Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si](C)(C)O[Si](C)(C)C.[NH2:24][C:25]1[CH:26]=[C:27]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:28]=[CH:29][C:30]=1[OH:31].[CH:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][C:40]=1[CH2:49][C:50](O)=O>O.ClC1C=CC=CC=1Cl>[CH:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][C:40]=1[CH2:49][C:50]1[O:31][C:30]2[CH:29]=[CH:28][C:27]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:26][C:25]=2[N:24]=1
Reactant: CCOC(=O)CCc1ccc(O)c(N)c1
Reactant: O=C(O)Cc1ccc2ccccc2c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Clc1ccccc1Cl
Solvent: O
Solvent: C[Si](C)(C)O[Si](C)(C)C
Product: CCOC(=O)CCc1ccc2oc(Cc3ccc4ccccc4c3)nc2c1
Yield: 72.9 %

Procedure:
A mixture of phosphorus pentoxide (P2O5) (12.9 g), hexamethyldisiloxane (29.5 g) and 1,2-dichlorobenzene was heated for 10 minutes under reflux. To the mixture were added ethyl 3-(3-amino-4-hydroxyphenyl)propionate (4.75 g) and 2-naphthylacetic acid (4.23 g). The mixture was heated for 3 hours under reflux. The reaction mixture was poured into water and allowed to extraction with ethyl acetate. The ethyl acetatae layer was washed with water and dried over magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography. From the fractions eluted with ethyl acetate-hexane (1:4, v/v), ethyl 3-[2-(2-naphthylmethyl)benzoxazol-5-yl]propionate (5.95 g, 73%) was obtained. Recrystallization from ether-isopropyl ether gave colorless needles. Melting point: 81-82° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][S:7][C:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[C:9]=1[CH2:15][C:16]([O-:18])=[O:17])=[O:5])[CH3:2].[C:19](OC(=O)C)(=[O:21])[CH3:20].S(=O)(=O)(O)O.[CH3:31][CH2:32]OCC>C(O)(=O)C.O>[C:19]([O:14][C:10]1[C:9]([CH2:15][C:16]([O:18][CH2:31][CH3:32])=[O:17])=[C:8]([S:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:13]=[CH:12][CH:11]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CCOCC
Reactant: CCOC(=O)CSC1=C(CC(=O)[O-])C(=O)CCC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CSc1cccc(OC(C)=O)c1CC(=O)OCC

Procedure:
To a solution of α-(2-ethoxycarbonylmethylthio-6-oxocyclohex-1-enyl)acetate (156 g) in acetic acid (500 mL) is added acetic anhydride (750 mL). The solution is heated to 100° and a solution of sulfuric acid (53 g) in acetic acid (250 mL) is added dropwise. After addition is completed, the solution is heated until gas evolution ceases and the solvent is then removed in high vacuo to yield an oil which is mixed with ether and water. The layers are separated and the organic layer is washed with water, saturated sodium bicarbonate until neutral and then again water. The organic layer is then dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to yield ethyl 6-acetoxy-2-(ethoxycarbonylmethylthio)-phenylacetate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH2:7][NH:8][CH2:9][CH:10](O)[CH3:11])=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O>>[ClH:1].[Cl:17][CH:10]([CH3:11])[CH2:9][NH:8][CH2:7][CH2:6][C:5]1[CH:13]=[CH:14][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CC(O)CNCCc1ccc(Cl)cc1
Product: CC(Cl)CNCCc1ccc(Cl)cc1
Product: Cl

Procedure:
In some embodiments, after reacting 1-(4-chlorophenethylamino)propan-2-ol with thionyl chloride, produces 2-chloro-N-(4-chlorophenethyl)propan-1-amine hydrochloride with a purity of about 95% or greater as determined by HPLC. In some embodiments, after reacting 1-(4-chlorophenethylamino)propan-2-ol with thionyl chloride, the 2-chloro-N-(4-chlorophenethyl)propan-1-amine hydrochloride with a purity of about 98% or greater as determined by HPLC. In some embodiments, “HPLC” refers to Reversed-Phase High Performance Liquid Chromatography. In some embodiments, “HPLC” refers to Normal-Phase High Performance Liquid Chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([CH3:14])[CH2:12][N:11]2[N:15]=[C:16]([I:21])[C:17]([C:18](O)=[O:19])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].C[N:25](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:18]([C:17]1[C:16]([I:21])=[N:15][N:11]2[CH2:12][CH:13]([CH3:14])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]=12)(=[O:19])[NH2:25]
Reactant: CC1Cn2nc(I)c(C(=O)O)c2CN1C(=O)OC(C)(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1Cn2nc(I)c(C(N)=O)c2CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.6 %

Procedure:
To a stirred solution of Intermediate 340E (0.65 g, 1.596 mmol) in DMF (3.0 mL) was added NH4Cl (0.427 g, 7.98 mmol), HATU (1.214 g, 3.19 mmol) and DIPEA (0.836 mL, 4.79 mmol) and the resulting solution was allowed to stir at RT for 3 h. It was diluted with ethyl acetate (10 mL), washed with water, brine, dried over Na2SO4, filtered and the filtrate concentrated. The crude compound was purified by silica gel chromatography (12 g REDISEP® column, eluting with 2% MeOH in CHCl3). Fractions containing the product were combined and evaporated to afford Intermediate 340F as a colorless liquid (0.38 g, 59%). MS(ES): m/z=407 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 8 ppm 6.79-7.56 (m, 2H), 5.01 (d, J=18.51 Hz, 1H), 4.66 (br. s., 1H), 4.39 (d, J=18.13 Hz, 1H), 3.96-4.20 (m, 2H), 1.44 (s, 9H), 1.07 (d, J=6.80 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][C@H:13]([CH2:15][C@H:16]([S:18][CH3:19])[CH3:17])[NH:12][CH2:11][C@@H:10]2[O:20][CH:21]([C:32]2[CH:33]=[CH:34][C:35]3[O:40][CH2:39][CH2:38][N:37]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:36]=3[CH:46]=2)S(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][CH:4]=1.C1C2C(=CC=CC=2)C=CC=1.[Na]>C(COC)OC.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][C@H:13]([CH2:15][C@H:16]([S:18][CH3:19])[CH3:17])[NH:12][CH2:11][C@@H:10]2[O:20][CH2:21][C:32]2[CH:33]=[CH:34][C:35]3[O:40][CH2:39][CH2:38][N:37]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:36]=3[CH:46]=2)=[CH:5][CH:4]=1
Reactant: COCCCN1CCOc2ccc(C(O[C@H]3CN[C@@H](C[C@@H](C)SC)C[C@@H]3c3ccc(OC)cc3)S(=O)(=O)c3ccc(C)cc3)cc21
Agent: [Na]
Solvent: c1ccc2ccccc2c1
Solvent: O
Solvent: COCCOC
Product: COCCCN1CCOc2ccc(CO[C@H]3CN[C@@H](C[C@@H](C)SC)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
To a solution of 92 mg of 6-[(3R,4R,6R)-4-(4-methoxy-phenyl)-6-((R)-2-methylsulfanyl-propyl)-1-(toluene-4-sulfonyl)-piperidin-3-yloxymethyl]-4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazine (diastereomer 1) in 2.0 ml of dimethoxyethane are added 100 mg of naphthalene and 20 mg of sodium. The reaction mixture is sonicated for 10 minutes, diluted with water and extracted with dichloromethane. The organic phases are combined, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH:10]2[CH:6]([CH2:7][NH:8][CH2:9]2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])([OH:11])[CH2:4][CH2:3]1.[CH3:21][N:22]([CH3:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30](O)=[O:31]>>[CH3:1][C:2]1([CH3:20])[CH:10]2[CH:6]([CH2:7][N:8]([C:30](=[O:31])[CH2:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]([CH3:33])[CH3:21])[CH2:9]2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])([OH:11])[CH2:4][CH2:3]1
Reactant: COc1ccccc1C1(O)CCC(C)(C)C2CNCC21
Reactant: CN(C)c1ccccc1CC(=O)O
Product: COc1ccccc1C1(O)CCC(C)(C)C2CN(C(=O)Cc3ccccc3N(C)C)CC21

Procedure:
By working according to the experimental procedure of Example 6, from 0.6 g of (3aRS, 4RS, 7aRS)-7,7-dimethyl-4-(2-methoxyphenyl)-4-perhydroisoindolol and 0.41 g of 2-dimethylaminophenylacetic acid, and after purification on a column of silca gel (particle size 0.04-0.06 m, diameter 2.8 cm, height 17 cm), 0.4 g of (3aRS,4RS,7aRS)-7,7-dimethyl-4-(2-methoxyphenyl)-2-[(2-dimethylaminophenyl)acetyl]-4-perhydroisoindolol is obtained, in the form of a white foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:20](Cl)([Cl:22])=[O:21].C1C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:20]([Cl:22])=[O:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)Cl
Reaction time: 2 h

Procedure:
A solution of proline t-butyl ester (10.0 g; 0.058 mol) and triethylamine (8.56 ml; 6.22g; 0.0614 mol) in dry THF (60 ml) was added to a cold (0° C.) solution of phosgene (12.5%) in benzene (61 ml; 0.070 mol) over 1 hour. An additional 50 ml of dry THF was added and stirring was continued for 2 hours. The reaction mixture was filtered and evaporated, giving N-chlorocarbonyl-(L)-proline t-butyl ester (1) as a dark-red oil (13.35 g).
Reaction SMILES: [C:1]([C:6]1[C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:8]([CH:18]=[O:19])[C:9]([CH:15]([CH3:17])[CH3:16])=[N:10][C:11]=1[CH:12]([CH3:14])[CH3:13])([O:3]CC)=O.[CH2:27]([Mg]Br)[CH3:28]>C(OCC)(=O)C.CCCCCC>[CH:15]([C:9]1[C:8]([CH2:18][OH:19])=[C:7]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[C:6]([CH:1]([OH:3])[CH2:27][CH3:28])=[C:11]([CH:12]([CH3:13])[CH3:14])[N:10]=1)([CH3:16])[CH3:17]
Reactant: CC[Mg]Br
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(C=O)c1-c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCC(O)c1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 5-carboethoxy-2,6-diisopropyl-4-(4-fluorophenyl)-3-pyridinecarboxaldehyde (Example 1, Step E) and ethyl magnesium bromide, according to the procedures described in Example 93. 1H NMR (300 MHz, CDCl3): δ 7.15 (m, 4 H), 4.40 (dq, J=3.7, J=5.2 Hz, 1 H), 4.30 (d, 5.5 Hz, 2 H), 3.72 (septet, J=6.6 Hz, 1 H), 3.42 (septet, 6.6 Hz, 1 H), 1.88 (m, 1 H), 1.63 (t, J=5.5 Hz, 1 H), 1.27 (m, 14 H), 0.804 (t, J=7.36 Hz, 3 H). FAB-MS: calcd for (C21H28NFO2) 345, found 346 (M+H). Anal. Calcd for C21H28NO2F: C, 76.84; H, 8.69; N, 3.90. Found: C, 76.67; H, 8.76; N, 3.77. mp 173-175° C. Rf=0.2 (20% ethyl acetate/hexane);
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:47]=[C:46]([S:48]([N:51](CC2C=CC(OC)=CC=2OC)[C:52]2[S:53][CH:54]=[N:55][N:56]=2)(=[O:50])=[O:49])[C:45]([F:68])=[CH:44][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([F:27])([F:26])[F:25])=[CH:14][C:13]=1[C:28]1[N:32]([CH:33]2[CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]2)[N:31]=[CH:30][CH:29]=1>ClCCl>[NH:35]1[CH2:34][CH:33]([N:32]2[C:28]([C:13]3[CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]([F:26])([F:27])[F:25])[CH:16]=[CH:17][C:12]=3[O:11][C:10]3[C:9]([Cl:8])=[CH:47][C:46]([S:48]([NH:51][C:52]4[S:53][CH:54]=[N:55][N:56]=4)(=[O:50])=[O:49])=[C:45]([F:68])[CH:44]=3)=[CH:29][CH:30]=[N:31]2)[CH2:36]1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccccc4C(F)(F)F)cc3-c3ccnn3C3CN(C(=O)OC(C)(C)C)C3)cc2F)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2ccc(-c3ccccc3C(F)(F)F)cc2-c2ccnn2C2CNC2)cc1F
Temperature: 40 °C
Yield: 143.6 %

Procedure:
Trifluoroacetic acid (0.55 mL, 7.18 mmol) was added to a solution of tert-butyl 3-{5-[4-(2-chloro-4-{[(2,4-dimethoxybenzyl)(1,3,4-thiadiazol-2-yl)amino]sulfonyl}-5-fluorophenoxy)-2′-(trifluoromethyl)biphenyl-3-yl]-1H-pyrazol-1-yl}azetidine-1-carboxylate (Preparation 45, 228 mg, 0.253 mmol) in dichloromethane (20 mL). The mixture was then heated to 40° C. for 18 hours under an atmosphere of nitrogen. The reaction was then cooled to room temperature and concentrated in vacuo to afford a clear oil (236.5 mg). The oil was then purified by preparative HPLC (Trilution method) to afford the title compound as a white solid (42.9 mg, 9% over 2 steps).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:11]([CH3:24])([CH3:23])[C:12]([N:14]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH2:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH:30][C:2]1[CH:3]=[C:4]([C:11]([CH3:24])([CH3:23])[C:12]([N:14]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)CN(CC(C)C)C(=O)C(C)(C)c1ccc([N+](=O)[O-])c(Cl)c1
Reactant: CN(C)CCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)CN(CC(C)C)C(=O)C(C)(C)c1ccc([N+](=O)[O-])c(NCCCN(C)C)c1
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of 2-(3-chloro-4-nitrophenyl)-N,N-diisobutyl-2-methylpropanamide (78 mg, 1 eq), 3-dimethylaminopropylamine (45 mg, 2 eq) and potassium carbonate (62 mg, 2 eq) in DMF (2 ml) is heated under reflux for 3 hours then cooled down to ambient temperature. The residue is taken up in ethyl acetate (20 ml) and water (8 ml). After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane/methanol 8:2) produces the expected compound in the form of a yellow oil (44 mg; 48% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:36][CH2:35][CH2:34][C:10]2([CH2:15][N:14]([C:16]3[CH:17]=[C:18]([CH3:33])[C:19]4[N:23]=[C:22]([C:24]5[C:25](=[O:31])[NH:26][CH:27]=[CH:28][C:29]=5Cl)[NH:21][C:20]=4[CH:32]=3)[CH2:13][CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:37][CH2:38][C@H:39]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=1)[OH:40].CCN(CC)CC>CCO>[CH2:1]([N:8]1[CH2:36][CH2:35][CH2:34][C:10]2([CH2:15][N:14]([C:16]3[CH:17]=[C:18]([CH3:33])[C:19]4[N:23]=[C:22]([C:24]5[C:25](=[O:31])[NH:26][CH:27]=[CH:28][C:29]=5[NH:37][CH2:38][C@H:39]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=5)[OH:40])[NH:21][C:20]=4[CH:32]=3)[CH2:13][CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC[C@@H](O)c1cccc(Cl)c1
Reactant: Cc1cc(N2CCCC3(CCCN(Cc4ccccc4)C3)C2)cc2[nH]c(-c3c(Cl)cc[nH]c3=O)nc12
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCCC3(CCCN(Cc4ccccc4)C3)C2)cc2[nH]c(-c3c(NC[C@@H](O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Yield: 36.9 %

Procedure:
A solution of 3-[6-(8-benzyl-2,8-diaza-spiro[5.5]undec-2-yl)-4-methyl-1H-benzoimidazol-2-yl]-4-chloro-1H-pyridin-2-one (17 mg, 0.034 mmol), (S)-2-amino-1-(3-chlorophenyl)-ethanol (29 mg, 0.17 mmol) and Et3N (34 mg, 0.34 mmol) in EtOH (0.5 mL) was heated at 80° C. for 16 h and then the reaction mixture was evaporated. The residue was purified by chromatography (25:1 CH2Cl2/MeOH) to afford the title compound (8 mg, 64%). 1H NMR (MeOH-d4) δ 1.28 (m, 2H), 1.50-1.83 (4H), 2.07-2.27 (2H), 2.48-2.61 (2H), 2.54 (s, 3H), 2.82-2.94 (2H), 3.041-3.23 (2H), 3.40-3.55 (2H), 3.59-3.73 (2H), 4.75 (m, 1H), 4.98 (m, 1H), 6.20 (d, J=6 Hz, 1H), 6.75 (s, 1H), 6.84 (s, 1H), 7.19-7.32 (8H), 7.35-7.42 (2H), 7.54 (s, 1H). ESI-MS m/z 637 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:25])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[CH:13][CH:12]=3)[O:8][C:7](=[O:23])[C:6]=2[CH:24]=1.O.[NH2:27][NH2:28].O1CCCC1>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:25])[C:5]([NH:10][C:9]([C:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)=[O:8])=[C:6]([C:7]([NH:27][NH2:28])=[O:23])[CH:24]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3ccnn3-c3ncccc3Cl)nc12
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=O)NN)c1NC(=O)c1ccnn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 0.50 g of 6-chloro-2-[1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazine-4-one, 0.13 ml of hydrazine monohydrate and 20 ml of tetrahydrofuran was stirred at room temperature for 4 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was washed with a mixed solvent of ethyl acetate and hexane to obtain 0.44 g of N-[4-chloro-2-(hydrazinocarbonyl)-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]([Si:29]([CH3:46])([CH3:45])[O:30][C@H:31]1[CH2:39][CH2:38][CH2:37][C@@:36]2([CH3:40])[C@H:32]1[CH2:33][CH2:34][C@@H:35]2[C@H:41]([CH3:44])[CH:42]=O)([CH3:28])([CH3:27])[CH3:26]>ClCCl>[C:25]([Si:29]([CH3:46])([CH3:45])[O:30][C@H:31]1[CH2:39][CH2:38][CH2:37][C@@:36]2([CH3:40])[C@H:32]1[CH2:33][CH2:34][C@@H:35]2[C@H:41]([CH3:42])[CH:44]=[C:2]([Br:5])[Br:1])([CH3:27])([CH3:28])[CH3:26]
Reactant: C[C@H](C=O)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@H](C=C(Br)Br)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Temperature: -20 °C
Yield: 81 %

Procedure:
Typically, tetrabromomethane (16.8 g; 50.6 mmol) is dissolved in dichloromethane (80 ml). Triphenylphosphine (26.5 g; 101.1 mmol) in solution in dichloromethane (40 ml) is added dropwise. The reaction mixture is cooled to -20° C. and the compound (S)-2-[(1R,3aR,4S,7aR)-4-(tert-Butyl-dimethyl-silanyloxy)-7a-methyl-octahydro-inden-1-yl]-propan-1-al (J. Org Chem: 1992, 57, 3173 ) in solution in dichloromethane (30 ml) is added dropwise. The reaction mixture is allowed to reach room temperature and is then poured on ice. The mixture is extracted twice with ethyl-acetate (250 ml); the organic phase is washed twice with brine (100 ml), dried over sodium sulfate. After evaporation of the solvents and flash-chromatography over silica gel (hexanes/ethyl acetate 98:2) the compound (1R,3aR,4S,7aR)-4-(tert-Butyl-dimethyl-silanyloxy)-1-[(S)-3,3-dibromo-1-methyl-allyl]-7a-methyl-octahydro-indene (8.94 g; Yield 81%) was obtained as a colorless oil.
Reaction SMILES: [CH:1](=[CH:8][C:9](=O)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17](=[NH:19])[NH2:18])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:8]=[C:9]([CH3:10])[NH:19][C:17]=1[NH2:18])=[O:20])[CH3:13]
Reactant: CC(=O)C=Cc1ccccc1
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(C)=CC1c1ccccc1
Yield: 73 %

Procedure:
Boiling a solution of 14.6 g of benzylideneacetone and 13.0 g of amidinoacetic acid ethyl ester in 150 ml of ethanol for 2 hours yields 2-amino-6-methyl-4-phenyl-1,4-dihydropyridine-3-carboxylic acid ethyl ester of melting point 150°C (ethanol). Yield: 73 percent of theory.
Reaction SMILES: [S:1](=[O:36])(=[O:35])([O:3][CH2:4][C@@H:5]1[C@@H:9]([O:10][Si](C(C)(C)C)(C)C)[CH2:8][C@H:7]([N:18]2[C:26]3[CH:25]=[CH:24][N:23]=[C:22]([NH:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:21]=3[CH:20]=[CH:19]2)[O:6]1)[NH2:2].F>C1COCC1.N1C=CC=CC=1.N1C=CC=CC=1.CCOC(C)=O>[S:1](=[O:36])(=[O:35])([O:3][CH2:4][C@@H:5]1[C@@H:9]([OH:10])[CH2:8][C@H:7]([N:18]2[C:26]3[CH:25]=[CH:24][N:23]=[C:22]([NH:27][CH2:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:21]=3[CH:20]=[CH:19]2)[O:6]1)[NH2:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(NCc4ccccc4)nccc32)O[C@@H]1COS(N)(=O)=O
Agent: F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: NS(=O)(=O)OC[C@H]1O[C@@H](n2ccc3c(NCc4ccccc4)nccc32)C[C@@H]1O
Reaction time: 8 h
Yield: 25 %

Procedure:
To a solution of ((2R,3S,5R)-5-[4-(benzylamino)-1H-pyrrolo[3,2-c]pyridin-1-yl]-3-{[tert-butyl(dimethyl)silyl]oxy}tetrahydrofuran-2-yl)methyl sulfamate (0.0300 g, 0.0563 mmol) in THF/pyridine (1 mL, 1:1) was added hydrofluoric acid in pyridine (3 drops) and stirred overnight. The reaction was diluted with EtOAc (5 mL) and quenched with saturated aq NaHCO3 (10 mL). The aq layer was extracted with EtOAc (3×10 mL) and the combined organics were dried (Na2SO4), filtered, and concentrated. The crude material was purified by preparative plate chromatography (10% MeOH/EtOAc) to give the final compound (0.00590 g, 25%).
Reaction SMILES: S1[CH:5]=[CH:4][C:3]([C:6]2[S:10][C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[N:8][CH:7]=2)=[CH:2]1.[Br:19][C:20]1C=C(CC=O)C=C[CH:25]=1>C(Cl)Cl.CO>[Br:19][C:20]1[CH:2]=[C:3]([C:6]2[S:10][C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[N:8][CH:7]=2)[CH:4]=[CH:5][CH:25]=1
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Reactant: O=CCc1cccc(Br)c1
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc(Nc2ncc(-c3cccc(Br)c3)s2)cc1

Procedure:
The title compound is prepared as described in Example 12 (Procedure B) for 4-(5-thiophen-3-yl-thiazol-2-yl-amino)-phenol but starting from (3-bromophenyl)-acetaldehyde. The title compound: ES-MS: 348.9 [M+2]+; single peak at tR=3.92 min (System 2); Rf=0.47 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][N:11]3[CH:14]=[N:15][CH:16]=[C:10]3[CH:9]=2)[CH2:4][CH2:3]1.Br[C:18]1C=CN=C(CNC(=O)C)C=1.BrC1C=CN=C(CNC=O)C=1>>[ClH:1].[CH3:18][C:14]1[N:11]2[CH:12]=[CH:13][C:8]([CH:5]3[CH2:4][CH2:3][NH:2][CH2:7][CH2:6]3)=[CH:9][C:10]2=[CH:16][N:15]=1
Reactant: c1cn2cncc2cc1C1CCNCC1
Reactant: CC(=O)NCc1cc(Br)ccn1
Agent: Cl
Agent: O=CNCc1cc(Br)ccn1
Product: Cc1ncc2cc(C3CCNCC3)ccn12

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 39.5, except N-((4-bromopyridin-2-yl)methyl)acetamide (compound 67.1) was used in place of N-((4-bromopyridin-2-yl)methyl)formamide (compound 39.2).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:17]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]3[N:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[C:15]([C:12]1[N:13]=[CH:14][C:9]2[CH:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:32](=[O:34])[CH3:33])=[CH:24][CH:23]=3)[N:17]([CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:10]=2[N:11]=1)#[N:16]
Reactant: CC(C)(C)Cn1c(Cc2ccc(N)cc2)cc2cnc(C#N)nc21
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Cc2cc3cnc(C#N)nc3n2CC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
To a solution of 6-(4-amino-benzyl)-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.3 mmol) in CH2Cl2 (4 mL), triethylamine(0.36 mmol) and acetyl chloride (0.36 mmol) is added at 0° C. The reaction mixture stirred at room temperature for 1 day. The mixture is quenched with saturated ammonium chloride and extracted with two 50 ml portions of AcOEt. The combined extracts are washed with brine, dried over sodium sulfate and concentrated under vacuum to crude product. Purification of the residue by silica gel column chromatography affords title compound in 84% yield.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[CH2:11]1[CH2:16][O:15][CH:14]=[CH:13][CH2:12]1>C(Cl)Cl.CC1C=CC(S(O)(=O)=O)=CC=1>[O:15]1[CH2:16][CH2:11][CH2:12][CH2:13][CH:14]1[O:7][CH2:6][C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[CH:2]=[O:1]
Reactant: O=Cc1cccc(CO)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=Cc1cccc(COC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
This alcohol (0.44 mole) was dissolved in CH2Cl2 (500 ml). DHP (50 g, 0.59 mole) and PTSA (1 g, 5 mmol) were added and the mixture was stirred overnight at r.t. After concentration in vacuo, the residue was purified by flash chromatography (5% to 15% EtOAc in toluene) to give 85 g of the title compound.