Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]CC)=[O:10])=[C:4]([F:14])[C:3]=1[F:15].C(N(CC)CC)C.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>CN(C=O)C>[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31](=[O:32])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([F:14])[C:3]=1[F:15]
Reactant: Cc1ccccc1N=C=O
Reactant: CCOC(=O)Cc1ccc(N)c(F)c1F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)c(F)c1F
Reaction time: 48 h
Yield: 41.6 %

Procedure:
To a stirred solution of ethyl 4-amino-2,3-difluorophenylacetate (323 mg, 1.5 mmol) in DMF (8 mL), were added triethylamine (0.209 ml, 1.5 mmol) and 2-methylphenyl isocyanate (0.372 ml, 3.0 mmol) at rt. The stirring was continued for 48 hour at 80° C. The reaction mixture was evaporated in vacuo, and the solid was suspended to n-hexane. The solid was collected through filtration. The solid was dissolved in THF—MeOH (1:1, v/v, 20 mL), and was added 4M NaOH (10 mL) at rt. The stirring was continued for 18 hours at rt. The reaction was poured into 1M HCl, and the resulting precipitate was collected through filtration. The solid was recrystallized with CHCl3-n-hexane to give 4-[(2-methylphenyl)ureido]-2,3-difluorophenylacetic acid (200 mg, 42%) as a white solid. 1H-NMR (CDCl3) δ2.30 (s, 3H), 3.35 (s, 2H), 6.98 (m, 1H), 7.04 (m, 1H), 7.18 (d, J=7.3 Hz, 2H), 7.69 (d, J=8.1 Hz, 1H), 7.90 (m, 1H); MS FAB) m/z 321 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]=[C:7]([N:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[C:10](=[O:19])[C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])[S:8][C:4]=2[CH:3]=1.CCN(CC)CC.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:10]([N:9]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)[C:7]1[S:8][C:4]2[CH:3]=[C:2]([NH:1][S:40]([CH3:39])(=[O:42])=[O:41])[CH:31]=[CH:30][C:5]=2[N:6]=1)=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(N(C(=O)c2ccc(Cl)cc2Cl)c2nc3ccc(N)cc3s2)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N(C(=O)c2ccc(Cl)cc2Cl)c2nc3ccc(NS(C)(=O)=O)cc3s2)cc1OC
Yield: 24.8 %

Procedure:
A mixture of 33.2 mg (0.07 mmol) N-(6-Amino-benzothiazol-2-yl)-2,4-dichloro-N-(3,4-dimethoxy-phenyl)-benzamide in 0.7 ml DCM, 18.2 mg (0.18 mmol) NEt3 and 10.3 mg (0.091 mmol) methanesulfonyl chloride in 0.2 ml DCM was reacted for 16 h at room temperature. After evaporation of all volatiles the residue was taken up in DMF/acetonitrile and subjected to preparative HPLC separation on reversed phase eluting with an acetonitrile/water gradient to yield 9.6 mg (25%) of the title compound. MS (m/e): 552.1 (MH+, 100%).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.[N:21]1([C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CN(C)C=O.C(O)C>[O:14]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:20]2[C:12]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[O:5][CH2:4][C@H:2]([OH:1])[CH2:3][N:24]2[CH2:25][CH2:26][N:21]([C:27]3[N:28]=[CH:29][CH:30]=[CH:31][N:32]=3)[CH2:22][CH2:23]2)=[N:13]1
Reactant: c1cc(OC[C@H]2CO2)cc(-c2noc3ncccc23)c1
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@@H](COc1cccc(-c2noc3ncccc23)c1)CN1CCN(c2ncccn2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-3-(3-oxiranylmethoxy-phenyl)-isoxazolo[5,4-b]pyridine in dimethylformamide and ethanol and 2-piperazin-1-yl-pyrimidine in ethanol essentially as described above in Example 102. Purity by LC/MS=100%, [M+H]+=433.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]2[C:7]([CH3:18])([CH3:17])[N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C:3]=12.C(N(CC)C(C)C)(C)C.[CH3:28][CH2:29][O:30][C:31](C)=[O:32]>C1COCC1>[NH2:1][C:2]1[N:6]([C:31]([O:30][CH2:29][CH3:28])=[O:32])[N:5]=[C:4]2[C:7]([CH3:18])([CH3:17])[N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C:3]=12
Reactant: CC(C)(C)OC(=O)N1Cc2c(n[nH]c2N)C1(C)C
Reactant: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)n1nc2c(c1N)CN(C(=O)OC(C)(C)C)C2(C)C
Yield: 38 %

Procedure:
15 g of tert-Butyl 3-amino-6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (59.4 mmol) were dissolved in anhydrous THF (150 ml) and treated, at 0° C. under Ar atmosphere, first with N,N-diisopropylethylamine (50 ml) and then with ClCO2 Et (4.65 ml, 1 eq.) dropwise. 90 minutes later, the solvent was diluted with EtOAc (1 l), washed with water and then with brine, dried over sodium sulfate and evaporated. The crude product was purified by flash chromatography (hexane/EtOAc 2/8) to afford 7.3 g of 5-tert-butyl 2-ethyl 3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate as the major compound in 38% yield, together with 5.7 g of 5-tert-butyl 1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate in 30% yield.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([C:35](=[O:37])[NH2:36])=[CH:32][CH:33]=4)[N:28]([CH3:38])[CH:27]=3)[C:23](O)=[O:24])=[CH:21][C:16]=2[O:15][CH2:14]1.CN(C1C=CC=CN=1)C.[C:48]1([CH3:58])[CH:53]=[CH:52][C:51]([S:54]([NH2:57])(=[O:56])=[O:55])=[CH:50][CH:49]=1>ClCCl.CN(C)C=O>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([C:35]([NH2:36])=[O:37])=[CH:32][CH:33]=4)[N:28]([CH3:38])[CH:27]=3)[C:23]([NH:57][S:54]([C:51]3[CH:52]=[CH:53][C:48]([CH3:58])=[CH:49][CH:50]=3)(=[O:55])=[O:56])=[O:24])=[CH:21][C:16]=2[O:15][CH2:14]1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: Cn1cc(C(C(=O)O)c2ccc3c(c2)OCO3)c2ccc(C(N)=O)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(C(N)=O)ccc23)cc1
Yield: 67.1 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (65 mg, 0.34 mmol) was added to a stirred solution. 2-(1,3-benzodioxol-5-yl)-2-(6-carbamoyl-1-methyl-1H-3-indolyl)acetic acid (from step (f). 100 mg, 0.28 mmol), dimethylaminopyridine (45 mg, 0.37 mmol) and p-toluenesulphonamide (53 mg, 0.31 mmol) in dichloromethane (5 ml) and dimethylformamide (1 ml) at room temperature under a nitrogen atmosphere. After 14 h the solvent was removed in vacuo and the product was extracted from 1N hydrochloric acid (50 ml) with ethyl acetate (2×50 ml). The organic layers were dried and concentrated to give a fawn foam. Flash column chromatography (elution with 95% dichloromethane/5% methanol) gave the product (95 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[NH:12][CH3:13].[CH3:21][O:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[S:32](Cl)(=[O:34])=[O:33].C(Cl)Cl>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:32]([C:24]1[CH:25]=[CH:26][C:27]([N+:29]([O-:31])=[O:30])=[CH:28][C:23]=1[O:22][CH3:21])(=[O:33])=[O:34])[C:6](=[O:11])[C:5]2([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[NH:12][CH3:13]
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Reactant: CNC1(CC2CCCCC2)C(=O)Nc2ccc(Cl)cc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC1(CC2CCCCC2)C(=O)N(S(=O)(=O)c2ccc([N+](=O)[O-])cc2OC)c2ccc(Cl)cc21
Yield: 58 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 16 from 1.49 g of 5-chloro-3-(cyclohexylmethyl)-1,3-dihydro-3-(methylamino)indol-2-one and 1.8 g of 2-methoxy-4-nitrobenzenesulfonyl chloride. Chromatography on silica using DCM and then a DCM/AcOEt mixture (95/5; v/v) as the eluent gives 1.5 g of the expected product after crystallization from AcOEt. M.p.=207° C.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[SH:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)[C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[O:11].C(CN(CC([O-])=O)CC(O)=O)N(CC(O)=O)CC([O-])=O.[Na+].[Na+].OCC[NH2+]CCO>O1CCCC1.O>[OH:4][CH2:3][CH2:2][NH2+:1][CH2:5][CH2:6][OH:7].[SH:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)[C:16]([NH:18][CH2:19][C:20]([O-:22])=[O:21])=[O:17])=[O:11]
Reactant: O=C(O)CNC(=O)c1cccc(NC(=O)CS)c1
Reactant: OCCNCCO
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: OCC[NH2+]CCO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])CNC(=O)c1cccc(NC(=O)CS)c1
Temperature: 42.5 °C
Reaction time: 8 h

Procedure:
A solution of 1.82 ml. diethanolamine (2 g., 0.0189 mole) in 10 ml. of tetrahydrofuran is added to a mixture of N-[3-(mercaptoacetylamino)benzoyl]glycine (5 g., 0.0186 mole), 5 mg. of disodium edetate, 4 ml. of water and 40 ml. of tetrahydrofuran under an atmosphere of nitrogen during a 5-minute period at room temperature. The resulting mixture is first warmed to 40-45° C. for 20 min. and then cooled in a dry ice-ethanol bath for 0.5 hr. to promote crystallization. Cooling is discontinued and the mixture stirred overnight under an atmosphere of nitrogen and filtered. The material collected is washed with tetrahydrofuran and then dried under vacuum over calcium chloride to provide 5.8 g., of the bis-(2-hydroxyethyl)ammonium salt of N-[3-(mercaptoacetylamino)benzoyl]glycine, m.p. 64-74.5° C. (dec.).
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH:18]([CH3:37])[N:19]([C:23]4[CH:28]=[C:27]([N:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)[N:26]=[C:25]([NH2:36])[N:24]=4)[CH2:20]3)=[CH:15][CH:14]=2)[CH:10]=[N:9]1)(C)(C)C.Cl.[CH3:40][NH:41][CH3:42]>>[NH2:36][C:25]1[N:24]=[C:23]([N:19]2[CH:18]([CH3:37])[CH2:17][C:16]3[C:21](=[CH:22][C:13]([C:11]4[CH:10]=[N:9][N:8]([CH2:7][C:6]([N:41]([CH3:42])[CH3:40])=[O:5])[CH:12]=4)=[CH:14][CH:15]=3)[CH2:20]2)[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[N:26]=1
Reactant: CC1Cc2ccc(-c3cnn(CC(=O)OC(C)(C)C)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CNC
Agent: Cl
Product: CC1Cc2ccc(-c3cnn(CC(=O)N(C)C)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 79 starting from tert-butyl(4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-1H-pyrazol-1-yl)acetate and dimethylamine hydrochloride. LCMS (M+H)+: m/z=490.3.
Reaction SMILES: Br[CH2:2][C:3]([N:5]([C:7]1[CH:49]=[CH:48][C:10]([O:11][CH2:12][C:13]([NH:15][C@H:16]([C:21]([NH:23][C@@H:24]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@H:25]([OH:40])[C:26]([N:28]2[CH2:39][CH2:38][CH2:37][C@H:29]2[C:30]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:27])=[O:22])[CH2:17][C:18](=[O:20])[NH2:19])=[O:14])=[CH:9][CH:8]=1)[CH3:6])=[O:4].[CH3:50][NH:51][CH3:52]>>[CH3:50][N:51]([CH2:2][C:3]([N:5]([C:7]1[CH:49]=[CH:48][C:10]([O:11][CH2:12][C:13]([NH:15][C@H:16]([C:21]([NH:23][C@@H:24]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@H:25]([OH:40])[C:26]([N:28]2[CH2:39][CH2:38][CH2:37][C@H:29]2[C:30]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:27])=[O:22])[CH2:17][C:18](=[O:20])[NH2:19])=[O:14])=[CH:9][CH:8]=1)[CH3:6])=[O:4])[CH3:52]
Reactant: CNC
Reactant: CN(C(=O)CBr)c1ccc(OCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc2ccccc2)[C@H](O)C(=O)N2CCC[C@H]2C(=O)NC(C)(C)C)cc1
Product: CN(C)CC(=O)N(C)c1ccc(OCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc2ccccc2)[C@H](O)C(=O)N2CCC[C@H]2C(=O)NC(C)(C)C)cc1
Yield: 97.5 %

Procedure:
Following a procedure similar to that described in Example 38, but using 100 mg (0.13 mmol) of 1-[(2S,3S)-3-{N2 -[4-(N-bromoacetyl-N-methylamino)phenoxy]acetyl-L-asparaginyl}amino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-L-prolinamide (prepared as described in Example 30) and 0.12 ml (1.3 mmol) of dimethylamine, 90 mg of the title compound were obtained as a colorless powder, melting at 129°-135° C.
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:6]([O:8][C:9](=[O:13])[CH2:10][N+:11]#[C-:12])[CH3:7]>>[CH2:6]([O:8][C:9]([CH:10]1[CH:1]([CH:2]=[CH:3][CH3:4])[O:5][CH:12]=[N:11]1)=[O:13])[CH3:7]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: C/C=C/C=O
Product: CC=CC1OC=NC1C(=O)OCC

Procedure:
The starting material is manufactured as follows: Reaction of crotonaldehyde with isocyanoacetic acid ethyl ester in a manner analogous to that described in Example 1 yields 5-(propen-1-yl)-2-oxazoline-4-carboxylic acid ethyl ester. By hydrolysis of the 5-(propen-1-yl)-2-oxazoline-4-carboxylic acid ethyl ester analogously to Example 1, 2-formylamino-3-hydroxy-4-hexenoic acid ethyl ester is obtained. Reaction of the 2-formylamino-3-hydroxy-4-hexenoic acid ethyl ester with thionyl bromide and subsequent treatment with triethyl phosphite in a manner analogous to that described in Example 1 (12 hours) yields E-2-formylamino-5-diethylphosphono-5-methyl-3-pentenoic acid ethyl ester.
Reaction SMILES: [N:1]1([C:7](OC(C)(C)C)=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:14][CH:15]([O:17][C:18](=[O:41])[NH:19][C@H:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30]3[S:31][C:32](C=O)=[CH:33][N:34]=3)[CH:28]=2)[N:23]([C:37](=[O:39])[CH3:38])[C@@H:22]([CH3:40])[CH2:21]1)[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].C(O)(C(F)(F)F)=O>ClCCl>[C:37]([N:23]1[C:24]2[C:29](=[CH:28][C:27]([C:30]3[S:31][C:32]([CH2:7][N:1]4[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]4)=[CH:33][N:34]=3)=[CH:26][CH:25]=2)[C@H:20]([NH:19][C:18](=[O:41])[O:17][CH:15]([CH3:14])[CH3:16])[CH2:21][C@@H:22]1[CH3:40])(=[O:39])[CH3:38]
Reactant: CC(=O)N1c2ccc(-c3ncc(C=O)s3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1c2ccc(-c3ncc(CN4CCNCC4)s3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.3 %

Procedure:
1,1-Dimethylethyl 1-piperazinecarboxylate (48.2 mg, 0.259 mmol), 1-methylethyl[(2S,4R)-1-acetyl-6-(5-formyl-1,3-thiazol-2-yl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 106) (104 mg, 0.259 mmol) and sodium triacetoxyborohydride (220 mg, 1.036 mmol) were dissolved in dichloromethane (DCM) (4 mL) and the resulting mixture was stirred at room temperature under nitrogen for 16 h before being treated with a saturated NaHCO3 aqueous solution. The two layers were separated using a phase separator cartridge and the organic phase was concentrated in vacuo. The residue was loaded on a 20 G SCX cartridge which was eluted with MeOH then with a 2M NH3 solution in MeOH. The ammonia fractions were concentrated in vacuo to give a residue which was dissolved in DCM (3 mL) and treated with TFA (0.5 mL, 6.49 mmol). After 1 h, the mixture was concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 1 to 10% (2M NH3 in MeOH) in DCM) gave 1-methylethyl {(2S,4R)-1-acetyl-2-methyl-6-[5-(1-piperazinyl methyl)-1,3-thiazol-2-yl]-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (70 mg, 0.148 mmol, 57.3% yield).
Reaction SMILES: [OH-:1].[Na+].O.BrBr.[Br:6][C:7]1[S:11][C:10]([C:12](=[O:14])C)=[CH:9][C:8]=1[Cl:15]>O1CCOCC1>[Br:6][C:7]1[S:11][C:10]([C:12]([OH:14])=[O:1])=[CH:9][C:8]=1[Cl:15]
Reactant: [OH-]
Reactant: CC(=O)c1cc(Cl)c(Br)s1
Agent: BrBr
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(Cl)c(Br)s1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Sodium hydroxide (50% in water) (5.82 ml, 110 mmol) was added to water (15 ml), and the mixture was chilled to 0° C. Bromine solution (1.669 ml, 32.6 mmol) was added, followed by dropwise addition of a solution of 1-(5-bromo-4-chlorothiophen-2-yl)ethanone (2.4 g, 10.02 mmol) in dioxane (18 ml). The mixture was stirred for 1.5 hours at room temperature, washed with dichloromethane, and then the aqueous phase was adjusted to pH 1 using 4N aqueous HCl. The precipitated solid was collected by filtration to give the title compound.
Reaction SMILES: C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[NH:22][CH:23]=1.O[CH2:26][C:27]1([CH3:31])[CH2:30][S:29][CH2:28]1>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[N:22]([CH2:26][C:27]2([CH3:31])[CH2:30][S:29][CH2:28]2)[CH:23]=1
Reactant: CC1(CO)CSC1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: CN(C)C=O
Product: CC1(Cn2cc(Cl)cnc2=O)CSC1
Temperature: 100 °C
Yield: 7.9 %

Procedure:
N,N-Dimethylformamide dineopentyl acetal (2.72 ml) was added to a stirred suspension of 5-chloropyrimidin-2-one (789 mg) and 3-hydroxymethyl-3-methylthietane (1.000 g) in dry N,N-dimethylformamide (15 ml) under nitrogen and the mixture was then heated at 100° C. After 42.5 h the reaction mixture was evaporated and the resulting black residue was dissolved in ethyl acetate (300 ml), washed with water (3×70 ml), dried (MgSO4) and evaporated to a dark brown gum. Trituration of the gum with diethyl ether gave a pale brown solid which was crystallised from ethyl acetate to give cream crystals of the title pyrimidinone (110 mg), m.p. 200°-202° C., νmax (nujol) 1663, 1510 cm-1 (C=O), 1612, 1582 cm-1 (C=C, C=N).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:57][CH3:58])=[C:10]([CH2:19][NH:20][C:21](=[O:56])[CH2:22][CH2:23][CH2:24][C:25]([NH:27][CH2:28][C:29]3[CH:30]=[C:31]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][N:42]5[CH2:47][CH2:46][N:45](C(OC(C)(C)C)=O)[C@@H:44]([CH3:55])[CH2:43]5)[CH:36]=4)[CH:32]=[CH:33][CH:34]=3)=[O:26])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(O)(C(F)(F)[F:62])=O>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:57][CH3:58])=[C:10]([CH2:19][NH:20][C:21](=[O:56])[CH2:22][CH2:23][CH2:24][C:25]([NH:27][CH2:28][C:29]3[CH:30]=[C:31]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][N:42]5[CH2:47][CH2:46][NH:45][C@@H:44]([CH3:55])[CH2:43]5)[CH:36]=4)[C:32]([F:62])=[CH:33][CH:34]=3)=[O:26])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCCC(=O)NCc1cccc(-c2cccc(CN3CCN(C(=O)OC(C)(C)C)[C@@H](C)C3)c2)c1
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCCC(=O)NCc1ccc(F)c(-c2cccc(CN3CCN[C@@H](C)C3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Process (A) To a mixture of 1,1-dimethylethyl (2S)-4-{[3′-({[5-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-5-oxopentanoyl]amino}methyl)-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate in DCM (2 mL) was added TFA (1 mL). It was stirred at room temperature for about 1 hour. The solution was filtered. Initial purification via Gilson using TFA afforded a mixture, which was re-purified by Gilson using a NH4OH buffer to provide the desired product (20 mg). LC-MS m/z 713 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13](=[O:15])[CH3:14].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:2]1([CH2:14][C:13]([C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)=[O:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: CC(=O)c1cccs1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1)c1cccs1
Temperature: 90 °C
Reaction time: 4 h
Yield: 41.2 %

Procedure:
1-Bromobenzene (2 g, 12 mmol) in toluene (30 mL) was treated 1-(thiophen-2-yl)ethanone (1.8 g, 14.4 mmol), potassium bis(trimethylsilyl)amide (28.8 mL of 0.5 M solution in toluene, 14.4 mmol), 2,2′-bis(diphenyl)phosphino-1,1′-binaphthyl (racemic BINAP, 1.86 g, 3 mmol). The reaction was heated to 90° C. in an oil bath under a nitrogen atmosphere. After 4 h, the reaction was allowed to cool to room temperature and diluted with ethyl acetate (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, concentrated and purified by flash chromatography using a gradient of 10 to 40% ethyl acetate in hexanes to yield a yellow oil (1 g). MS (M+H)+ 203.
Reaction SMILES: C1C2C(C[O:15][C:16]([N:18]([CH2:34][C:35]3[N:39](C)[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=3)[CH2:19][CH2:20][NH:21][C@@H:22]([C@@H:30]([CH3:33])[CH2:31][CH3:32])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=O)C3C(=CC=CC=3)C=2C=CC=1.[CH2:45](NCC)C.[N+](C1C=CC(OC(=O)OC2C=CC([N+]([O-])=O)=CC=2)=CC=1)([O-])=O>CN(C)C=O.ClCCCl>[CH3:33][C@@H:30]([CH2:31][CH3:32])[C@H:22]([N:21]1[CH2:20][CH2:19][N:18]([CH2:34][C:35]2[N:39]([CH3:45])[C:38]3[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=3[N:36]=2)[C:16]1=[O:15])[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24]
Reactant: CCNCC
Reactant: CC[C@H](C)[C@H](NCCN(Cc1nc2ccccc2n1C)C(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Agent: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CCN(Cc2nc3ccccc3n2C)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
A solution of the product of Example 96A (0.81 mmol) in N,N-dimethylformamide (5 mL) was treated with diethylamine (0.8 mL), stirred at 25° C. for 2 hours and concentrated. A solution of the residue in 1,2-dichloroethane (16 mL) was treated with bis-(p-nitrophenyl)carbonate (0.296 g, 0.973 mmol), stirred at 60° C. for 16 hours and concentrated. The residue was chromatographed on silica gel, eluting with 0-100% ethyl acetate/dichloromethane to give the title compound (0.192 g, 59% yield).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[NH2:16][CH2:17][CH:18]([OH:27])[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.O>CO>[OH:9][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([NH:16][CH2:17][CH:18]([OH:27])[CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Reactant: NCC(O)CCN1CCOCC1
Solvent: O
Solvent: CO
Product: OC(CCN1CCOCC1)CNC(c1ccccc1)C(O)c1ccccc1
Yield: 88.8 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mol) and 4-(4-amino-3-hydroxybutyl)morpholine (3.48 g, 0.020 mol) was heated on a steam bath for 18 hours. The resulting viscous oil was dissolved in methanol (20 mL) and the solution poured into water (150 mL). The aqueous mixture was extracted twice with 100 mL portions of methylene chloride. The extract was dried (MgSO4) and concentrated to obtain 3.29 g of the impure product as an oil. The material was chromatographed on silica gel (60 g) using increasing portions of acetone in ethyl acetate to elute the product. After combining the desired fractions and concentration under vacuum, 2.21 g (67%) of the product was obtained. The product was purified and characterized as the cyclohexyl sulfamic acid salt, mp 159°-160° C. (methanol/isopropyl ether).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.C(=O)([O-])[O-].[K+].[K+].[K].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.O>C(#N)C>[Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:22]1[C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]2[C:18]1=[O:28]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1c(Cl)cccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CC#N
Product: Cc1c(Cl)cccc1CN1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
700 mg of 3-chloro-2-methylbenzyl chloride was dissolved in 10 mL of acetonitrile, and 829 mg of potassium carbonate and 889 mg of phthalimide potassium were added thereto at room temperature, followed by warming to 80° C., and then continuously reacting overnight. After completion of the reaction, the reaction liquid was left to be cooled, and water was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 1.15 g (yield 100%) of a title compound as a white crystal.