29])[CH:11]=1.CS(C)=O>C1COCC1>[CH2:2]([CH:3]([O:6][C:10]1[C:19]2[C:14](=[C:15]([C:20]3[C:21]([CH3:28])=[CH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])[CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([CH3:29])[CH:11]=1)[CH2:4][CH3:5])[CH3:1]
Reactant: Cc1cc(C)c(-c2cccc3c(Cl)cc(C)nc23)c(C)c1
Reactant: CCC(O)CC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCC(CC)Oc1cc(C)nc2c(-c3c(C)cc(C)cc3C)cccc12
Temperature: 12 °C

Procedure:
To a solution of 3-pentanol (5.8 ml, 52.7 mmol) in dry THF (5 ml) was added sodium hydride (NaH) portionwise over a period of 10 min. A solution of 4-chloro-2-methyl-8-(2,4,6-trimethyl-phenyl)-quinoline (4.0006 g, 13.52 mmol) in dry THF (10 ml) was added. After stirring at room temperature as for 10 min, 15 ml of dry DMSO was added. The resulting mixture was heated in a 12° C. oil bath for 1.5 hours. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, dried, filtered, and concentrated to give the title compound as 5.002 g of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:16][S:17][CH2:18][C:19]([OH:21])=O)[O:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][O:9]2)=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37]1([C@H:43]2[CH2:47][O:46][C:45](=[O:48])[NH:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:16][S:17][CH2:18][C:19]([N:44]3[C@@H:43]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:47][O:46][C:45]3=[O:48])=[O:21])[O:9][CH2:10][C:11]([CH3:15])([CH3:14])[CH2:12][O:13]2)=[CH:6][CH:7]=1
Reactant: CC1(C)COC(CSCC(=O)O)(c2ccc(Cl)cc2)OC1
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)COC(CSCC(=O)N2C(=O)OC[C@@H]2c2ccccc2)(c2ccc(Cl)cc2)OC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
({[2-(4-Chlorophenyl)-5,5-dimethyl-1,3-dioxan-2-yl]methyl}thio)acetic acid (2.00 g, 6.05 mmol) was dissolved in dry CH2Cl2 (45 ml) and cooled to 0° C. N,N′-Dicyclohexylcarbodiimide (DCC, 1.43 g, 6.93 mmol) and 4-(dimethylamino)pyridine (DMAP, 1.70 g, 10.4 mmol) were added and the mixture was stirred at 0° C. for 20 minutes. (S)-(+)-4-Phenyl-2-oxazolidinone (1.40 g, 11.5 mmol) was added and the mixture was stirred at room temperature for 70 h. The mixture was filtered, concentrated under reduced pressure and purified by flash-chromatography (20%-30% EtOAc in hexane). This afforded 1.27 g (44%) of the title compound as a white solid. 1H-NMR (CDCl3, 300 MHz): δ 0.62 (s, 3H), 1.34 (s, 3H), 2.78 (s, 2H), 3.42 (s, 4H), 3.85 (s, 2H), 4.27-4.33 (dd, 1H), 4.69-4.78 (t, 1H), 5.34-5.42 (dd, 1H), 7.29-7.38 (m, 9H).
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[C:15]([O:23][CH3:24])[CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:7][C:6]=1[CH3:25].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:46]>CN(C=O)C>[Br:46][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[C:15]([O:23][CH3:24])[CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:7][C:6]=1[CH3:25]
Reactant: BrC(Br)(Br)Br
Reactant: COc1cccc2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)nc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cccc2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-8-methoxy-3H-quinazolin-4-one (1.20 g, 3.53 mmol) in DMF (10 mL) were added PPh3 (1.02 g, 3.88 mmol) and CBr4 (1.29 g, 3.88 mmol). The reaction mixture was stirred at room temperature for 16 hours. Solvent was removed under reduced pressure. The residue was triturated with ether and ethyl acetate. The solid was dried under vacuum and purified by the Simpliflash system, using 2% methanol in CH2Cl2 as eluent, to give 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-8-methoxy-3H-quinazolin-4-one as a white solid. Yield: 0.547 g (38%).
Reaction SMILES: [P:1]([OH:12])([O:7][CH2:8][CH2:9][CH2:10][CH3:11])[O:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:13][C:14]1[CH:19]2[C:20]([CH3:22])([CH3:21])[CH:17]([CH2:18]2)[CH2:16][CH:15]=1>>[CH:14]1([CH3:13])[CH:15]([P:1](=[O:12])([O:7][CH2:8][CH2:9][CH2:10][CH3:11])[O:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:16][CH:17]([CH:20]([CH3:21])[CH3:22])[CH2:18][CH:19]1[P:1](=[O:12])([O:7][CH2:8][CH2:9][CH2:10][CH3:11])[O:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCOP(O)OCCCC
Reactant: CC1=CCC2CC1C2(C)C
Product: CCCCOP(=O)(OCCCC)C1CC(C(C)C)CC(P(=O)(OCCCC)OCCCC)C1C
Yield: 69 %

Procedure:
Dibutyl hydrogen phosphite and α-pinene were reacted in substantially the same manner as reported in Example 3 to make the titled compound (69% theory yield). The NMR spectrum was in agreement with the expected structure.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N+:27]([O-:29])=[O:28])[N:15]=2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.NC1CCCN(C2C=CN=C(NC3C=CC=CC=3[N+]([O-])=O)N=2)C1.[CH2:61]([S:64](Cl)(=[O:66])=[O:65])[CH2:62][CH3:63].C(N(CC)CC)C>C(Cl)Cl>[N+:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH:20][C:16]1[N:15]=[C:14]([N:10]2[CH2:11][CH2:12][CH2:13][CH:8]([NH:7][S:64]([CH2:61][CH2:62][CH3:63])(=[O:66])=[O:65])[CH2:9]2)[CH:19]=[CH:18][N:17]=1)([O-:29])=[O:28]
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ccnc(Nc3ccccc3[N+](=O)[O-])n2)C1
Reactant: CCCS(=O)(=O)Cl
Agent: NC1CCCN(c2ccnc(Nc3ccccc3[N+](=O)[O-])n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)NC1CCCN(c2ccnc(Nc3ccccc3[N+](=O)[O-])n2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
To a solution tert-butyl(1-(2-((2-nitrophenyl)amino)pyrimidin-4-yl)piperidin-3-yl)carbamate (0.14 g, 0.34 mmol) in DCM (2.0 mL) was added TFA (1.0 mL) and the mixture was stirred for 1 h. An aliquot of the reaction mixture was analyzed by LCMS, which indicated that the reaction had proceeded to completion. The solvents were removed and the residue was dried on high vacuum. The crude product was used for the next step without further purification. To a solution of 4-(3-aminopiperidin-1-yl)-N-(2-nitrophenyl)pyrimidin-2-amine (0.34 mmol) in DCM (3.5 mL) at 0° C. was added propane-1-sulfonyl chloride (0.045 mL, 0.4 mmol) and triethylamine (0.12 mL, 0.85 mmol) and the mixture was warmed to room temperature overnight. The crude reaction mixture was concentrated and purified by flash chromatography (0-7.5% MeOH/DCM) to give the title compound (36 mg, 24% yield). MS (ES+) C18H24N6O4S requires: 420. found: 421 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:10](Cl)=[O:11])[S:8][CH:9]=1)(=[O:4])=[O:3].[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23]([NH2:25])=[O:24])[C:18](=[O:26])[CH2:17]2>CN(C1C=CN=CC=1)C.C(O)(=O)C>[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23]([NH2:25])=[O:24])[C:18](=[O:26])[CH:17]2[C:10](=[O:11])[C:7]1[S:8][CH:9]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Reactant: CS(=O)(=O)c1csc(C(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)O
Product: CS(=O)(=O)c1csc(C(=O)C2C(=O)N(C(N)=O)c3ccc(Cl)cc32)c1
Yield: 49 %

Procedure:
The title compound was prepared according to the procedure of Example 32. The reaction of 10 ml of thionyl chloride with 1.39 g (6.7 mmoles) of 4-methylsulfonyl-2-thiophenecarboxylic acid (prepared according to Arndt, F., et al., Chem. Ber. 94:1757 (1961)) gave 1.54 g of the crude acid chloride as a solid. The entire amount of 4-methylsulfonyl-2-thiophenecarbonyl chloride was coupled to 1.28 g (6.1 mmoles) of 5-chloro-2-oxindole-1-carboxamide in the presence of 2.24 g (18.3 mmoles) 4-(N,N-dimethylamino)pyridine. Acidic workup gave 2.28 g of crude product as an orange solid. Recrystallization from 2-butanone gave two crops of slightly impure yellow crystalline solid which had a combined mass of 2.18 g. Further purification by recrystallization provided 1.19 g (2.98 mmoles, 49% yield) of pure 5-chloro-3-(4-methylsulfonyl-2-thenoyl)-2-oxindole -1-carboxamide as a yellow crystalline solid, m.p. 228°-30° C. (acetic acid).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=1[NH2:27])[C:20]([O:22][CH3:23])=[O:21]>>[NH2:27][C:26]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[NH:16][C:9](=[O:10])[C:8]1[CH:12]=[CH:13][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: Cl
Product: COC(=O)c1ccc(N)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1
Yield: 44 %

Procedure:
Using the procedure described in Example 146, Part A, 4-tert-butylbenzoyl chloride (6.00 mmol) was reacted with methyl 3,4-diaminobenzoate dihydrochloride. As the product did not precipitate directly, the reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo to provide 0.885 g (44%) of the title compound as a crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](Cl)([Cl:10])[Cl:9])[N:3]=1.[OH-].[Na+].P([O-])(OC)OC.O>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([Cl:10])[Cl:9])[N:3]=1
Reactant: Clc1cccc(C(Cl)(Cl)Cl)n1
Agent: COP([O-])OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Clc1cccc(C(Cl)Cl)n1
Reaction time: 0.08 h
Yield: 71.3 %

Procedure:
In a reaction vessel fitted with a magnetic stirrer, 2.31 grams (10 mmole) of 2-chloro-6-(trichloromethyl)pyridine was dissolved in 25 ml of N-methylpyrrolidone. To this mixture was added 2.0 grams of 50% aqueous sodium hydroxide and 1.29 grams (10.2 mmole) of dimethyl phosphite. Within five minutes the temperature rose from 24° C. to 55° C. Analysis by glc indicated a ratio of 97.6/1.7 for reduced product to starting material. The reaction mixture was poured into 100 ml of water and the oil which separated was crystallized to form 1.4 grams of 2-chloro-6-(dichloromethyl)pyridine (mp 50°-53° C.). The yield was calculated to be 71% of theoretical.