Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[N:8]=[C:7]2[C:3]=1[N:4]([CH3:35])[C:5](=[O:34])[N:6]2[C@H:21]1[CH2:26][CH2:25][C@H:24]([O:27]C2CCCCO2)[CH2:23][CH2:22]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(O)C.O>[Cl:1][C:2]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[N:8]=[C:7]2[C:3]=1[N:4]([CH3:35])[C:5](=[O:34])[N:6]2[C@H:21]1[CH2:22][CH2:23][C@H:24]([OH:27])[CH2:25][CH2:26]1
Reactant: Cn1c(=O)n([C@H]2CC[C@H](OC3CCCCO3)CC2)c2nc(-n3cnc4ccc(F)cc43)nc(Cl)c21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: O
Product: Cn1c(=O)n([C@H]2CC[C@H](O)CC2)c2nc(-n3cnc4ccc(F)cc43)nc(Cl)c21

Procedure:
A solution of 6-chloro-2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-7-methyl-9-(trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl)-7H-purin-8(9H)-one (0.06 mmol) and PPTS (5 mg) in ethanol/water (4.5 mL/0.5 mL) was stirred at reflux for 1 h. The solvent was evaporated in vacuo and the residue could be purified by chromatography or used in the next step without purification. MS (EI) m/z 417.0 (MH)+.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13]Cl>>[OH:4][CH2:3][CH2:2][N:1]([CH2:13][C:12]1[CH:15]=[CH:16][CH:17]=[C:10]([O:9][CH3:8])[CH:11]=1)[CH2:5][CH2:6][OH:7]
Reactant: OCCNCCO
Reactant: COc1cccc(CCl)c1
Product: COc1cccc(CN(CCO)CCO)c1

Procedure:
2-[(2-Hydroxy-ethyl)-(3-methoxy-benzyl)-amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (3.1 g, 29.5 mmol) and 3-methoxybenzyl chloride (5 g, 31.9 mmol). Yield 9.28 g, (99%); yellow oil; MS: 226 (M+H).
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=2)=[N:5][CH:4]=1)=O.[CH3:23][CH:24]([CH3:28])[CH2:25][CH2:26][NH2:27].[BH4-].[Na+].O>CN(C=O)C>[CH3:23][CH:24]([CH3:28])[CH2:25][CH2:26][NH:27][CH2:1][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=2)=[N:5][CH:4]=1
Reactant: CC(C)CCN
Reactant: NC(=O)c1ccc(Oc2ncc(C=O)c3ccccc23)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCNCc1cnc(Oc2ccc(C(N)=O)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 4-(4-formylisoquinolin-1-yloxy)benzamide (Preparation 16) (100 mg, 0.34 mmol) in DMF (10 mL) was added 3-methylbutylamine (40 μL, 0.34 mmol) and 4 Å molecular sieves (200 mg). The mixture was stirred at rt for 72 h before adding NaBH4 (65 mg, 1.7 mmol). After 16 h water (1 mL) was added. Solvent was removed in vacuo and the residue purified by column chromatography (NEt3: MeOH:DCM 3:30:500) to give the title compound: RT=2.47 min; m/z (ES+)=364.0 [M+H]+.
Reaction SMILES: [C:1]([N:5]1[CH2:26][CH2:25][CH2:24][CH2:23][C:8]2[CH:9]=[C:10]3[C:19]4[CH:18]=[C:17]([Br:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:27])([CH3:4])([CH3:3])[CH3:2].[Cl:28]N1C(=O)CCC1=O.O>CN(C=O)C.[O-]S([O-])(=S)=O.[Na+].[Na+]>[C:1]([N:5]1[CH2:26][CH2:25][CH2:24][CH2:23][C:8]2[C:9]([Cl:28])=[C:10]3[C:19]4[CH:18]=[C:17]([Br:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(cc1Br)-c1cc3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1Br)-c1c(Cl)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a solution of 66 mg of 19d in 1 ml of DMF was added at 0° C. 27 mg of N-chlorosuccinimide. The mixture was stirred for 2 h. Then, 5 ml of water was added and 1 drop of a sat. Na2S2O3 solution. Stirring was continued for 5 min and the product was extracted into ethyl acetate. The extract was washed with water, dried, concentrated and the residue was treated with cold pentane, to provide 65 mg of 19e as a white crystalline material; Mp 203-205° C. MS-ESI: [M+1] 464.12, 465.10, 466.09, 467.08, 468.08 and 469.07.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[Cl:11].[CH2:13]([Sn](CCCC)(CCCC)C=C)[CH2:14]CC>C1COCC1>[Cl:11][C:5]1[CH:6]=[C:7]([CH:13]=[CH2:14])[CH:8]=[CH:9][C:4]=1[C:3]([OH:2])=[O:12]
Reactant: COC(=O)c1ccc(Br)cc1Cl
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: C=Cc1ccc(C(=O)O)c(Cl)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 4-bromo-2-chlorobenzoic acid methyl ester (500 mg, 2 mmol) in THF (15 mL) was added tributyl(vinyl)tin (620 μl, 2.1 mmol) and PdCl2(dppf)-2-DCM (165 mg, 0.2 mmol). The solution was heated to 60° C. for 12 hours. The crude reaction mixture was then concentrated down and taken up in 20 mL EtOAc and 100 mL concentrated KF solution. The reaction stirred at room temperature for 3 hours, filtered through a pad of celite and concentrated down. The residual oil was subjected to flash chromatography (Isco Companion, 40 g SiO2 cartridge, solid loaded SiO2, neat heptanes to EtOAc gradient) to give 2-chloro-4-vinylbenzoic acid as a yellow oil. Amount obtained: 235 mg (60%). LCMS (M/Z): 197 (M+H). 1H NMR (Chloroform-d) δ: 3.93 (s, 3 H) 5.42 (d, J=10.9 Hz, 1 H) 5.86 (d, J=17.6 Hz, 1 H) 6.66 (dd, J=17.6, 10.7 Hz, 1 H) 7.28-7.35 (m, 1 H) 7.43-7.50 (m, 1 H) 7.82 (d, J=8.0 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](OCC)=[O:12])=[CH:5][C:4]=1[O:16][CH2:17][O:18][CH3:19].[OH-].[Na+]>C1(C)C=CC=CC=1.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[CH2:11][OH:12])=[CH:5][C:4]=1[O:16][CH2:17][O:18][CH3:19]
Reactant: CCOC(=O)/C=C/c1ccc(OC)c(OCOC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COCOc1cc(/C=C/CO)ccc1OC
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 95.7 %

Procedure:
A solution of the compound (4.54 g, 17.0 mmol) of Example 9-2 in toluene (60 ml) was stirred at −78° C., and thereto was dropped diisobutylalminumhydride (1.0M in hexane: 35.8 ml, 35.8 mmol). The mixture was stirred for 1.5 hours at −78° C., followed by addition of an aqueous 2N sodium hydroxide solution. The precipitate was filtered off and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and an aqueous sodium chloride solution in the order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the subject compound (3.65 g, 95.7%).
Reaction SMILES: C1(S[CH2:8][N:9]2[C:13](=[O:14])[CH:12]([CH2:15][CH2:16][C:17]([CH3:20])([Cl:19])[CH3:18])[N:11]([CH3:21])[S:10]2(=[O:23])=[O:22])C=CC=CC=1.S(Cl)([Cl:27])(=O)=O>C(Cl)Cl>[Cl:27][CH2:8][N:9]1[C:13](=[O:14])[CH:12]([CH2:15][CH2:16][C:17]([CH3:20])([Cl:19])[CH3:18])[N:11]([CH3:21])[S:10]1(=[O:23])=[O:22]
Reactant: CN1C(CCC(C)(C)Cl)C(=O)N(CSc2ccccc2)S1(=O)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CN1C(CCC(C)(C)Cl)C(=O)N(CCl)S1(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.4 %

Procedure:
To a solution of 2-phenylthiomethyl-4-(3-methyl-3-chlorobutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (1. 396 g, 3.82 mmol) in 30 ml of methylene chloride was added sulfuryl chloride (0.366 ml, 4.58 mmol) and the mixture was stirred for 2 hours at room temperature. The mixture was concentrated in vacuo and the residue was purified by silica column chromatography (10% ethyl acetate in hexane) to afford 410 mg (35.4%) of 2-chloromethyl-4-(3-methyl-3-chlorobutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula II: R1 =H; R2 =(CH2)2C(Cl) (CH3)2 ; R3 =CH3 ; X'=Cl).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:16](Cl)(=[O:20])[CH:17]([CH3:19])[CH3:18]>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)Nc1ccc(-c2ccc(C#N)n2C)cc1

Procedure:
The title compound was prepared according to the general procedure for acylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using isobutyryl chloride (58 μL, 0.55 mmol) to provide N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]-2-methylpropanamide (0.026 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:13][O:14][C:15](=[O:29])[CH:16]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([OH:28])[CH:24]=2)[CH:19]=1)[CH3:17].C(N(CC)CC)C>CC(C)=O>[CH3:13][O:14][C:15](=[O:29])[CH:16]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:28][C:10](=[O:11])[CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:24]=2)[CH:19]=1)[CH3:17]
Reactant: COC(=O)C(C)c1ccc2cc(O)ccc2c1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C(C)c1ccc2cc(OC(=O)COCc3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
Benzyloxy acetyl chloride (24 gm, 86.95 mmol) was added drop-wise to a mixture of 2-(6-Hydroxynaphthalen-2-yl)-propionic acid methyl ester 6 (20 g, 86.95 mmol) and triethylamine (22.5 g, 222.35 mmol) in acetone (300 ml) and stirred for 2 hrs at room temp. Solids were filtered off, acetone distilled off, and water (100 ml) added. Crude 99 was extracted into chloroform, washed with 5% sodium bicarbonate (2×50 ml), water (2×50 ml), dried over sodium sulphate and distilled. Crude 99 was purified by recrystallising in chloroform:hexane (1:6) to get pure 99 (21 g, 63.9%) as a white powder. M.p: 58-60° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[Cl-].[OH:14][NH3+:15].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]([F:12])([F:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[N:15][OH:14]
Reactant: [NH3+]O
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C(c1ccccc1)C(F)(F)F
Yield: 89.6 %

Procedure:
25 g (0.144 mol) of 2,2,2-Trifluoro-1-phenyl-ethanone are dissolved in 40 ml of ethanol at 80° C. To the solution are added dropwise 10.5 g (0.151 mol) of hydroxylammonium chloride and 20.1 g (0.245 mol) of sodium acetate dissolved in 20 ml of water. The reaction mixture is refluxed overnight, and the solvent is distilled off by a rotary evaporator. The residue is poured into water, the white precipitate is rinsed with water and dried under vacuum, yielding 24.4 g of 2,2,2-trifluoro-1-phenyl-ethanone oxime. The crude product is used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[C:18]([F:21])([F:20])[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:31])=O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:31])=[O:14])=[CH:11][C:10]=1[C:18]([F:21])([F:20])[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
To 4-benzyloxy-3-trifluoromethylbenzoic acid (444 mg), toluene (5 mL), N,N-dimethylformamide (2 droplets) and thionyl chloride (0.16 mL) were added, and then the mixture was stirred at 60° C. for 20 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene, and the obtained product was used for the synthesis of (h).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH2:10][CH:11]([OH:16])[CH2:12]2.[C:19](O)(=[O:21])[CH3:20]>>[C:19]([O:16][CH:11]1[CH2:10][CH:9]2[CH:13]([CH2:14][CH2:15][CH:8]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:17][CH3:18])[CH2:12]1)(=[O:21])[CH3:20]
Reactant: CCC(CCCCC1CCC2CC(O)CC12)OC
Reactant: CC(=O)O
Product: CCC(CCCCC1CCC2CC(OC(C)=O)CC12)OC

Procedure:
The procedure followed is the same as that described in Example 24 substituting 2-(5-methoxyhept-1-yl)bicyclo[3.3.0]-7octanol {octahydro-4-(5-methoxyheptyl)-2-pentalenol} (1.0 g, 4.0 mmoles), and glacial acetic acid (7 ml). The product is kugelrohred under reduced pressure leaving a clear, colorless oil (0.7 g, 2.5 mmoles).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:43]=[CH:42][C:20]([CH2:21][N:22]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:23](=[O:33])[C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C1COCC1>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]([N:22]([CH2:34][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:21][C:20]2[CH:19]=[CH:18][C:17]([C:14]3[N:13]=[C:12]([NH:11][S:8]([C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=4)(=[O:10])=[O:9])[O:16][N:15]=3)=[CH:43][CH:42]=2)=[O:33])=[CH:25][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccc(CN(CC(=O)OC(C)(C)C)C(=O)c4ccc([N+](=O)[O-])cc4)cc3)no2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccc(CN(CC(=O)OC(C)(C)C)C(=O)c4ccc(N)cc4)cc3)no2)cc1
Temperature: 65 °C
Yield: 65 %

Procedure:
Prepared using General Procedure 5. To a stirred solution of tert-butyl 2-(N-(4-(5-(4-methylphenylsulfonamido)-1,2,4-oxadiazol-3-yl)benzyl)-4-nitrobenzamido)acetate INT-68 (20 mg, 0.033 mmol) in THF (3 mL) and water (1 mL) was added sodium dithionite (17.2 mg, 0.099 mmol) and heated to 65° C. for 2 h. The reaction mixture was extracted with EA (10 mL) and washed with brine (10 mL). The organics were concentrated in vacuo to afford 13 mg (65%) of tert-butyl 2-(4-amino-N-(4-(5-(4-methylphenylsulfonamido)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetate INT-69 as a white solid. LCMS-ESI (m/z) calculated for C29H31N5O6S: 577; found 576 [M−H]−, tR=2.41 min (Method 5).
Reaction SMILES: [CH2:1]([C@@H:3]([C@@H:7]([OH:34])[CH2:8][C@@H:9]([O:27]C1CCCCO1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]([OH:6])=O)[CH3:2]>CO>[CH2:1]([C@H:3]1[C@H:7]([CH2:8][C@@H:9]([OH:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[O:34][C:4]1=[O:6])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCC[C@@H](C[C@H](O)[C@H](CC)C(=O)O)OC1CCCCO1
Solvent: CO
Product: CCCCCCCCCCCCCCCCC[C@H](O)C[C@@H]1OC(=O)[C@H]1CC

Procedure:
from a diastereomer mixture which consisted chiefly of (2S,3S,5S)-2-ethyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl) oxy]docosanoic acid. 10.B.k) In analogy to Example 8, (3S,4S)-3-ethyl-4-[(S)-2-hydroxynonadecyl]-2-oxetanone, m.p. 82°-84° C. (MeOH), was obtained
Reaction SMILES: [CH3:1][C@@:2]12[C@H:12]3[CH2:13][CH2:14][C@:15]4([CH3:21])[C@@H:19]([OH:20])[CH2:18][CH2:17][C@H:16]4[C@@H:11]3[CH2:10][CH2:9][C@H:8]1[CH2:7][C:5](=[O:6])[CH2:4][CH2:3]2.C(N(CC)CC)C.[Cl:29][CH2:30][C:31](Cl)=[O:32]>C(Cl)Cl.ClCl>[Cl:29][CH2:30][C:31]([O:20][C@H:19]1[CH2:18][CH2:17][C@H:16]2[C@H:11]3[C@H:12]([CH2:13][CH2:14][C@:15]12[CH3:21])[C@:2]1([CH3:1])[C@H:8]([CH2:7][C:5](=[O:6])[CH2:4][CH2:3]1)[CH2:9][CH2:10]3)=[O:32]
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Reactant: O=C(Cl)CCl
Agent: ClCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(=O)CCl)CC[C@@H]12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Dihydrotestosterone (2.6 mmol) was dissolved in anhydrous methylene chloride (3 mL) and triethylamine (2.6 mmol) under argon. The solution was stirred at 0° C. for 30 minutes at which time chloroacetyl chloride (3.75 mmol) dissolved in anhydrous methylene chloride (2 mL) was added. The resulting mixture was stirred for an additional 30 min at 0° C. and at room temperature for 4 hr. The solution was diluted with CH2 Cl2 (30 mL) and was washed with aqueous 0.05N hydrochloric acid (2×30 mL) and water (2×30 mL). The organic layer was dried over sodium sulfate and evaporated under vacuum to give crude product as a white solid. The product was purified by silica gel column chromatography (Davisil grade 633, 200-425 mesh, 60 Å) using CHCl3 as eluent. Yield, 0.38 g (41%); mp 135°-136° C. (lit. Ferguson et al., J. Chem. Soc., Perkin II, 3, 267-272 (1978)), 138° C.); 1H NMR δ0.78 (s, 3 H, CH3 -19), 0.98 (s, 3 H, CH3 -18), 0.78-2.49 (m, 22 H), 4.37 (d, 2 H, CH2Cl), 4.62 (t, 1 H, H-17); MS (EI) calcd m/z for C21H31O335Cl 366.1961, found, 366.1932; calcd. m/z for C21H31O337Cl 368.1932, found, 368.1911.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:10])=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:11]12[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=1)NC(=O)O[C:12]2=[O:13]>C(O)(=O)C>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]2[NH:9][C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=3[C:12](=[O:13])[NH:10][C:3]=2[C:2]=1[CH3:1]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Cc1ccc(N)c(N)c1C
Solvent: CC(=O)O
Product: Cc1ccc2c(c1C)NC(=O)c1ccccc1N2
Temperature: 85 °C

Procedure:
3,4-Dimethyl-1,2-phenylenediamine (0.1 mol) was dissolved in acetic acid (70%) and then isatoic anhydride (0.1 mol) was added to the solution. The resulting mixture was heated at 85° C. for 3 hrs. The mixture was poured into ice-cold water and 8,9-dimethyl-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-11-one was isolated (97%) by neutralization and filtration.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][CH:3]=1.[C:31]1([CH3:40])[CH:36]=[CH:35][CH:34]=[C:33]([N:37]=[C:38]=[O:39])[CH:32]=1>N1C=CC=CC=1>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:38]([NH:37][C:33]4[CH:34]=[CH:35][CH:36]=[C:31]([CH3:40])[CH:32]=4)=[O:39])=[CH:7][CH:6]=3)[C:16]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(N)cc4)c4c(N)ncnc43)CC2)CC1
Reactant: Cc1cccc(N=C=O)c1
Solvent: c1ccncc1
Product: Cc1cccc(NC(=O)Nc2ccc(-c3nn([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)c1
Temperature: 25 °C

Procedure:
cis-3-(4-Aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.123 mmol) was dissolved in pyridine (3.5 mL) then cooled to 0° C. m-Tolylisocyanate (18 mg, 0.135 mmol) was added and the reaction was allowed to warm to room temperature over 16 hours. The reaction mixture was concentrated under reduced pressure to yield a pale yellow oil (200 mg). Purification was achieved by RP-HPLC (Waters PrepLC 4000, flow rate: 10 mL/min. λ=254 nm Gradient: 10% to 30% acetonitrile/0.1M aqueous ammonium acetate gradient over 40 minutes; Deltapak C18, 300A, 15 μm, 40×100 mm column). The desired product was collected as a white solid (52 mg). HPLC-RT: 12.58 min. (flow rate: 1 mL/min λ=254 nm Gradient: 5% to 85% acetonitrile/0.1M aqueous ammonium acetate gradient over 20 min.; Deltapak C18, 300A, 5 μm, 150×3.9 mm column); m/z (MH+)=540.1.
Reaction SMILES: C([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=2)=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.[CH3:29][N:30]([C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=1)C1CCNCC1>C(OCC)C>[CH3:28][S:25]([NH:24][C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:15](=[O:16])[CH2:14][N:11]2[CH2:10][CH2:9][CH:8]([N:30]([CH3:29])[C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)[CH2:13][CH2:12]2)=[CH:23][CH:22]=1)(=[O:26])=[O:27]
Reactant: Cc1ccc(N(C)C2CCNCC2)cc1
Reactant: CS(=O)(=O)Nc1ccc(NC(=O)CN2CCC(Cc3ccccc3)CC2)cc1
Solvent: CCOCC
Product: Cc1ccc(N(C)C2CCN(CC(=O)Nc3ccc(NS(C)(=O)=O)cc3)CC2)cc1

Procedure:
The title compound is prepared from 2-chloro-N-(4-methanesulfonylamino-phenyl)-acetamide (Example 180) and 4-(methyl-p-tolyl-amino)-piperidine [Arzneimittel Forschung/Drug Research 44(II), 989. (19994)]) according to the method described in Example 142b. Melting Point: 128-130° C. (diethylether)
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4]SC.C(O)[C@H]1[O:16][C@H:15]([O:17][C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O>O>[CH2:3]([CH:2]([NH2:1])[C:7]([OH:9])=[O:8])[CH2:4][C:15]([OH:17])=[O:16]
Reactant: CSCC[C@H](N)C(=O)O
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: O
Product: NC(CCC(=O)O)C(=O)O

Procedure:
An excipients solution is prepared according to a protocol similar to that of Preparation 3 using 0.02 g of methionine, 0.96 g of sucrose and 9.01 g of water for injection (WFI). 8.42 g of the previous excipients solution were added to 9.66 g of water for injection (WFI) and to 7.31 g of polymer P2 solution (46.7 mg/mL polymer P2 solution) obtained by the method described in Preparation 7. This solution was gently stiffed for at least 15 min at room temperature.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:27])=[C:6]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N:19]4[CH2:25][CH2:24][CH2:23][N:22]([CH3:26])[CH2:21][CH2:20]4)[CH:15]=3)[N:10]=[CH:9]2)[CH:7]=1.[Cl:28][C:29]1[CH:34]=[C:33]([C:35](Cl)=[O:36])[CH:32]=[CH:31][N:30]=1>>[Cl:28][C:29]1[CH:34]=[C:33]([C:35]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:27])=[C:6]([N:8]3[C:17](=[O:18])[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([N:19]5[CH2:25][CH2:24][CH2:23][N:22]([CH3:26])[CH2:21][CH2:20]5)[CH:15]=4)[N:10]=[CH:9]3)[CH:7]=2)=[O:36])[CH:32]=[CH:31][N:30]=1
Reactant: Cc1ccc(N)cc1-n1cnc2ccc(N3CCCN(C)CC3)cc2c1=O
Reactant: O=C(Cl)c1ccnc(Cl)c1
Product: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-n1cnc2ccc(N3CCCN(C)CC3)cc2c1=O

Procedure:
Using an analogous procedure to that described in Example 5, 3-(5-amino-2-methylphenyl)-6-(4-methylhomopiperazin-1-yl)-3,4-dihydroquinazolin-4-one was reacted with 2-chloropyridine-4-carbonyl chloride to give the title compound; NMR Spectrum: (DMSOd6) 1.84-1.96 (m, 2H), 2.06 (s, 3H), 2.29 (s, 3H), 2.42-2.49 (m, 2H), 2.62-2.68 (m, 2H), 3.53 (t, 2H), 3.58-3.64 (m, 2H), 7.22 (d, 1H), 7.34 (m, 1H), 7.44 (m, 1H), 7.58 (d, 1H), 7.73-7.78 (m, 2H), 7.82-7.86 (m, 1H), 7.96-7.98 (m, 2H), 8.50-8.62 (m, 1H), 10.68 (s, 1H); Mass Spectrum: M+H+503 & 505.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].[C:17]([N:25]=[C:26]=[S:27])(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC>[CH2:17]([NH:25][C:26]([NH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])=[S:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1C(=O)Nc1ccccc1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CCOCC
Product: O=C(Nc1ccccc1)c1ccccc1NC(=S)NCc1ccccc1
Yield: 1015.8 %

Procedure:
To a stirred mixture of 1.0 g of 2-amino-N-phenylbenzamide and 500 ml of ether was added dropwise, a solution of 7.7 g of benzoyl isothiocyanate in 100 ml of ether over 20 minutes. After standing several hours, the solid was collected, giving 17.3 g of the desired product as cream- colored crystals mp 197°-200° C. (dec.).
Reaction SMILES: [C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]\[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].II>C(O)C>[C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[C:6]([OH:8])=[O:7]
Reactant: O=C(O)/C=C\C=C\C(=O)O
Agent: II
Solvent: CCO
Product: O=C(O)/C=C/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.7 %

Procedure:
cis,trans-Muconic acid (105 mg, 0.739 mmol) is dissolved in ethanol (10 mL) at room temperature and a crystal of iodine (13 mg, 0.05 mmol) is added. The reaction mixture is allowed to stir at room temperature for 24 hour. The precipitate is filtered, washed with acetonitrile and dried under reduced pressure to yield 70 mg of trans,trans-muconic acid, a 67 percent yield.