Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10](=[S:22])[C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=1[F:21].[H-].[Na+]>CN1CCCC1=O.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[S:22][C:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=3[F:21])=[N:9][C:3]=2[CH:4]=1
Reactant: CS(=O)(=O)c1ccc(C(=S)Nc2cc(Br)ccc2Br)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2nc3cc(Br)ccc3s2)c(F)c1
Temperature: 140 °C
Reaction time: 3 h
Yield: 65.4 %

Procedure:
Intermediate 37 (0.48 g, 1.03 mmol) dissolved in N-Methylpyrrolidinone (0.97 ml) and added NaH (52 mg, 2.2 mmol). This mixture was stirred at 140° C. for 3 h. Reaction mixture cooled to rt and diluted with water to obtain the solid. Solid was filtered and dried to obtain the crude. Crude was purified on column chromatography using 60-120 mesh silicagel and DCM as eluent to afford the titled compound (260 mg) as a white solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.71-8.66 (m, 1H), 8.32 (d, J 1.7, 1H), 7.92-7.83 (m, 3H), 7.59 (dd, J 1.8, 8.6, 1H), 3.13 (s, 3H).
Reaction SMILES: [Cl:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[NH:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].CCN(C(C)C)C(C)C>C(O)(C)C>[Cl:1][CH:2]1[CH2:7][CH2:6][N:5]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])[CH2:4][CH:3]1[NH:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CCOP(=O)(NC1CNCCC1Cl)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCOP(=O)(NC1CN(c2ccncc2[N+](=O)[O-])CCC1Cl)OCC
Temperature: 70 °C
Yield: 69 %

Procedure:
To a solution of diethyl 4-chloropiperidin-3-ylphosphoramidate (1.0 equiv.) in isopropyl alcohol (0.1M) was added 4-chloro-3-nitropyridine (2.0 equiv.) and DIEA (1.1 equiv.). The reaction was heated to 70° C. for 18 h, then quenched with water and extracted with ethyl acetate. The organics were dried and concentrated under vacuo. The crude was purified via ISCO (ethyl acetate and hexanes then 10% methanol in DCM) to yield diethyl 4-chloro-1-(3-nitropyridin-4-yl)piperidin-3-ylphosphoramidate in 69% yield. LCMS (m/z): 393.1 (MH+), Rt=2.01 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:19])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[N:15]=[N:16][NH:17][CH:18]=2)[CH2:3][CH2:2]1.[C:20](Cl)(=[O:31])[O:21][CH2:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=1.[OH-].[Na+]>C(Cl)Cl>[NH:17]1[CH:18]=[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([NH:7][CH:4]2[CH2:3][CH2:2][N:1]([C:20]([O:21][CH2:22][C:23]3[CH:24]=[C:25]([Cl:30])[CH:26]=[C:27]([Cl:29])[CH:28]=3)=[O:31])[CH2:6][CH2:5]2)=[O:19])[N:15]=[N:16]1
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Reactant: O=C(CCCCCc1c[nH]nn1)NC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(CCCCCc1c[nH]nn1)NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
N-(Piperidin-4-yl)-6-(1H-1,2,3-triazol-4-yl)hexanamide (135 mg, 0.509 mmol) in DCM (50 ml) was treated with 3,5-dichlorobenzyl carbonochloridate (134 mg, 0.560 mmol) and 2M sodium hydroxide (25 ml, 50 mmol). The reaction mixture was stirred at room temperature for 5 hrs. The organics were removed, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by mass directed preparative LC to give the title compound, after concentration of the relevant fractions.
Reaction SMILES: [O:1]=[S:2]1(=[O:41])[C:8]2[CH:9]=[CH:10][C:11]([O:13][C:14]3[CH:15]=[C:16]([CH:26]=[C:27]([O:29][C@@H:30]([CH3:33])[CH2:31][OH:32])[CH:28]=3)[C:17]([NH:19][C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[O:18])=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][N:3]1CC1C=CC=CC=1>[Pd].C1COCC1.C(O)C>[O:41]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][C:11]([O:13][C:14]3[CH:15]=[C:16]([CH:26]=[C:27]([O:29][C@@H:30]([CH3:33])[CH2:31][OH:32])[CH:28]=3)[C:17]([NH:19][C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[O:18])=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][NH:3]1
Reactant: C[C@@H](CO)Oc1cc(Oc2ccc3c(c2)OCCN(Cc2ccccc2)S3(=O)=O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@@H](CO)Oc1cc(Oc2ccc3c(c2)OCCNS3(=O)=O)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 25.3 %

Procedure:
10% Palladium on carbon (30 mg) was added to 3-{[1,1-dioxido-2-(phenylmethyl)-3,4-dihydro-2H-5,1,2-benzoxathiazepin-7-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide (100 mg; 0.17 mmol) in dry THF (4 mL) and dry ethanol (4 mL) under an argon atmosphere. The reaction was degassed and placed under a hydrogen atmosphere then stirred for 24 hours at 50° C. and 20 bar. The mixture was filtered through diatomaceous earth and the filtrate evaporated. Purification via column chromatography, eluting with 50-100% ethyl acetate in isohexane, yielded a colourless oil which solidified under vacuum to give the title compound as a white foam (21 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]2[NH:7][C:8]([S:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=3[NH2:19])=[N:9][C:5]=2[CH:4]=1.C([O:24]CC)C>>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]2[NH:7][C:8]([S:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=3[NH2:19])=[O:24])=[N:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2[nH]c(SCc3cccc(C)c3N)nc2c1
Reactant: CCOCC
Product: COc1ccc2[nH]c(S(=O)Cc3cccc(C)c3N)nc2c1

Procedure:
The title compound was prepared by the method of Example 3 using 2.00 g of the title product of Example 35 instead of the title product of Example 2. Trituration with diethylether gave 1.58 g of the title compound: m.p. 142-144° C. Analysis. Calc'd. for C16H17N3O2S: C, 60.93; H, 5.43; N, 13.32; S, 10.17. Found: C, 60.60; H, 5.42; N, 12.83; S, 9.86.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[N+:9]([O-])([OH:11])=[O:10]>O>[N+:9]([C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])([O-:11])=[O:10]
Reactant: Cc1ccc(C)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Product: Cc1ccc(C)c([N+](=O)[O-])c1

Procedure:
A mixture of p-xylene (25 ml), and Fe3+ montmorillonite or Zn2+ montmorillonite (0.5 g) were taken in a 50 ml two-necked round-bottomed flask equipped with Dean-Stark apparatus. Fuming nitric acid (5 ml) was added dropwise into the reaction mixture. The reaction mixture was heated to reflux where upon the required amount of liberated water was collected in the Dean-Stark apparatus which usually takes 1.5 hr. Later on, the catalyst was filtered and the reaction mixture was concentrated to obtain the nitro p-xylene.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14](O)=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[Cl-].[NH4+:28]>>[NH2:28][C:14](=[O:15])[CH:13]([NH:12][C:10]([C:7]1[CH:6]=[C:5]([O:21][CH2:22][C:23]([F:25])([F:24])[F:26])[C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:9][N:8]=1)=[O:11])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(=O)O
Reactant: [NH4+]
Agent: [Cl-]
Product: CC(C)(C)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-3,3-dimethyl-butanoic acid (Example 194b) and ammonium chloride as starting materials and isolated (490 mg, 92%); MS (ESI, m/z): 374.5 (M+H+).
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([NH2:10])=[S:9])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl-].[CH3:16][C:17]1[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=1[CH:19]=[N+:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[N:20]1([CH:19]([C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[CH3:16])[C:5]2[N:1]([C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[C:8]([NH2:10])=[S:9])[CH:2]=[CH:3][CH:4]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1ccccc1C=[N+]1CCCCC1
Reactant: NC(=S)c1ccccc1-n1cccc1
Agent: [Cl-]
Product: Cc1ccccc1C(c1cccn1-c1ccccc1C(N)=S)N1CCCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-pyrrol-1-yl-thiobenzamide and 1-(2-methyl-benzylidene)-piperidinium chloride.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2]1.[F:13][C:14]([F:24])([F:23])[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[F:13][C:14]([F:23])([F:24])[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][N:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH2:2]1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1CN(Cc2cccc(C(F)(F)F)c2)C1

Procedure:
To a solution of tert-butyl azetidin-3-ylcarbamate (0.34 g, 2 mmol) in dichloroethane was added 3-(trifluoromethyl)benzaldehyde (0.45 g, 2.6 mmol) and sodium triacetoxyborohydride (0.64 g, 3 mmol). The resultant mixture was stirred at room temperature for 16 hours, and then the mixture was diluted with dichloromethane and washed with aqueous NaHCO3 solution. The organic layer was separated, dried over MgSO4, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 30-70% ethyl acetate/hexane to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@@H:26]4[CH2:30][CH2:29][CH2:28][O:27]4)[CH:20]=3)[C:15]2=[O:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1.[NH:32]1[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]1>>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@@H:26]4[CH2:30][CH2:29][CH2:28][O:27]4)[CH:20]=3)[C:15]2=[O:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH:10]([N:32]2[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]2)[CH2:9]1
Reactant: O=C1CCN(c2ccc(N3CCc4cc(OC[C@@H]5CCCO5)ccc4C3=O)cc2F)C1
Reactant: OC1CCNCC1
Product: O=C1c2ccc(OC[C@@H]3CCCO3)cc2CCN1c1ccc(N2CCC(N3CCC(O)CC3)C2)c(F)c1

Procedure:
According to Method J1, 2-[3-fluoro-4-(3-oxo-pyrrolidin-1-yl)-phenyl]-6-[(S)-1-(tetrahydrofuran-2-yl)methoxy]-3,4-dihydro-2H-isoquinolin-1-one was reacted with piperidin-4-ol. In this way the product was obtained with molecular weight 509.63 (C29H36FN3O4); MS (ESI): 510 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[O:21]=[C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:22])[N:12]1[CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][O:1][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:9][CH:8]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1ccc(CCO)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: CS(=O)(=O)OCCc1ccc(CCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 2 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A solution of 2-{2-[4-(2-hydroxy-ethyl)phenyl]-ethyl}-isoindole-1,3-dione (Preparation 10, 21.0 g, 71.25 mmol) in methyl ethyl ketone (315 mL) was cooled to 0° C. Triethylamine (14.9 mL, 106.87 mmol) was added followed by the dropwise addition of methane sulfonyl chloride (6.07 mL, 78.37 mmol). The reaction was stirred at 0-4° C. for 1 hour and then allowed to warm to room temperature. An aqueous solution of potassium carbonate (1M, 210 mL) was added and the mixture stirred. The organic and aqueous layers were separated and the aqueous re-extracted with methyl ethyl ketone (50 mL). The combined organic layers were concentrated to 40 mL by distillation. Tert-butyl methyl ether (300 mL) was slowly added to the hot solution causing crystallisation to occur. The mixture was allowed to cool to room temperature and then allowed to stir for 72 hours. The solid was removed by filtration and washed with tert-butyl methyl ether (3×25 mL). The solid was dried in vacuo at 45° C. for 4 hours to yield the title compound as a light brown solid, in 92% yield, 24.6 g.
Reaction SMILES: O.[OH-].[Li+].[NH2:4][C:5]1[C:10]2[C:11](=[O:31])[N:12]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]([CH3:30])([CH3:29])[C:25]([O:27]C)=[O:26])=[N:20][CH:21]=3)[CH2:13][CH2:14][O:15][C:9]=2[N:8]=[CH:7][N:6]=1>O1CCOCC1.O>[NH2:4][C:5]1[C:10]2[C:11](=[O:31])[N:12]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]([CH3:29])([CH3:30])[C:25]([OH:27])=[O:26])=[N:20][CH:21]=3)[CH2:13][CH2:14][O:15][C:9]=2[N:8]=[CH:7][N:6]=1
Reactant: COC(=O)C(C)(C)COc1ccc(N2CCOc3ncnc(N)c3C2=O)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(COc1ccc(N2CCOc3ncnc(N)c3C2=O)cn1)C(=O)O
Temperature: 60 °C
Yield: 56 %

Procedure:
Lithium hydroxide monohydrate (16.4 mg, 0.39 mmol) was added at room temperature to a solution of methyl 3-(5-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)pyridin-2-yloxy)-2,2-dimethylpropanoate B-21 (50.4 mg, 0.13 mmol) in 1,4-dioxane (2.0 mL) and water (1.0 mL). The reaction mixture was heated at 60° C. for 2 h and then concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on C18 reverse phase (water:acetonitrile gradient with 0.05% formic acid) to give 3-(5-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)pyridin-2-yloxy)-2,2-dimethylpropanoic acid B-22 (27.0 mg, Yield=56%). 1H NMR (500 MHz, METHANOL-d4) δ ppm 1.33 (s, 6H), 4.13 (m, 2H), 4.35 (s, 2H), 4.85 (m, 2H), 6.90 (d, J=8.83 Hz, 1H), 7.71 (d, J=8.83 Hz, 1H), 8.16 (s, 1H), 8.29 (s, 1H); MS (ESI) [M+1]+ 374.
Reaction SMILES: [NH2:1][C:2]1[C:18]([CH3:19])=[CH:17][C:16](Br)=[CH:15][C:3]=1[C:4]([O:6][CH2:7][CH:8]([CH2:13][CH3:14])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:5].[Cu](C#N)[C:22]#[N:23]>CN(C)C(=O)C>[NH2:1][C:2]1[C:18]([CH3:19])=[CH:17][C:16]([C:22]#[N:23])=[CH:15][C:3]=1[C:4]([O:6][CH2:7][CH:8]([CH2:13][CH3:14])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:5]
Reactant: N#C[Cu]C#N
Reactant: CCCCC(CC)COC(=O)c1cc(Br)cc(C)c1N
Solvent: CC(=O)N(C)C
Product: CCCCC(CC)COC(=O)c1cc(C#N)cc(C)c1N
Yield: 86.1 %

Procedure:
The above-described method (Example 2) was repeated to react 2-ethylhexyl 2-amino-5-bromo-3-methylbenzoate (2.00 g, 5.84 mmol) with copper cyanide (0.53 g, 5.96 mmol) in N,N-dimethylacetamide at 160° C. for 8 hours. Following working up similar to Example 2 and additional washing with aqueous 5% ethylenediamine solution, 2-ethylhexyl 2-amino-5-cyano-3-methylbenzoate (1.45 g, 76.7% of theory, 89.1 area % LC) was obtained as a brown oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH2:12])=[C:7]([N+:13]([O-])=O)[CH:6]=1)(=[O:4])=[O:3].CCOC(C)=O>CC(O)=O.[Fe]>[CH2:11]([C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][C:7]=1[NH2:13])[CH3:12]
Reactant: C=Cc1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCc1ccc(S(C)(=O)=O)cc1N
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 4-(methylsulfonyl)-2-nitro-1-vinylbenzene (Intermediate 121; 3.60 g; 15.8 mmol) in AcOH (100 mL) was treated with a solution of iron (15.9 g; 285 mmol) in AcOH (20 ml) and the reaction mixture was stirred at 60° C. for 1 h. EtOAc was added and the solution was filtered, the solvents removed under reduced pressure. The residue was taken up in EtOAc, washed with a sat. NaHCO3 solution in water, then with brine. The organic layer was dried, filtered and concentrated to give the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:9](O)=[O:10].S(Cl)([Cl:22])=O.CN(C=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:9]([Cl:22])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: COCCOc1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COCCOc1c(S(C)(=O)=O)ccc(C(=O)Cl)c1C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
3-(2-Methoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoic acid (100 g) and toluene (300 mL) were mixed, and thionyl chloride (47.5 g) and DMF (2.5 g) were added, followed by heating and stirring at 100° C. for 2 hours. After completion of the reaction, 180 mL of toluene was distilled off under reduced pressure to obtain a solution of 3-(2-methoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoyl chloride.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:37]=[CH:36][C:26]([C:27]([NH:29][CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[O:28])=[CH:25][C:24]=4[O:38][CH3:39])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:40][N:41]([CH3:46])[CH2:42][C:43](Cl)=[O:44]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:37]=[CH:36][C:26]([C:27]([NH:29][CH:30]5[CH2:35][CH2:34][N:33]([C:43](=[O:44])[CH2:42][N:41]([CH3:46])[CH3:40])[CH2:32][CH2:31]5)=[O:28])=[CH:25][C:24]=4[O:38][CH3:39])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)CC(=O)Cl
Reactant: COc1cc(C(=O)NC2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Product: COc1cc(C(=O)NC2CCN(C(=O)CN(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-4-yl)benzamide and 2-(dimethylamino)acetyl chloride. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14-1.25 (m, 1H) 1.33-1.46 (m, 3H) 1.48-1.65 (m, 3H) 1.72-1.90 (m, 6H) 2.35 (s, 6H) 2.72 (t, J=12.2 Hz, 1H) 2.72 (t, 1H) 3.10 (t, J=11.8 Hz, 1H) 3.31 (s, 3H) 3.47 (d, 1H) 3.94 (s, 3H) 4.06 (t, J=13.5 Hz, 2H) 3.97-4.12 (m, 2H) 4.35 (d, 1H) 4.46 (br. s., 1H) 7.47 (dd, J=8.4, 1.6 Hz, 1H) 7.50 (d, J=1.7 Hz, 1H) 7.91 (s, 1H) 8.19 (d, J=8.1 Hz, 1H) 8.21 (s, 1H) 8.27 (d, J=8.3 Hz, 1H). Melting point: 190-191° C. [M+H] calc'd for C31H42F2N8O4 629. found 629.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([O:15][C:16](=[O:18])[CH3:17])([CH3:14])([CH3:13])[CH3:12].Br[CH2:20][C:21]1[C:22]([Cl:37])=[N:23][C:24]([S:35][CH3:36])=[N:25][C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34].CO>C1COCC1>[Cl:37][C:22]1[C:21]([CH2:20][CH2:17][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:18])=[C:26]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])[N:25]=[C:24]([S:35][CH3:36])[N:23]=1
Reactant: CSc1nc(Cl)c(CBr)c(-c2ccc(F)cc2F)n1
Reactant: CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CSc1nc(Cl)c(CCC(=O)OC(C)(C)C)c(-c2ccc(F)cc2F)n1
Temperature: -50 °C
Reaction time: 0.17 h

Procedure:
To a −78° C. solution of LiHMDS (4.1 mL) in 3 mL of THF was added t-butylacetate (0.6 mL). After stirring for 10 min, 1.0 g of 5-(bromomethyl)-4-chloro-6-(2,4-difluorophenyl)-2-(methylthio)pyrimidine (COMPOUND VV-3) in 4 mL of THF was added dropwise. The mixture was stirred at −78° C. for 1.5 h, then warmed to −50° C. The reaction mixture was recooled to −78° C. and 3 mL of methanol was added. The solution stirred for 24 h at rt. The crude mixture was purified by flash chromatography, eluting with 2% diethyl ether/hexanes. Mass spectrum m/z (ESI) 401.5 (M+1).
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([NH:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=O)=[CH:8][CH:7]=1)([O-:5])=[O:4].CO>C1COCC1>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:15][CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][N:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:22][CH2:23]2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=C(Cc1ccc([N+](=O)[O-])cc1)NCCN1CCN(c2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CCNCCN2CCN(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a stirred solution of NaBH4 (0.449 g, 11.81 mmol) in 50 mL of dry THF at 0° C. under N2 was added dropwise 48% w/w BF3 ether complex (1.47 mL, 11.68 mmol). The cooling bath was removed and the solution was stirred for 1 h at room temperature. Into the above was added dropwise a solution of 2-(4-nitro-phenyl)-N-[2-(4-phenyl-piperazin-1-yl)-ethyl]-acetamide 26a (0.55 g, 1.49 mmol) dissolved in THF (5 mL). The reaction mixture was refluxed for 6 h. After the solution cooled to room temperature, methanol (5 mL) was added slowly. The solvent was removed under reduced pressure and 10% HCl/MeOH (25 mL) was added to the residue and the solution refluxed for 1 h. Solid NaHCO3 was added and methanol was removed in vacuo. The mixture was extracted with EtOAc. The combined organic phase was dried over Na2SO4 and evaporated to give the crude product which was purified by chromatography (EtOAc/MeOH=4/1) to give 27a: 0.385 g (73% yield) as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ 1.62 (1H, bs, NH), 2.50 (2H, t, J=5.6 Hz, CH2—CH2NH), 2.58 (4H, t, J=4.8 Hz, (CH2)2N), 2.76 (2H, t, J=5.6 Hz, CH2Ar), 2.90-2.96 (4H, m, (CH2)2NH), 3.14 (4H, t, J=4.8 Hz, (CH2)2NPh), 6.85 (1H, t, J=7.2, ArH), 6.90 (2H, d, J=9.2, ArH), 7.25 (2H, t, J=9.2, ArH), 7.37 (2H, d, J=8.8, ArH), 8.15 (2H, d, J=8, ArH).
Reaction SMILES: C([O-])(=O)C.[Na+].C(OC[O:10][CH2:11][CH3:12])C.P(Cl)(Cl)(Cl)=O.C[C@H:19]1[C@@:36]2([CH3:37])[C:23]([CH2:24][CH2:25][C@@H:26]3[C@@H:35]2[CH2:34][CH2:33][C@@:31]2([CH3:32])[C@H:27]3[CH2:28][CH2:29][C:30]2=[O:38])=[CH:22][C:21](=O)[CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:24][C@H:23]1[C@@:36]2([CH3:37])[C:19]([C:20](=[CH2:21])[CH2:25][C@@H:26]3[C@@H:35]2[CH2:34][CH2:33][C@@:31]2([CH3:32])[C@H:27]3[CH2:28][CH2:29][C:30]2=[O:38])=[CH:12][C:11](=[O:10])[CH2:22]1
Reactant: CCOCOCC
Reactant: C[C@@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@]2(C)C1=CC(=O)C[C@H]2C
Yield: 60 %

Procedure:
A mixture of sodium acetate (1 g), absolute chloroform (30 ml), formaldehyde-diethylacetal (30 ml, 0.24 mol), phosphoryl chloride (3.8 ml, 0.04 mol), and 1β-methylandrost-4-ene-3,17-dione (0.811 g, 2.7 mmol) was stirred at reflux for about 7 hours, i.e. until the starting material had disappeared. The suspension was allowed to cool and under vigorous stirring a saturated sodium carbonate solution was added dropwise until the pH of the aqueous layer became alkaline (~1 hour). The organic layer was separated, neutralized with water, and dried with sodium sulfate. After concentration under reduced pressure the oily residue was purified by chromatography on silica gel using hexane/ethylacetate as eluent. Thus the pure 1β-methyl-6-methylenandrost-4-ene-3,17-dione was obtained in 60% yield (0.195 g); I.R. (KBr): 3100 (6=CH2), 1735 (17-oxo), 1680 (3-oxo), 1630, 1660 cm-1 (Δ4 and 6=CH2).