Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH2:15])=[O:14].[C:16]1([C:22]2[NH:26][C:25]3[CH:27]=[C:28](B4OC(C)(C)C(C)(C)O4)[CH:29]=[CH:30][C:24]=3[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])(O)=O.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:29]3[CH:28]=[CH:27][C:25]4[N:26]=[C:22]([C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=5)[NH:23][C:24]=4[CH:30]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH2:15])=[O:14]
Reactant: NC(=O)c1nnc2c(Br)cccc2c1N
Reactant: CC1(C)OB(c2ccc3nc(-c4ccccc4)[nH]c3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: NC(=O)c1nnc2c(-c3ccc4nc(-c5ccccc5)[nH]c4c3)cccc2c1N
Temperature: 140 °C
Yield: 31.5 %

Procedure:
4-Amino-8-bromocinnoline-3-carboxamide (0.040 g, 0.150 mmol), 2-phenyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (0.048 g, 0.150 mmol), PdCl2(dppf) (5.48 mg, 7.50 μmol), dioxane (8 mL) and saturated NaHCO3 (2 mL) were combined and heated at 140° C. for 30 minutes in a microwave reactor. The reaction mixture was subsequently concentrated and purified via preparative HPLC (Phenomenex Gemini Prep 5 μm C18, 75×30 mm column) eluting with a gradient of 30-35% ACN/H2O (80/20 v/v, containing 10 mM NH4HCO3) in H2O (containing 10 mM NH4HCO3). The product-containing fractions were combined and acetonitrile was evaporated. The aqueous phase was diluted with saturated NaHCO3 and extracted with EtOAc. The organic phase was washed with water and the volatiles were evaporated to give the title compound as a light yellow solid (0.018 g, 32%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.47-7.65 (m, 4 H), 7.65-7.75 (m, 2 H), 7.83 (dd, J=8.21, 7.20 Hz, 1 H), 7.91-8.00 (m, 2 H), 8.23 (d, J=7.07 Hz, 2 H), 8.43 (d, J=7.58 Hz, 1 H), 8.54 (br s, 1 H); ESI-MS ma/z [(M+2H)/2]+ 191.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.Cl[C:19]([O:21][CH3:22])=[O:20]>O>[NH:1]=[C:2]1[N:6]([C:19]([O:21][CH3:22])=[O:20])[C:5]2[CH:7]=[CH:8][C:9]([O:11][C:19]([O:21][CH3:22])=[O:20])=[CH:10][C:4]=2[S:3]1
Reactant: COC(=O)Cl
Reactant: Nc1nc2ccc(O)cc2s1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)Oc1ccc2c(c1)sc(=N)n2C(=O)OC
Reaction time: 5 h

Procedure:
1 g of 2-amino-1,3-benzothiazol-6-ol is introduced into 15 cm3 of pyridine in a three-necked flask. 1.02 cm3 of methyl chloroformate are added dropwise, while taking care not to exceed a temperature of 25° C. After stirring for five hours, 0.5 cm3 of methyl chloroformate is added. The reaction medium is stirred at a temperature in the region of 20° C. overnight. 30 cm3 of water are added and the precipitate is then filtered off by suction, washed with three times 5 cm3 of water and then dried over phosphorus pentoxide. 956 mg of methyl 2-imino-6-[(methoxycarbonyl)oxy]-1,3-benzothiazole-3(2H)-carboxylate are obtained in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].CCN=C=NCCCN(C)C.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.O>ClCCl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(Br)c(F)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.5 %

Procedure:
To a room temperature solution containing 10 g of 4-bromo-3-fluorobenzoic acid (45.7 mmols) in 228 mL of dichloromethane was added 1.67 g of DMAP (13.7 mmols), 11.3 g of EDCI (59.2 mmols), and 5.11 mL of morpholine (59.4 mmols). After stirring at ambient temperature for 18 h, 20 mL of water was added to the reaction mixture. The layers were separated, and the organic layer was washed with water (3×20 mL), dried over MgSO4, and filtered through a frit. The resulting solution was concentrated to a pale yellow oil which was purified by silica gel chromatography (120 g redisep column, silica 40 um, 60 A, 85 ml/min, A: EtOAc, B: hexanes, A: 50% for 5 min, then 50-70% for 8 min) to give 8.62 g (66%) of title compound as a yellow oil. MS (ES) m/e 288 [M+]+.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH2:19][C:20](Cl)=[O:21])[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1>>[C:1]12([C:11]3[CH:12]=[C:13]([CH2:19][C:20]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=4)=[O:21])[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COC(=O)c1ccc(N)cc1
Reactant: COc1ccc(CC(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Product: COC(=O)c1ccc(NC(=O)Cc2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1

Procedure:
In a manner similar to Example 1(d), by reaction of 3.8 g (11.9 mmol) of 3-(1-adamantyl)-4-methoxyphenylacetyl chloride with 1.81 g (12 mmol) of methyl 4-aminobenzoate, 3.2 g (63%) of the expected methyl ester, melting point 146°-147° C., are obtained.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][NH:11][C:12]([C:14]1[CH:31]=[CH:30][C:17]2[CH2:18][CH:19]([CH2:25][C:26]([O:28]C)=[O:27])[C:20](=[O:24])[N:21]([CH3:23])[CH2:22][C:16]=2[CH:15]=1)=[O:13].O[Li].O.C1COCC1>O>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][NH:11][C:12]([C:14]1[CH:31]=[CH:30][C:17]2[CH2:18][CH:19]([CH2:25][C:26]([OH:28])=[O:27])[C:20](=[O:24])[N:21]([CH3:23])[CH2:22][C:16]=2[CH:15]=1)=[O:13]
Reactant: COC(=O)CC1Cc2ccc(C(=O)NCc3nc4ccccc4[nH]3)cc2CN(C)C1=O
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CN1Cc2cc(C(=O)NCc3nc4ccccc4[nH]3)ccc2CC(CC(=O)O)C1=O
Yield: 35.9 %

Procedure:
A solution of methyl (±)-8-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (0.10 g, 0.24 mmol), LiOH.H2O (0.013 g, 0.31 mmol), THF (2 mL), and H2O (2 mL) was stirred at RT for 18 h, then was concentrated to dryness. The residue was dissolved in H2O, and the solution was brought to pH 4-5 with 3N HCl. The resulting precipitate was collected by filtration and dried. Recrystallization from boiling isopropanol gave the title compound (0.035 g, 36%) as a colorless solid: 1H NMR (DMSO-d6) δ 9.13 (t, J=5.7 Hz, 1H), 7.79 (m, 1H), 7.48 (m, 2H), 7.23 (d, J=7.9 Hz, 1H), 7.14 (m, 2H), 5.32 (d, J=16.9 Hz, 1H), 4.69 (d, J=5.7 Hz, 2H), 4.03 (d, J=16.7 Hz, 1H), 3.79 (m, 1H), 3.14 (dd, J=18, 2 Hz, 1H), 2.90 (s, 3H), 2.70 (m, 2H), 2.38 (dd, J=11.4, 3 Hz, 1H); MS (ES) m/e 407 (M+H)+. Anal. Calcd for C22H22N4O4.1.5 H2O.0.5 C3H8O: C, 60.90; H, 6.31; N, 12.09. Found: C, 60.68; H, 6.05; N, 12.05.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]2[S:10][C:11]([Cl:14])=[CH:12][CH:13]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:21][CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][NH:26][C:25]1=[O:29].C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[Br:1][C:2]1[C:3]([C:9]2[S:10][C:11]([Cl:14])=[CH:12][CH:13]=2)=[N:4][C:5]([NH:21][CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][NH:26][C:25]2=[O:29])=[N:6][CH:7]=1
Reactant: NCCN1CCNC1=O
Reactant: Clc1ncc(Br)c(-c2ccc(Cl)s2)n1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C1NCCN1CCNc1ncc(Br)c(-c2ccc(Cl)s2)n1
Temperature: 150 °C

Procedure:
5-Bromo-2-chloro-4-(5-chlorothiophen-2-yl)pyrimidine (0.4g, 1.3 mmol), N-methyl pyrrolidone (3 mL), potassium carbonate (0.358 g, 2.6 mmol) and 1-(2-aminoethyl)-imidazolidin-2-one (0.2 g, 1.54 mmol) were all placed in a microwave tube. The reaction was heated to 150° C. for 20 min in a Personal Chemistry microwave. A saturated solution of sodium bicarbonate was added to the reaction mixtue, which was extracted three times with dichloromethane. The organic layer was dried with sodium sulfate and purified by flash chromatography on silica gel using gradient of 0 to 10% methanol in dichloromethane to obtain a white solid. Yield=0.41 g. MS (M+H)+ 402/404.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl[S:39]([C:42]1[CH:50]=[CH:49][C:45]([C:46]([OH:48])=[O:47])=[CH:44][CH:43]=1)(=[O:41])=[O:40]>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:10][N:9]2[S:39]([C:42]2[CH:43]=[CH:44][C:45]([C:46]([OH:48])=[O:47])=[CH:49][CH:50]=2)(=[O:41])=[O:40])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1CN(S(=O)(=O)c2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 6 h
Yield: 385 %

Procedure:
To a mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (80 mg, 0.0189 mmol) and diisopropylethylamine (122 mg, 0.942 mmol) in CH2Cl2 (6 mL) was added p-(chlorosulfonyl)benzoic acid (70.0 mg, 0.283 mmol, Eastman) and the reaction mixture was stirred at room temp. for 6 hrs. The resulting mixture was diluted with EtOAc, washed with aqueous Na2CO3, 1N HCl and brine, and concentrated to dryness to give rac-4-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-sulfonyl]-benzoic acid (44.2 mg, 38%) as a white solid. HRMS (ES+) m/z Calcd for C29H26Cl2F2N2O4S H [(M+H)+]: 607.1031; Found: 607.1032.
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:14])[C@@H:5]([NH:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]([CH3:8])[CH3:7].[C:15]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:20]=[CH:19][C:18]([CH2:21][C@@H:22]([NH:31]C(OC(C)(C)C)=O)[CH2:23][C@:24]([CH2:29][OH:30])([CH3:28])[C:25]([OH:27])=[O:26])=[CH:17][CH:16]=1.CCN(CC)CC.Cl.O1CCOCC1>CC(C)=O.CC#N>[CH3:13][O:12][C:10]([NH:9][C@@H:5]([CH:6]([CH3:8])[CH3:7])[C:4]([O:3][CH2:2][O:27][C:25](=[O:26])[C@@:24]([CH2:29][OH:30])([CH3:28])[CH2:23][C@H:22]([NH2:31])[CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:16][CH:17]=1)=[O:14])=[O:11]
Reactant: COC(=O)N[C@H](C(=O)OCCl)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@](C)(CO)C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: CC#N
Product: COC(=O)N[C@H](C(=O)OCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(C)C
Reaction time: 0.5 h

Procedure:
(S)-2-Methoxycarbonylamino-3-methyl-butyric acid chloromethyl ester (140 mg, 630 μmol) was added to a mixture of (2S,4R)-5-biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (0.2 g, 484 μmol) and Et3N (71 μL, 508 μmol) in acetone (10 mL). The mixture was refluxed for 24 hours and the reaction monitored for completion. When the reaction was complete, the product was purified (Interchim reverse phase chromatography column) the solvent was removed under vacuum. MeCN (2 mL) and 4 M HCl in 1,4-dioxane (2 mL, 8 mmol) was added and the resulting mixture was stirred for 30 minutes. The solvent was evaporated under vacuum and the product was azeotroped with toluene (1×) to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid (S)-2-methoxycarbonylamino-3-methyl-butyryloxymethyl ester.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([O:17]C)[CH:15]=[CH:16][C:11]=2[CH:10]=1)=[O:8].[CH3:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[S:24].Cl>ClCCl.O>[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([OH:17])[C:15]([C:23](=[S:24])[C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([CH3:19])[CH:21]=3)=[CH:16][C:11]=2[CH:10]=1)=[O:8]
Reactant: Cc1cccc(C(=S)Cl)c1
Reactant: COC(=O)C1=Cc2ccc(OC)cc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1=Cc2cc(C(=S)c3cccc(C)c3)c(O)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
28.26 g of aluminium trichloride are suspended in 70 ml of dichloromethane and, over a period of 15 minutes, 10.19 g of 5-methoxybenzocyclobutene-1-carboxylic acid methyl ester are added dropwise at from 20° to 30°. Stirring is carried out for 30 minutes, 20.8 g of m-methylthiobenzoyl chloride are added dropwise over a period of 20 minutes and the whole is stirred for 4 hours at room temperature, poured into a mixture of 200 g of ice, 20 ml of concentrated hydrochloric acid and 200 ml of water, stirred for 30 minutes and extracted by shaking twice with 50 ml of dichloromethane each time and once with 50 ml of a mixture of trichloromethane and methanol (3:1). The organic phases are combined, washed twice with water, dried over magnesium sulphate, treated with kieselguhr and concentrated by evaporation. Chromatography over silica gel using hexane/ethyl acetate (4:1) as eluant yields 4-(m-methylthiobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid methyl ester in the form of a yellow oil.
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C@H:12]1[C:26](=[O:27])[N:25]([CH2:28][C:29]([F:32])([F:31])[F:30])[CH2:24][C:15]2[C:16]3[CH:17]=[N:18][NH:19][C:20]=3[C:21]([Cl:23])=[CH:22][C:14]=2[CH2:13]1.[O:33]=[C:34]1[NH:42][C:37]2=[N:38][CH:39]=[CH:40][CH:41]=[C:36]2[C:35]21[CH2:50][C:49]1[C:44](=[CH:45][CH:46]=[C:47]([C:51](O)=[O:52])[CH:48]=1)[CH2:43]2.C(N(CC)C(C)C)(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:23][C:21]1[C:20]2[NH:19][N:18]=[CH:17][C:16]=2[C:15]2[CH2:24][N:25]([CH2:28][C:29]([F:31])([F:30])[F:32])[C:26](=[O:27])[C@H:12]([NH:11][C:51]([C:47]3[CH:48]=[C:49]4[C:44](=[CH:45][CH:46]=3)[CH2:43][C:35]3([C:36]5[C:37](=[N:38][CH:39]=[CH:40][CH:41]=5)[NH:42][C:34]3=[O:33])[CH2:50]4)=[O:52])[CH2:13][C:14]=2[CH:22]=1
Reactant: O=C(O)c1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: N[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O
Agent: CS(=O)(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O)c1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (7R)-7-amino-4-chloro-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one bis-methanesulfonate from Step B (20 mg, 0.038 mmol), (±)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylic acid (11 mg, 0.038 mmol) [Bell et al. WO 2006/031606], N,N-diisopropylethylamine (25 mg, 33 uL, 0.19 mmol), HOBT (7.0 mg, 0.046 mmol), and EDC (8.8 mg, 0.046 mmol) in DMF (0.5 mL) was stirred at ambient temperature for 2 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were concentrated in vacuo to provide the title compound. MS: m/z=595.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]2[C:11](=O)[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[O:7][C:6]=12.P(Cl)(Cl)(Cl)(Cl)[Cl:18]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[S:3][CH:4]=[C:5]2[C:11]([Cl:18])=[N:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[O:7][C:6]=12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C1Nc2ccccc2Oc2c1csc2Cl
Solvent: Cc1ccccc1
Product: ClC1=Nc2ccccc2Oc2c1csc2Cl

Procedure:
A 4.0 g. portion of 3-chlorothieno[3,4-b][1,5]benzoxazepin-10(9H)-one (Example 12) and 4.0 g. of phosphorus pentachloride in 103 ml. of dry toluene is refluxed for 41/2 hours. The reaction temperature is concentrated, then is triturated with toluene to give 3,10-dichlorothieno[3,4-b][1,5]benzoxazepine. A 25 ml. amount of dry N-(2-hydroxyethyl)piperazine and 25 ml of dry toluene is added to the product above and the mixture is heated at 120° C. for 16 hours. The reaction mixture is concentrated to a thick oil, the oil is dissolved in hot 2N aqueous acetic acid, treated with activated charcoal and filtered through diatomaceous earth. The filtrate is cooled and precipitated with concentrated ammonium hydroxide. The precipitate is collected and extracted into methylene chloride, the organic solution is dried over anhydrous sodium sulfate and eluted through magnesium silicate with 2.5 liters of methylene chloride followed by one liter of 1:1 ethyl acetate:methylene chloride. The combined organic solvents are evaporated to yield 2.0 g. of 4-(3-chlorothieno[3,4-b][1,5]-benzoxazepin-10-yl)-1-piperazineethanol.
Reaction SMILES: O=[C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH3:11][NH2:12]>C(O)C>[CH3:11][N:12]=[C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: CN
Reactant: O=C1CCCc2scnc21
Solvent: CCO
Product: CN=C1CCCc2scnc21
Yield: 86 %

Procedure:
6 g (0.039 mole) of the ketone obtained in step (d) are dissolved in 50 ml anhydrous ethanol and treated for 30 minutes with a gaseous methylamine stream. After evaporation to dryness, the residue is taken up into ether and filtered, to give 5.6 g (86%) of product, M.p. 233°-235° C.
Reaction SMILES: [CH2:1]([O:19][CH:20]([CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:21]=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C(OCC)C>[CH2:25]([O:24][CH2:23][CH:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:21]([OH:22])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOCC(C=O)OCCCCCCCC/C=C\C/C=C\CCCCC
Solvent: CCOCC
Product: CCCCC/C=C\C/C=C\CCCCCCCCOCC(OCCCCCCCC/C=C\C/C=C\CCCCC)C(O)CCCCCCCC/C=C\C/C=C\CCCCC
Yield: 41.9 %

Procedure:
To a solution of 2,3-bis((9Z,12Z)-octadeca-9,12-dienyloxy)propanal (1.5 g, 2.62 mmol) in anhydrous diethyl ether (10 mL) was added LinMgBr Grignard (2.56 mL, 5.23 mmol). Upon completion, the solution was quenched with 5% HCl (50 mL) and washed with diethyl ether (3×50 mL). The combined ethyl ether extracts were dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography on silica gel 60 (eluted with a gradient of 100% hexanes to 2% ethyl acetate in hexanes) to afford (12Z,15Z)-1,2-bis((9Z,12Z)-octadeca-9,12-dienyloxy)henicosa-12,15-dien-3-ol as a colorless oil (460 mg, 21%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Br:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:34])=[C:29]([CH:33]=1)[C:30](Cl)=O.C(N(CC)CC)C>C(#N)C>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:34])=[C:29]([C:30]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[C:7]3[CH2:17][CH2:18][CH3:19])[N:16]=2)[CH:33]=1
Reactant: O=C(Cl)c1cc(Br)ccc1Cl
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(Br)ccc2Cl)n1
Temperature: 150 °C
Yield: 26 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.05 g, 0.154 mmol) in anhydrous acetonitrile (10.0 mL) under N2, was added 5-bromo-2-chlorobenzoyl chloride (0.134 g, 0.529 mmol) and triethylamine (1.0 mL, 13.6 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.021 g (26% yield) of pure product: MS (ES) m/z 523 (M+1).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH3:5].[C:8]1([CH2:14][CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:19][CH2:18]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[C:8]1([CH2:14][CH2:15][CH2:16][CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][C:25]([OH:31])([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:21][CH2:22]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCCCC(=O)CCN1CCC(CCCc2ccccc2)CC1
Reactant: CCCCC[Mg]Br
Solvent: C1CCOC1
Product: CCCCCC(O)(CCCCC)CCN1CCC(CCCc2ccccc2)CC1

Procedure:
1 equivalent of pentylmagnesium bromide was reacted with 1 equivalent of the compound obtained in Example 2, in anhydrous THF, under nitrogen, at room temperature. The product thus obtained was worked up and purified on a column of silica. The results of the NMR and mass spectrometry analyses were in accordance with the expected structure.
Reaction SMILES: C(Cl)(Cl)=O.[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]>>[C:13](=[O:14])([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Oc1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C(Cl)Cl
Product: O=C(Oc1ccccc1)Oc1ccccc1
Yield: 119.3 %

Procedure:
In a planar-section pot with flow spoilers, blower/stirrer and reflux condenser, 0.75 mol/h of phosgene was bubbled through 141 g (1.50 mol) of phenol in the presence of 14.1 g (10 wt. % w.r.t. phenol) of powdered H-SAPO 5. After about 2 hours reaction at 140° C., the phenol conversion was 7.1%, wherein 4.9 g of phenyl chloroformate and 8.0 g of diphenyl carbonate were formed. The selectivity to give the carbonate and phenyl chloroformate was greater than 99%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([CH3:24])([CH3:23])[C:18]([CH3:22])([CH3:21])[CH2:19][NH2:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[S:25]1[CH:29]=[CH:28][N:27]=[C:26]1[NH:30][C:31](=O)[O:32]C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(#N)C>CO.C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([CH3:24])([CH3:23])[C:18]([CH3:22])([CH3:21])[CH2:19][NH:20][C:31]([NH:30][C:26]4[S:25][CH:29]=[CH:28][N:27]=4)=[O:32])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Nc1nccs1)Oc1ccccc1
Reactant: CC(C)(CN)C(C)(C)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CC#N
Product: CC(C)(CNC(=O)Nc1nccs1)C(C)(C)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 80 °C
Yield: 29 %

Procedure:
A mixture of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,3-trimethylbutan-1-amine (10 mg, 0.031 mmol), phenyl thiazol-2-ylcarbamate (15 mg, 0.068 mmol), diisopropylethylamine (0.1 mL), and anhydrous acetonitrile (0.1 mL) was stirred under nitrogen at 80° C. till the reaction completed (ca 30 min) The mixture was dissolved in methanol and TFA. Purification using reverse phase HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA) gave the title compound (4 mg, 0.009 mmol, 29% yield) as a white solid. MS found: (M+H)+=452. 1H-NMR (400 MHz, CHLOROFORM-d) δ ppm 8.16 (s, 1 H) 7.79 (s, 1 H) 7.69 (dd, J=8.90, 4.83 Hz, 2 H) 7.60 (d, J=9.10 Hz, 1 H) 7.52 (dd, J=9.10, 1.70 Hz, 1 H) 7.21-7.31 (m, 3 H) 6.91 (d, J=4.07 Hz, 1 H) 5.56 (t, J=6.00 Hz, 1 H) 3.28 (d, J=6.10 Hz, 2 H) 1.52 (s, 6 H) 0.96 (s, 6 H).