Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.O[CH2:8][C:9]1[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=1[CH:11]=[CH:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.S(Cl)([Cl:27])=O>C(Cl)(Cl)Cl>[Cl:27][CH2:8][C:9]1[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=1[CH:11]=[CH:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCc1ccccc1C=CCOc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: ClCc1ccccc1C=CCOc1ccccc1
Reaction time: 1 h

Procedure:
47.4 g (0.6 mol) of pyridine was added to a solution which had been obtained by adding 500 ml of chloroform to 120 g (0.5 mol) of o-hydroxymethylphenoxy methylstyrene. 71.4 g (0.6 mol) of thionyl chloride was dropwise added to the mixture with stirring while keeping the temperature at 3° to 4° C. in an ice bath. The mixture was stirred at the same temperature for 1 hour and then at a temperature of 30° C. for 1 hour. After being washed with water, the mixture was dried by sodium sulfate. The chloroform was removed from by distillation under reduced pressure to obtain a yellow liquid as the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][N:10]([CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[CH2:9][CH2:8][NH:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]Br)=[CH:35][CH:34]=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][N:10]([CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH:39]([C:36]1[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=1)[C:46]1[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=1)=[O:5])[CH3:2]
Reactant: Fc1ccc(C(CCCCCBr)c2ccc(F)cc2)cc1
Reactant: CCOC(=O)C1CN(Cc2cc(OC)c(OC)c(OC)c2)CCN1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CN(Cc2cc(OC)c(OC)c(OC)c2)CCN1CCCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 1 h
Yield: 56 %

Procedure:
4-(3,4,5-trimethoxy-benzyl)-piperazine-2-carboxylic acid ethyl ester (2.0 g, 5.91 mmol) was dissolved in dry benzene (30 ml) followed by addition of triehylamine (0.65 g, 6.5 mmol) and resulting solution stirred for 1 hr. 1-[6,6-bis-(4-fluoro-phenyl)-hexyl bromide(2.08 g, 5.91 mmol) in dry benzene (30 ml) was added dropwise. The resulting mixture was stirred under nitrogen at room temperature overnight. The mixture was washed twice with water (30 ml) and dried over MgSO4 and evaporated. The crude product was purified by column chromatography using hexane:ethyl acetate (3:1) to give the desired product in 56% yield
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[C:14]([F:20])=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH2:28]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[C:29]1[O:33][CH:32]=[CH:31][CH:30]=1>CS(C)=O.C(N(CC)CC)C>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[C:14]([F:20])=[C:15]([N:37]5[CH2:38][CH2:39][N:34]([CH2:28][C:29]6[O:33][CH:32]=[CH:31][CH:30]=6)[CH2:35][CH2:36]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Reactant: c1coc(CN2CCNCC2)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(C2CC2)c2nc3c(F)c(N4CCN(Cc5ccco5)CC4)c(F)cc3cc2c1=O
Yield: 59.4 %

Procedure:
Ethyl 1-cyclopropyl-7,9-difluoro-8-(4-furfurylpiperazin-1-yl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate was prepared under the conditions of Example 3, but from 1.8 g of ethyl 1-cyclopropyl-7,8,9-trifluoro-4-oxo-1,4-dihydrobenzo-[b][1,8]naphthyridine-3-carboxylate and 4.8 g of 4-furfurylpiperazine hydrochloride in 30 cm3 of dimethyl sulphoxide and 5.2 cm3 of triethylamine. 1.5 g of ethyl 1-cyclopropyl-7,9-difluoro-8-(4-furfurylpiperazin-1-yl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate were obtained in the form of a yellow-brown solid melting at about 125-128° C., which solid was used without additional purification in the subsequent stages.
Reaction SMILES: CS([O:5][CH:6]([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8])(=O)=O.[C:13]1([C:19]2[CH:27]=[CH:26][CH:25]=[C:21]([C:22](O)=[O:23])[C:20]=2[OH:28])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:8][CH:7]([CH:6]([O:5][C:22]([C:21]1[CH:25]=[CH:26][CH:27]=[C:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:20]=1[OH:28])=[O:23])[CH:10]([CH3:12])[CH3:11])[CH3:9]
Reactant: O=C(O)c1cccc(-c2ccccc2)c1O
Reactant: CC(C)C(OS(C)(=O)=O)C(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(OC(=O)c1cccc(-c2ccccc2)c1O)C(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
In a four-neck flask having an inner volume of 100 ml, 4.86 g (25 m.mols) of (2,4-dimethyl-3-pentyl) methanesulfonate, 5.36 g (25 m.mols) of 3-phenylsalicylic acid, 2.65 g (25 m.mols) of sodium carbonate, and 50 ml of dimethyl formamide were placed and left reacting at 90° C. for three hours. After the reaction, the reaction mass was thrown into 100 ml of ice water and extracted twice with 150 ml of ethyl acetate. The organic layer obtained consequently was washed twice with 50 ml of water. Then, by distilling the organic layer thereby expelling the solvent by evaporation, 5.00 g (16 m.mols) of 2-(2,4-dimethyl-3-pentyloxy)carbonyl-6-phenylphenol was obtained as the product aimed at.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH2:10][C:11]1[N:12]=[N:13][CH:14]=[CH:15][CH:16]=1.I[CH3:19]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH:10]([C:11]1[N:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH3:19]
Reactant: O=C(Cc1cccnn1)c1ccc(F)cc1F
Reactant: CI
Product: CC(C(=O)c1ccc(F)cc1F)c1cccnn1
Yield: 64.3 %

Procedure:
Methylation of the product of part (i) (3.30 g) with iodomethane (5.0 g) according to the method of Example 11(ii) gave the title compound as a gum (2.25 g) which was used directly in the next stage.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH:19]([CH:25](OC)OC)[CH:20](OC)OC)[CH2:15][C@H:14]1[C@@H:13]([CH3:30])[S:12][C:11]([NH:31]C(=O)C1C=CC=CC=1)=[N:10]2.[CH3:40][NH:41][NH2:42].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>O.C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([C:19]3[CH:25]=[N:42][N:41]([CH3:40])[CH:20]=3)[CH2:15][C@H:14]1[C@@H:13]([CH3:30])[S:12][C:11]([NH2:31])=[N:10]2
Reactant: CNN
Reactant: COC(OC)C(C(OC)OC)[C@H]1C[C@H]2[C@@H](C)SC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@H]1SC(N)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](c3cnn(C)c3)C[C@@H]12
Temperature: 70 °C

Procedure:
N-[(4R,4aR,6R,8aS)-8a-(2,4-Difluorophenyl)-4-methyl-6-(1,1,3,3-tetramethoxypropan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C75) [prepared from P4 via a method similar to that used for the conversion of P1 to C44 in Preparation P3 and Example 5](297 mg, 0.526 mmol) was combined with ethanol (1.75 mL) and methyl hydrazine (36.4 mg, 0.789 mmol) followed by addition of water (0.6 mL). Concentrated sulfuric acid (55 μL, 1.0 mmol) was slowly added and the reaction mixture was heated at 70° C. for 18 hours. Saturated aqueous sodium bicarbonate solution was added, and the aqueous layer was extracted three times with ethyl acetate; the combined organic layers were extracted three times with 0.2 M aqueous hydrochloric acid, and the combined aqueous layers were washed with ethyl acetate. The pH was adjusted to 9-10 by addition of 1 M aqueous sodium hydroxide solution, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (Gradient: 0% to 15% methanol in dichloromethane) provided the product as an off-white solid. Yield: 109 mg, 0.287 mmol, 55%. LCMS m/z 379.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 7.48 (s, 1H), 7.36 (s, 1H), 7.22-7.28 (m, 1H), 6.85-6.92 (m, 2H), 4.57 (dd, J=11.3, 2.3 Hz, 1H), 4.16 (dd, J=11.1, 2.1 Hz, 1H), 3.76 (s, 3H), 3.69 (d, J=11.3, 1H), 3.01-3.06 (m, 1H), 2.78 (dt, J=11.9, 3.8 Hz, 1H), 1.75-1.80 (m, 1H), 1.59-1.68 (m, 1H), 1.10 (d, J=7 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[CH:15]([CH:17]=O)=[O:16].O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[CH:17][CH:15]=[O:16]
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=CC=O
Solvent: CC(=O)O
Solvent: O
Product: O=CC=NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2,6-dichloro-4-trifluoromethylphenylhydrazine (5 g) in acetic acid was added dropwise to a mixture of 40% aqueous glyoxal (50 ml) and water (400 ml). The mixture was stirred at room temperature for 2 hours and solid collected by filtration. A sample was recrystallised from ethanol to give 2-(2,6-dichloro-4-trifluoromethylphenylhydrazono)acetaldehyde, m.p. 131°-133°. This crude product (2.85 g) in ethanol (30 ml) was added to a solution of hydroxylamine hydrochloride (0.7 g) in water (10 ml), which had been neutralized with sodium acetate (0.82 g). The mixture was stirred at room temperature and then extracted with ethyl acetate. The extract was washed with brine, dried and evaporated to 2-(2,6-dichloro-4-trifluoromethylphenylhydrazono)acetaldehyde oxime. This was then treated with copper sulphate, in a similar manner to Example 1, to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole 1-oxide, m.p. 153°-154°, which in turn was treated with trimethyloxonium tetrafluoroborate and sodium methanethiolate, in a similar manner to Example 3, to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylthio-2H-1,2,3-triazole, m p. 100°-101°. (Compound 11)
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f18) and commercially methoxyacetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.S(=O)(=O)(O)O.[I:21]N1C(=O)CCC1=O>ClCCl.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([I:21])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc(-c2ccc(F)cc2)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: ClCCl
Product: Oc1cc(Cl)c(-c2ccc(F)cc2)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
2-Chloro-4′-fluorobiphenyl-4-ol (Preparation 73, 503 mg, 2.26 mmol) was dissolved in dichloromethane (5 mL) and acetic acid (5 mL). Concentrated sulfuric acid (0.05 mL) was added followed by N-iodosuccinimide (508 mg, 2.26 mmol) and the reaction stirred at room temperature for 2 hours before partitioning it between water and dichloromethane. The organic layer was separated and washed twice with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (20% ethyl acetate in heptane) to afford the title compound (553 mg, 70%) as an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH:14]([CH3:16])[CH3:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N+:17]([C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26]Br)=[C:22]([N:30]2[CH:34]=[CH:33][CH:32]=[CH:31]2)[CH:21]=1)([O-:19])=[O:18].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:17]([C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26][N:13]([CH2:12][CH2:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:14]([CH3:16])[CH3:15])=[C:22]([N:30]2[CH:34]=[CH:33][CH:32]=[CH:31]2)[CH:21]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(OCCBr)c(-n2cccc2)c1
Reactant: COc1ccc(CCNC(C)C)cc1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CCN(CCOc2ccc([N+](=O)[O-])cc2-n2cccc2)C(C)C)cc1OC
Temperature: 85 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
2-(3,4-Dimethoxyphenyl)-N-isopropylethylamine (2.4 g, 11 mmol) and 1-[4-nitro-2-(1H-pyrrol-1-yl)phenoxy]-2-bromoethane (3.04 g, 10 mmol) were dissolved in DMF and, thereafter, potassium iodide (1.61 g, 11 mmol) and anhydrous potassium carbonate (1.5 g, 10 mmol) were added and the mixture was stirred at 80-90° C. for 1 h; thereafter, ice water was added and extraction was conducted with ethyl acetate. The extracted organic layer was dried with magnesium sulfate and the solvent was evaporated; the resulting residue was purified by being subjected to column chromatography on silica gel using a 7:3:1 solvent system of cyclohexane, ethyl acetate and methanol as an eluent. The fractions containing the product were collected and the solvent was evaporated to yield the end compound 1-[4-nitro-2-(1H-pyrrol-1-yl)phenoxy]-2-[N-(3,4-dimethoxyphenethyl)-N-isopropylamino]ethane (0.9 g).
Reaction SMILES: [ClH:1].Cl.[CH:3]1(NC(C2C3C=C(C4C(F)=CN=C(NCCCC5CCN(C)CC5)N=4)SC=3C=CC=2)=O)CC1.[CH3:36][NH:37][C:38]([C:40]1[C:48]2[CH:47]=[C:46]([C:49]3[C:54]([Br:55])=[CH:53][N:52]=[C:51]([NH:56][CH2:57][CH2:58][CH:59]4[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]4)[N:50]=3)[S:45][C:44]=2[CH:43]=[CH:42][CH:41]=1)=[O:39]>>[ClH:1].[ClH:1].[CH3:36][NH:37][C:38]([C:40]1[C:48]2[CH:47]=[C:46]([C:49]3[C:54]([Br:55])=[CH:53][N:52]=[C:51]([NH:56][CH2:57][CH2:58][CH:59]4[CH2:60][CH2:61][N:62]([CH3:3])[CH2:63][CH2:64]4)[N:50]=3)[S:45][C:44]=2[CH:43]=[CH:42][CH:41]=1)=[O:39]
Reactant: CN1CCC(CCCNc2ncc(F)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Reactant: CNC(=O)c1cccc2sc(-c3nc(NCCC4CCNCC4)ncc3Br)cc12
Agent: Cl
Product: CNC(=O)c1cccc2sc(-c3nc(NCCC4CCN(C)CC4)ncc3Br)cc12

Procedure:
Using the method of 2-{5-fluoro-2-[3-(1-methylpiperidin-4-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound is synthesized from 2-[5-bromo-2-(2-piperidin-4-yl-ethylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid methylamide and isolated as a yellow solid. ES+(m/z) 488 (79Br) and 490 (81Br) [M(free base)+H].
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1N(C2C=C(C#N)SC=2)N=[C:8]([C:18]([F:21])([F:20])[F:19])[CH:7]=1.[Cl-].[C:23]([C:25]1[S:29][C:28]([NH2+:30][NH2:31])=[CH:27][CH:26]=1)#[N:24]>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:30]([C:28]2[S:29][C:25]([C:23]#[N:24])=[CH:26][CH:27]=2)[N:31]=[C:8]([C:18]([F:19])([F:20])[F:21])[CH:7]=1
Reactant: N#Cc1cc(-n2nc(C(F)(F)F)cc2-c2ccco2)cs1
Reactant: N#Cc1ccc([NH2+]N)s1
Agent: [Cl-]
Product: N#Cc1ccc(-n2nc(C(F)(F)F)cc2-c2ccco2)s1
Yield: 37 %

Procedure:
Following the same procedure as described for compound 14 (step 4, scheme 2, example 1c) except using 21 (278 mg, 1.58 mmol) instead of 13 to afford 22 (182 mg, 37%) as a beige solid. LRMS (ESI): calc. 309.1; found 310.1 (MH)+.
Reaction SMILES: BrC1C=CC(CC[OH:10])=C(C)C=1.[Br:12][C:13]1[CH:14]=[C:15]([CH2:23][CH3:24])[C:16]([CH:21]=[CH2:22])=[C:17]([CH2:19][CH3:20])[CH:18]=1.B1C2CCCC1CCC2>>[Br:12][C:13]1[CH:18]=[C:17]([CH2:19][CH3:20])[C:16]([CH2:21][CH2:22][OH:10])=[C:15]([CH2:23][CH3:24])[CH:14]=1
Reactant: Cc1cc(Br)ccc1CCO
Reactant: C=Cc1c(CC)cc(Br)cc1CC
Agent: B1C2CCCC1CCC2
Product: CCc1cc(Br)cc(CC)c1CCO
Yield: 58 %

Procedure:
Using a procedure analogous to that used to prepare 30B, 37B (1.2 g, 5 mmol) was heated in a pressure vessel with 9-BBN at 115° C. for 1 h to yield 37C (735 mg, 58%) as an orange oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.21 (t, J=7.58 Hz, 6 H) 2.66 (q, J=7.49 Hz, 4 H) 2.92 (t, J=7.58 Hz, 2 H) 3.66-3.77 (t, J=7.57 Hz, 2 H) 7.17 (s, 2 H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].[CH3:12][C:13]([CH3:20])([CH3:19])[C:14](=O)[CH2:15][C:16]#[N:17]>CCO.O>[C:13]([C:14]1[CH:15]=[C:16]([NH2:17])[N:10]([C:4]2[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=2[CH3:2])[N:11]=1)([CH3:20])([CH3:19])[CH3:12]
Reactant: Cc1ccc(NN)c(C)c1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N)c(C)c1
Yield: 36 %

Procedure:
To a heated solution of 2,4-dimethylphenylhydrazine hydrochloride (1.38 g, 8 mmol) in EtOH/water/1M NaOH (20 mL/12 mL/8 mL) at 50° C., 4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8 mmol) was added and the reaction heated until finished by LC-MS. The solution was partitioned between EtOAc and water, and extracted twice. The extracts were washed with brine, dried with magnesium sulfate, filtered, and concentrated. Purification using silica gel chromatography eluting with an EtOAC/hexane gradient (5-20%) gave 3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-amine (700 mg, 36% yield). 1H NMR (300 MHz, DMSO d6) δ 1.09 (s, 9H), 1.98 (s, 3H), 2.32 (s, 3H), 4.76 (s, 2H), 5.26 (s, 1H), 7.11 (m, 3H). LC-MS (ESI) m/z 244 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22][CH2:23][C:24](OC(C)(C)C)=O)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.C(OC(=O)CN)(C)(C)C.N[C:48]1[CH:53]=CC=[CH:50][CH:49]=1>>[NH:22]([C:20]([C@H:19]([NH:18][C:16]([N:13]1[C:14](=[O:15])[CH:8]([CH2:7][C:6]2[CH:34]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:35][CH3:36])[CH2:9][NH:10][C:11](=[O:33])[CH2:12]1)=[O:17])[CH2:31][CH3:32])=[O:21])[C:23]1[CH:50]=[CH:49][CH:48]=[CH:53][CH:24]=1
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Reactant: Nc1ccccc1
Agent: CC(C)(C)OC(=O)CN
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)Nc1ccccc1

Procedure:
Instead of the starting material compound of Example 220, that is, glycine tert-butyl ester hydrochloride, aniline was used for the similar procedure as in Example 220 to obtain the title compound.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][C:2]1=[O:12].C[Si](C)(C)N[Si](C)(C)C.[I:22]I.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[I:22][CH:3]1[CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:1][C:2]1=[O:12]
Reactant: II
Reactant: O=C1CCCc2ccccc2N1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C1Nc2ccccc2CCC1I
Temperature: 30 °C
Yield: 57.5 %

Procedure:
A suspension of 1.8 Kg (11.17mol) of 2,3,4,5-tetrahydro-1H-1-benzazepin-2-one in a mixture of 22.33 L of methylene chloride and 11.78 L (55.83 mol) of hexamethyldisilazane was heated at reflux for 10 minutes, then cooled to 30° C. and treated with 8.503 Kg (33.5 mol) of iodine in one portion. The mixture was heated at reflux for 2.5 hours, then cooled to room temperature. Aqueous sodium sulfite containing 4.926 Kg of sodium sulfite in 44 L of water was cooled to 0° C. and into it was poured the reaction mixture in several portions with vigorous stirring while maintaining the temperature below 10° C. The reaction vessel was rinsed with 22.33 L of methylene chloride and the washing transferred to the quenching mixture. The quenching mixture was stirred vigorously and the layers allowed to separate. The aqueous layer was removed and reextracted with 22.33 L of methylene chloride. The combined organic layers were washed with 11 L of water and concentrated under vacuum to a final volume of approximately 5 L. The residue was treated with 55 L of toluene and concentrated under vacuum to a final volume of 10 L. The resulting slurry was isolated by filtration and the filter cake washed with an additional 5 L of toluene and dried under vacuum at ambient temperature for 24 hours to give 1.842 Kg (6.42 mol, 57%) of product. 1H NMR (200 MHz, CDCl3): δ 2.6-2.8 (m, 3H), 2.93 (m, 1H), 4.64 (t, 8 Hz, 1H), 6.97 (d, 8 Hz, 1H), 7.10-7.35 (m, 3H), 7.55 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][CH2:13][OH:14])[C:5]=2[CH2:4][O:3]1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1COCC1.CCOC(C)=O>[CH3:16][S:17]([O:14][CH2:13][CH2:12][C:11]1[C:5]2[CH2:4][O:3][C:2]([CH3:15])([CH3:1])[O:7][C:6]=2[CH:8]=[CH:9][CH:10]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OCc2c(CCO)cccc2O1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OCc2c(CCOS(C)(=O)=O)cccc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of 2-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-5-yl)ethanol (400 mg, 1.92 mmol, 1 eq.) in THF (20 mL) were added MsCl (438 mg, 3.84 mmol, 2.0 eq.) and TEA (0.8 mL, 5.76 mmol, 3.0 eq.) at rt. The mixture was stirred at rt for 1 h and diluted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated to give 2-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-5-yl)ethyl methanesulfonate (400 mg, crude) as a pale brown oil, which was used for next step without purification.
Reaction SMILES: Cl.[C:2]1([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]3[O:24][CH2:23][CH2:22][C@@H:21]4[C@H:16]([O:17][CH2:18][CH2:19][NH:20]4)[C:14]=3[CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([N:20]1[CH2:19][CH2:18][O:17][C@@H:16]2[C:14]3[CH:15]=[C:10]([O:9][CH2:8][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:11]=[CH:12][C:13]=3[O:24][CH2:23][CH2:22][C@@H:21]12)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: c1ccc(COc2ccc3c(c2)[C@H]2OCCN[C@@H]2CCO3)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCO[C@@H]2c3cc(OCc4ccccc4)ccc3OCC[C@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3.47 g of trans-10-phenylmethoxy-3,4,4a,5,6,11b-hexahydro-2H-[1]benzoxepino[5,4-b]-1,4-oxazine hydrochloride, 50 ml of triethylamine and 25 ml of methylene chloride is cooled in ice and 1.0 ml of acetyl chloride dissolved in 25 ml of methylene chloride is added dropwise thereto. The solution is stirred overnight at room temperature, washed with a dilute hydrochloric acid solution and dried over anhydrous magnesium sulfate. The drying agent is removed via filtration and the filtrate evaporated to yield trans-4-acetyl-10-phenylmethoxy-3,4,4a,5,6,11b-hexahydro-2H-[1]benzoxepino[5,4-b]-1,4-oxazine as an oil.