Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[C:9]([O:13][C:14]([N:16]1[C:24]2[C:19](=[C:20]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=3[F:36])[C:21]([N+:25]([O-])=O)=[CH:22][CH:23]=2)[CH:18]=[N:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1COCC1.C(=O)([O-])O.[Na+]>O.O1CCOCC1>[C:9]([O:13][C:14]([N:16]1[C:24]2[C:19](=[C:20]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=3[F:36])[C:21]([NH2:25])=[CH:22][CH:23]=2)[CH:18]=[N:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)n1ncc2c(Nc3ccc(I)cc3F)c([N+](=O)[O-])ccc21
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)n1ncc2c(Nc3ccc(I)cc3F)c(N)ccc21
Reaction time: 20 h
Yield: 115.6 %

Procedure:
A suspension of sodium dithionite (978 mg, 4.21 mmol) and 4-(2-fluoro-4-iodo-phenylamino)-5-nitro-indazole-1-carboxylic acid tert-butyl ester (700 mg, 1.4 mmol) in water (35 mL) was treated with a 1:1 mixture of THF:dioxane (34 mL), the homogeneous reaction mixture stirred at room temperature for 4 hours. Further sodium dithionite (978 mg, 4.21 mmol) was added and stirring continued for 20 hours. The reaction mixture was basified by the addition of saturated aqueous sodium hydrogen carbonate and then extracted with ethyl acetate (150 mL). The organic extract was washed with water, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a yellow solid (758 mg, quant.). LCMS (Method B) RT=4.09 min, [M+H]+=469.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Br:9])[CH:5]=[CH:6][C:7]=1I.CCCCCC.C([Li])CCC.FC(F)(F)S(O[Si:27]([CH3:30])([CH3:29])[CH3:28])(=O)=O>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([Br:9])[CH:5]=[CH:6][C:7]=1[Si:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Clc1cc(Br)ccc1I
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: C[Si](C)(C)c1ccc(Br)cc1Cl
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
3-chloro-4-iodobromobenzene (3.1 g) was dissolved in diethyl ether (100 ml). To the solution was then added dropwise a hexane solution of n-butyl lithium (1.59 M, 6.1 ml) at −78° C. The mixture was then stirred at the same temperature for 30 minutes. To the mixture was then added dropwise trimethylsilyl trifluoromethane sulfonate (3.77 ml; 17.4 mmol). The mixture was then stirred for 1 hour. After the quenching of the reaction by gradually adding water over an ice bath, the product was then extracted with ether. The resulting organic phase was then dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The crude product thus obtained was then purified twice through silica gel column chromatography (silica gel produced by Merck Ltd., Japan; hexane) to obtain 3-chloro-4-trimethylsilyl-bromobenzene (2.3 g) (yield: 90%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[N:8]1.[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[F:31][C:17]([F:16])([F:30])[C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=[N:8]3)[CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1
Reactant: ClCCCCCn1nnc2ccccc21
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1cccc(N2CCN(CCCCCn3nnc4ccccc43)CC2)c1
Temperature: 25 °C
Yield: 61.5 %

Procedure:
1-(5-chloropentyl)-1H-benzotriazole (8.0 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-trifluoro methylphenylpiperazine (6.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 7.7 g compound (I-42) with a yield of 61.5%. ESI-MS [M+H]+: m/z 417.2.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.[C:12]([N:31]1[CH:35]=[C:34]([C:36]([OH:38])=O)[N:33]=[CH:32]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.CN(C)CCCN=C=NCC.Cl.[NH2:52][CH2:53][C:54]1[CH:79]=[CH:78][C:57]([CH2:58][O:59][C:60]2[CH:65]=[CH:64][C:63]([C:66](=[O:72])[CH2:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[C:62]([OH:73])[C:61]=2[C:74]([F:77])([F:76])[F:75])=[CH:56][CH:55]=1.C(N(CC)CC)C>C(#N)C>[CH3:69][C:68]([CH3:71])([CH3:70])[CH2:67][C:66]([C:63]1[CH:64]=[CH:65][C:60]([O:59][CH2:58][C:57]2[CH:78]=[CH:79][C:54]([CH2:53][NH:52][C:36]([C:34]3[N:33]=[CH:32][N:31]([C:12]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:35]=3)=[O:38])=[CH:55][CH:56]=2)=[C:61]([C:74]([F:75])([F:76])[F:77])[C:62]=1[OH:73])=[O:72]
Reactant: O=C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)(C)CC(=O)c1ccc(OCc2ccc(CN)cc2)c(C(F)(F)F)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CC(C)(C)CC(=O)c1ccc(OCc2ccc(CNC(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)cc2)c(C(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
Add 1-hydroxybenzotriazole hydrate (63.8 mg; 417 μmol), 1-trityl-1H-imidazole-4-carboxylic acid (148 mg, 417 μmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (79.9 mg, 417 μmol) to anhydrous acetonitrile (7 mL). Stir the reaction mixture at room temperature for 1 hr. Then add 1-[4-(4-aminomethyl-benzyloxy)-2-hydroxy-3-trifluoromethyl-phenyl]-3,3-dimethyl-butan-1-one hydrochloride (150 mg, 347 μmol) and triethylamine (97 μL, 695 μmol). Stir the reaction mixture at room temperature overnight. Quench the reaction with water and the solid, filter the solid and dry to give the title compound (220 mg, 301 μmol). MS (m/z): 730 (M−1).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:17](=O)[C:16](=O)[N:15]3[C@@H:10]([CH2:11][O:12][CH2:13][CH2:14]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]1([CH2:7][N:8]2[CH2:17][CH2:16][N:15]3[C@@H:10]([CH2:11][O:12][CH2:13][CH2:14]3)[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C(=O)N2CCOC[C@H]2CN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CN2CCN3CCOC[C@H]3C2)cc1
Temperature: 70 °C
Yield: 79.4 %

Procedure:
To a 0° C. solution of (9aR)-8-(phenylmethyl)hexahydropyrazino[2,1-c][1,4]oxazine-6,7-dione (2.5610 g, 9.84 mmol) in THF (100 mL) was added LiAlH4 (1.12 g, 29.51 mmol) portionwise. The mixture was heated at 70° C. and stirred for 1 week. The mixture was then cooled to 0° C. and quenched by addition of Na2SO4.10H2O (2 g) followed by 1 N aq. NaOH (100 mL). The mixture was extracted with Et2O (2×150 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in DCM (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by gradient silica gel chromatography (0% to 100% EtOAc in hexanes; 1% Et3N) to give (9aR)-8-(phenylmethyl)octahydropyrazino[2,1-c][1,4]oxazine (1.8147 g, 79%) as a colorless oil. LCMS: (M+H)+: 233.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:17][C:18]1[C:27]([CH2:28][C:29](Cl)=[O:30])=[C:26]([F:32])[CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[N:23]2>CN(C)C=O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH:9][C:29](=[O:30])[CH2:28][C:27]2[C:18]([F:17])=[C:19]3[C:24](=[CH:25][C:26]=2[F:32])[N:23]=[CH:22][CH:21]=[CH:20]3)=[CH:4][CH:3]=1
Reactant: NNc1ccc(Cl)nn1
Reactant: O=C(Cl)Cc1c(F)cc2ncccc2c1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cc1c(F)cc2ncccc2c1F)NNc1ccc(Cl)nn1

Procedure:
(6-Chloro-pyridazin-3-yl)-hydrazine (531 mg, 3.67 mmol) was added to an oven-dried round-bottom flask and dissolved in dimethylformamide (7 mL) and triethylamine (1.54 ml, 11.01 mmol). The solution was cooled to 0° C. (5,7-Difluoro-quinolin-6-yl)-acetyl chloride (887 mg, 3.67 mmol) was dissolved in dimethylformamide (8 mL) and added to the reaction mixture dropwise. The reaction was complete upon addition of the acid chloride. The solution was concentrated down under vacuo to dryness to afford (5,7-difluoro-quinolin-6-yl)-acetic acid N′-(6-chloro-pyridazin-3-yl)-hydrazide. LCMS [M+H+]=350.0. (5,7-Difluoro-quinolin-6-yl)-acetic acid N′-(6-chloro-pyridazin-3-yl)-hydrazide (1.28 g, 3.67 mmol) was suspended in acetic acid (30 mL) and the solution heated to 60° C. for 16 hours. The mixture was then concentrated in vacuo and the residue dissolved in dichloromethane (125 ml) and washed with saturated NaHCO3 (100 ml) and brine (100 ml). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting solid was triturated with methanol and the title compound was collected in quantitative via filtration and dried. Analytical data presented in Table 1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([NH:23][C:24]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:27]=2)=[O:25])[CH:20]=[CH:21][CH:22]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[CH:27]=2)=[O:25])[CH:18]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1cccc(NC(=O)c2ccnc(N3CCOCC3)c2)c1
Product: COc1cc2ncnc(Nc3cccc(NC(=O)c4ccnc(N5CCOCC5)c4)c3)c2cc1OC
Yield: 33 %

Procedure:
Using an analogous procedure to that described in Example 26, 4-chloro-6,7-dimethoxyquinazoline was reacted with N-(3-aminophenyl)-2-morpholinopyridine-4-carboxamide. The material so obtained was purified by column chromatography eluting with 96:3:1 methylene chloride/methanol/saturated aqueous ammonium hydroxide. The material so obtained was triturated under methylene chloride to give the title compound in 33% yield; NMR: 3.51 (m, 4H), 3.71 (m, 4H), 3.93 (s, 3H), 3.96 (s, 3H), 7.11 (d, 1H), 7.18 (s, 1H), 7.24 (s, 1H), 7.35 (m, 1H), 7.44 (d, 1H), 7.57 (d, 1H), 7.86 (s, 1H), 8.23 (s, 1H), 8.29 (d, 1H), 8.46 (s, 1H), 9.49 (s, 1H), 10.34 (s, 1H); Mass: M+H+ 487.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([C:14]2[CH2:18][CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[N:15]=2)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.C[CH2:40][N:41](C(C)C)C(C)C>ClCCl.CN.ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([C:14]2[CH2:18][CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[N:15]=2)=[N:41][CH3:40])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(NS(=O)(=O)c1ccc(Cl)cc1)C1=NN(c2ccc(Cl)cc2)C(c2ccccc2)C1
Agent: CN
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Solvent: ClCCl
Product: CN=C(NS(=O)(=O)c1ccc(Cl)cc1)C1=NN(c2ccc(Cl)cc2)C(c2ccccc2)C1
Temperature: 140 °C
Yield: 14.8 %

Procedure:
Part B: A stirred mixture of N-[(4-chlorophenyl)sulfonyl]-1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide (2.36 gram, 5 mmol), PCl5 (1.15 g, 5.5 mmol) and chlorobenzene (50 ml) is heated for 90 minutes at 140° C. After cooling the mixture to room temperature the residue is dissolved in dichloromethane and methylamine.HCl (0.34 g, 5 mmol) and DIPEA (1.74 ml, 10 mmol) are successively added. The resulting mixture is stirred for 16 hours at room temperature, twice washed with water, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue is further purified by flash chromatography (silica gel, dichloromethane/acetone=99/1 (v/v/), followed by crystallization from diisopropyl ether to give N-[(4-chlorophenyl)sulfonyl]-N′-methyl-1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamidine (0.36 gram, 15% yield). Melting point: 134-144° C. Rf (silica gel, diethyl ether=0.4).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=O)[CH2:11][CH2:12][CH:13]1[CH2:16][CH:15]([N:17]([CH2:19][C@@H:20]2[C@@H:27]3[C@@H:23]([O:24][C:25]([CH3:29])([CH3:28])[O:26]3)[C@H:22]([N:30]3[C:34]4[N:35]=[CH:36][N:37]=[C:38]([NH:39][CH2:40][C:41]5[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][C:42]=5[O:49][CH3:50])[C:33]=4[CH:32]=[CH:31]3)[CH2:21]2)[CH3:18])[CH2:14]1.C(O)(=O)C>>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[NH:9][C:10]([CH2:11][CH2:12][CH:13]3[CH2:14][CH:15]([N:17]([CH2:19][C@@H:20]4[C@H:27]5[O:26][C:25]([CH3:28])([CH3:29])[O:24][C@H:23]5[C@H:22]([N:30]5[C:34]6[N:35]=[CH:36][N:37]=[C:38]([NH:39][CH2:40][C:41]7[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][C:42]=7[O:49][CH3:50])[C:33]=6[CH:32]=[CH:31]5)[CH2:21]4)[CH3:18])[CH2:16]3)=[N:1][C:2]=2[CH:7]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCC(=O)Nc4ccc(Br)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: CC(=O)O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCc4nc5cc(Br)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1

Procedure:
A solution of N-(2-amino-4-bromophenyl)-3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanamide (1.2 g, 1.6 mmol) in Acetic acid (4 ml, 70 mmol) was stirred overnight at 60° C., the volatiles were removed in vacuo and remaining residue purified directly by flash chromatography (DCM/7N NH3 in MeOH 91:9) to give (0.9 g) as a foam.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:30](O)(=[O:34])[C:31]([CH3:33])=[CH2:32]>>[C:30]([O:12][C:10]1[CH:11]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:7])=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:9]=1)(=[O:34])[C:31]([CH3:33])=[CH2:32]
Reactant: C=C(C)C(=O)O
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C=C(C)C(=O)Oc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
3,5-di tert.butyl-4-hydroxyphenyl methacrylate was prepared by stirring a mixture of 16.3 grams of 2,6-di tert.butyl hydroquinone, 18.5 grams of trifluoroacetic acid anhydride, and 8.2 grams of methacrylic acid for 3 hours at room temperature. The product, which has precipitated during the course of the reaction, was filtered off, washed first with dilute sodium carbonate solution, then with water, and then dried. After recrystallization from hexane, there was obtained 10 grams of product melting at 138° C. to 139° C.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:9][C:10]1[C:15](B(O)O)=[CH:14][CH:13]=[CH:12][N:11]=1.Br[C:20]1[CH:33]=[CH:32][C:31]2[O:30][C:29]3[C:24](=[CH:25][C:26]([O:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:27][CH:28]=3)[C@@:23]3([N:44]=[C:43]([NH2:45])[CH2:42][O:41][CH2:40]3)[C:22]=2[CH:21]=1.O>O1CCOCC1>[CH3:37][C:36]([CH3:39])([CH3:38])[CH2:35][O:34][C:26]1[CH:27]=[CH:28][C:29]2[O:30][C:31]3[C:22](=[CH:21][C:20]([C:15]4[C:10]([F:9])=[N:11][CH:12]=[CH:13][CH:14]=4)=[CH:33][CH:32]=3)[C@:23]3([N:44]=[C:43]([NH2:45])[CH2:42][O:41][CH2:40]3)[C:24]=2[CH:25]=1
Reactant: CC(C)(C)COc1ccc2c(c1)[C@]1(COCC(N)=N1)c1cc(Br)ccc1O2
Reactant: OB(O)c1cccnc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)COc1ccc2c(c1)[C@]1(COCC(N)=N1)c1cc(-c3cccnc3F)ccc1O2
Temperature: 135 °C

Procedure:
In a microwave vessel, potassium phosphate (0.012 g, 0.056 mmol), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (0.985 mg, 1.391 μmol) and 2-fluoropyridin-3-ylboronic acid (5.23 mg, 0.037 mmol) were loaded as solids, and (3R)-2′-bromo-7′-(2,2-dimethylpropoxy)-6H-spiro[1,4-oxazine-3,9′-xanthen]-5-amine (0.008 g, 0.019 mmol) was added via cannula as a solution in dioxane (1 mL). Water (0.25 mL) was added to the vessel, and the mixture was purged with argon gas, then the vessel was sealed and heated in microwave radiation at 135° C. for 30 min. The material was taken up in water (10 mL) and the aqueous phase was extracted with DCM (3×20 mL). The organics were combined, washed with dilute brine (5 mL), dried over sodium sulfate, and concentrated. The material was purified by preparative TLC (13% MeOH/DCM) to afford (3S)-2′-(2,2-dimethylpropoxy)-7′-(2-fluoro-3-pyridinyl)-6H-spiro[1,4-oxazine-3,9′-xanthen]-5-amine.
Reaction SMILES: [CH:1]1([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.BrBr.C1C(=O)N([Br:30])C(=O)C1>C(#N)C>[Br:30][C:13]1[C:8]([O:7][CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:9][CH:10]=[C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)CCc1ccc(OCC2CCCC2)nc1
Agent: BrBr
Solvent: CC#N
Product: CCOC(=O)CCc1cnc(OCC2CCCC2)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
A solution of Intermediate 31 (5.20 g) in acetonitrile (50 ml) was warmed to 35° C., added dropwise with bromine (1.1 ml, WAKO), then added with NBS (3.72 g), and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, then added with ethyl acetate (200 ml), and washed successively with saturated aqueous ammonium chloride, 5% aqueous sodium sulfite, saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate=10:1) to obtain the title compound (Compound No. E-1, 6.51 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:3]1.[CH2:23](Br)[CH:24]=[CH2:25].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.ClCCl.CN(C)C=O>[CH2:25]([N:19]1[CH2:18][CH2:17][N:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:4]2[CH2:3][C:2]([CH3:22])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]2)[CH2:21][CH2:20]1)[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCN1CCN(c2ccccc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
A mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (30 mg, 0.1 mmol) produced in Example (8b), allyl bromide (14.8 mg, 0.12 mmol), potassium carbonate (20.8 mg, 0.15 mmol) and dimethylformamide (1 mL) was stirred for 4 hours and 20 minutes at an external temperature of 80° C. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate-dichloromethane. The separated organic layer was washed with water, and then the solvent was distilled off by nitrogen stream. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-allyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[CH:6]=1)=O>FC(F)(F)C(O)=O.C([SiH](CC)CC)C>[Cl:1][CH2:2][CH2:3][C:5]1[CH:14]=[CH:13][C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[CH:6]=1
Reactant: O=C(CCl)c1ccc2c(c1)OCCO2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: ClCCc1ccc2c(c1)OCCO2
Yield: 89.9 %

Procedure:
A solution of 2-chloro-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethanone (0.5 g) in trifluoroacetic acid/triethylsilane (4 ml/1.3 ml) was stirred overnight then partitioned between dichloromethane and dilute aqueous sodium bicarbonate solution. The organic extract was dried and evaporated to give a brown oil (0.42 g) This was chromatographed on silica eluting with a dichloromethane/petroleum ether gradient affording the product as a clear oil (0.23 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[O:8]C.N.OO.[CH3:14][C:15]1[C:20]([CH3:21])=[C:19]([NH2:22])[CH:18]=[CH:17][C:16]=1[OH:23]>O.CC(C)=O>[NH2:1][C:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([OH:23])=[C:15]([CH3:14])[C:20]=2[CH3:21])[C:4](=[O:10])[CH:3]=1
Reactant: COc1ccc(O)cc1N
Reactant: Cc1c(N)ccc(O)c1C
Agent: N
Agent: OO
Solvent: CC(C)=O
Solvent: O
Product: Cc1c(O)ccc(NC2=CC(=O)C(N)=CC2=O)c1C
Reaction time: 3 h

Procedure:
0.01 mole (1.39 g) of 3-amino-4-methoxy phenol is dissolved in 100 cc of water to which have been added 50 cc of acetone and 10 cc of ammonia (22° Be). To this solution there are added 100 cc of H2O2 (20 volumes) and immediately thereafter, with good agitation, 0.01 mole (1.37 g) of 2,3-dimethyl-4-amino phenol in suspension in 100 cc of water. The resulting reaction mixture is agitated for three hours at which time it is filtered to recover the 2-amino-5-(4'-hydroxy-2',3'-dimethyl anilino)-1,4-benzoquinone which is first washed with water and then with acetone. It is dried for 8 hours under a vacuum with a boiling water bath and is chromatographically pure, melting at 320° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:45])[CH2:3][N:4]([C:26]([C:28]1[N:29]([CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C@H:5]1[CH2:10][C@@H:9]([C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1.C(OCC)(=O)C.[ClH:52]>>[ClH:52].[CH3:1][CH:2]([CH3:45])[CH2:3][N:4]([C@H:5]1[CH2:10][C@@H:9]([C:11]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[O:12])[CH2:8][NH:7][CH2:6]1)[C:26]([C:28]1[N:29]([CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27]
Reactant: CC(C)CN(C(=O)c1cc2ccccc2n1CCc1ccccc1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)CN(C(=O)c1cc2ccccc2n1CCc1ccccc1)[C@@H]1CNC[C@H](C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
tert-Butyl (3S,5R)-3-[(2-methylpropyl){[1-(2-phenylethyl)-1H-indol-2-yl]carbonyl}amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (83 mg) was dissolved in 4M hydrogen chloride-ethyl acetate (2 ml), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated to give the object product (75 mg).
Reaction SMILES: [C:1]([CH:3]([NH:13][C:14]([CH:16]1[CH2:18][CH2:17]1)=O)[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:39]>C(#N)C>[Cl:39][C:1]1[N:2]=[C:14]([CH:16]2[CH2:18][CH2:17]2)[NH:13][C:3]=1[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: N#CC(COCc1ccccc1)NC(=O)C1CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Clc1nc(C2CC2)[nH]c1COCc1ccccc1
Reaction time: 0.17 h
Yield: 51.8 %

Procedure:
A solution of N-{1-cyano-2-[(phenylmethyl)oxy]ethyl}cyclopropanecarboxamide (1.84 g, 7.5 mmol), triphenylphosphine (4.8 g, 18.3 mmol), and carbon tetrachloride (1.9 mL, 19.7 mmol) in acetonitrile (74 mL) was heated at 45° C. for 6 h. The reaction was concentrated and the residue was stirred in CH2Cl2 (80 mL) and 0.5 N NaOH (70 mL) for 10 min. The organic layer was isolated, dried (Na2SO4), filtered, concentrated and the residue was purified by silica gel flash column chromatography (5-50% EtOAc:hexanes) to give the title compound (1.02 g, 52%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 10.90 (br. s., 1H), 7.26-7.36 (m, 5H), 4.50 (s, 2H), 4.47 (s, 2H), 1.74-1.84 (m, 1H), 0.81-0.95 (m, 4H).