Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[C:4](=[N:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH3:16])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:18][C:19]([NH2:21])=[S:20].C([O-])(=O)C.[Na+].C(O)C>O>[ClH:1].[NH2:21][C:19]1[S:20][CH:2]=[C:3]([C:4](=[N:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH3:16])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:18]=1
Reactant: CCOCCON=C(C(=O)CCl)C(=O)OCC
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOCCON=C(C(=O)OCC)c1csc(N)n1
Product: Cl
Temperature: 40 °C
Reaction time: 5 h
Yield: 33.4 %

Procedure:
A mixture of ethyl 4-chloro-2-(2-ethoxyethoxyimino)-3-oxobutyrate (syn isomer, 56.5 g.), thiourea (19.4 g.), sodium acetate (20.9 g.), ethanol (140 ml.) and water (140 ml.) was stirred at 40° C. for 5 hours. After removing the ethanol from the resultant solution in vacuo, the aqueous solution was adjusted to pH 6.5 with aqueous sodium bicarbonate and then extracted with ethyl acetate. Conc. hydrochloric acid was added to the stirred ethyl acetate extract under ice-cooling to form the precipitates. The precipitates were collected by filtration washed with chilled water and diethyl ether in turn and dried over phosphorus pentoxide under reduced pressure to give ethyl 2-(2-aminothiazol-4-yl)-2-(2-ethoxyethoxyimino)acetate hydrochloride (syn isomer, 23 g.).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1)=[O:3].[I-:14].[CH3:15][N+:16](=[CH2:18])[CH3:17].Cl>C(O)C>[IH:14].[CH3:15][N:16]([CH3:18])[CH2:17][CH2:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=1)=[O:3]
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Reactant: [I-]
Reactant: C=[N+](C)C
Agent: Cl
Solvent: CCO
Product: CN(C)CCC(=O)c1cccc(C(F)(F)F)c1
Product: I
Yield: 71.6 %

Procedure:
A mixture of 1-(3-(trifluoromethyl)phenyl)ethanone (5.0 g) (II), N-methyl-N-methylenemethanaminium iodide (5.4 g), 31% w/w aqueous hydrochloric acid (0.1 mL) in ethanol (7 mL) was stirred at reflux temperature for 24 hrs, then cooled down and the solvent flushed with toluene (50 mL). The precipitated pale yellow solid was then filtrated, washed with toluene and dried to give the title compound (IV) (7.1 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:29])=[C:16]([C:24](OCC)=[O:25])[C:17](=[O:23])[C:18]2([CH3:22])[CH3:21])=[CH:13][CH:12]=1.Cl.[NH2:31][C@@H:32]([CH3:40])[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>O1CCOCC1>[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:29])=[C:16]([C:24]([NH:31][C@H:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH3:40])=[O:25])[C:17](=[O:23])[C:18]2([CH3:21])[CH3:22])=[CH:13][CH:12]=1
Reactant: CCOC(=O)C1=C(O)c2ccc(Br)cc2C(C)(C)C1=O
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)C1=C(O)c2ccc(Br)cc2C(C)(C)C1=O)C(=O)OC(C)(C)C
Temperature: 75 °C
Reaction time: 16 h
Yield: 67.9 %

Procedure:
DIPEA (120 μL, 690 μmol, 1.5 eq) was added to a mixture of ethyl 7-bromo-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-carboxylate (156 mg, 460 μmol, prepared in Example 53A-D) and (S)-tert-butyl 2-aminopropanoate hydrochloride (100 mg, 552 μmol) in dioxane (5 mL). The reaction mixture was stirred at 75° C. for 16 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (MgSO4), and concentrated in vacuo to give a yellow oil. The crude oil was purified by silica flash chromatography (0-50% DCM/hexane) to give the desired ester as a transparent oil (137 mg). MS (m/e)=382.1 (M+H-tBu)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[NH:15][C:14]2=O)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].P(Cl)(Cl)([Cl:27])=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]2[Cl:27])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
using methyl 2-chloro-5-[3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzoate with phosphorus oxychloride and pyridine within 7 hours at room temperature there is obtained methyl 2-chloro-5-[2-chloro-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-4-fluorobenzoate, m.p. 89°-91° C.;
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=O)[CH3:9])[CH:5]=[CH:4][CH:3]=1.[CH2:11]([C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[C:14]=1[NH2:15])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1.[Cl-].[Cl-].[Ca+2]>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[N:15][C:14]2[C:16]([CH2:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:13]=2[CH2:11][CH3:12])[CH3:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CCc1cccc(CC)c1N
Reactant: CC(=O)c1cccc(Br)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCc1cccc(CC)c1N=C(C)c1cccc(Br)n1
Temperature: 25 °C

Procedure:
In argon atmosphere, a mixture of 6.00 g (30.0 mmol) of 1-(6-bromopyridin-2-yl)ethanone, 4.69 g (31.5 mmol) of 2,6-diethylaniline, 50 mg of TsOH, and 300 ml of toluene was refluxed for 2-3 h using a Soxhlet apparatus with an extraction thimble filled with anhydrous CaCl2. The reaction mixture was cooled to ambient temperature, passed through a short layer of silica gel 60 (40-63 um), and then evaporated to dryness. The crude product was recrystallized from 50 ml of methanol. Yield 6.20 g (63%) of a yellow crystalline solid. Anal. calc. for C17H19BrN2: C, 61.64; H, 5.78, N, 8.46. Found: C, 61.83; H, 5.88, N, 8.39. 1H NMR (CDCl3): δ 8.32 (dd, J=7.8 Hz, J=0.7 Hz, 1H, 3-H in pyridine), 7.65 (t, J=7.8 Hz, 1H, 4-H in pyridine), 7.57 (dd, J=7.8 Hz, J=0.7 Hz, 1H, 5-H in pyridine), 7.09-7.11 (m, 2H, 3, 5-H in 2, 6-Et2C6H3), 7.02 (m, 1H, 4-H in 2, 6-Et2C6H3), 2.33 (m, 4H, CH2Me), 2.16 (s, 3H, CH3C═N), 1.11 (t, J=7.6 Hz, 6H, CH2Me).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[S:21]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)(=[O:23])=[O:22])=[CH:7][CH:8]=1)[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CCc1ccc([C@@H]2CCCN2)cc1
Product: CCc1ccc(C2CCCN2S(=O)(=O)c2ccc(F)cc2)cc1

Procedure:
The title compound, white solid, m.p. 93° C. and MS: m/e=334.2 (M+H+) was prepared in accordance with the general method of example 1e from (S)-2-(4-ethyl-phenyl)-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Reaction SMILES: CO[C:3]1[CH2:4][CH:5]([CH3:26])[CH:6]([CH2:8][CH2:9][CH2:10][CH:11]([NH:18]C(=O)OC(C)(C)C)[CH:12]2[CH2:16][O:15][C:14](=[O:17])[O:13]2)[N:7]=1.[Cl-:27].[NH4+:28].Cl.CCOC(C)=O>CO>[ClH:27].[ClH:27].[NH2:18][CH:11]([CH:12]1[CH2:16][O:15][C:14](=[O:17])[O:13]1)[CH2:10][CH2:9][CH2:8][CH:6]1[CH:5]([CH3:26])[CH2:4][C:3](=[NH:28])[NH:7]1
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: COC1=NC(CCCC(NC(=O)OC(C)(C)C)C2COC(=O)O2)C(C)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1CC(=N)NC1CCCC(N)C1COC(=O)O1

Procedure:
The product of EXAMPLE 262 in MeOH is reacted with ammonium chloride by the method of EXAMPLE 27, then teated with 3M HCl/EtOAc to generate the title material.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([CH2:29][OH:30])[CH2:24]1>>[OH:30][CH2:29][C@@H:25]1[CH2:26][CH2:27][CH2:28][N:23]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:24]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: OC[C@@H]1CCCNC1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCC[C@@H](CO)C1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)-piperidin-3-ylmethanol (1.2 equiv) via to give 165 (18.1 mg, M+1 411.1)
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([Cu]C(=O)C)(=O)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1[N:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1c(C)[nH]c2ccccc12
Agent: CC(=O)[Cu]C(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1c(C)n(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.7 %

Procedure:
A mixture of methyl 2-methyl-1H-indole-3-carboxylate (500 mg, 2.65 mmol), phenylboronic acid (384 mg, 3.17 mmol), diacetylcopper (453 mg, 3.98 mmol), triethylamine (0.44 ml, 3.98 mmol), N,N-dimethylpyridin-4-amine (486 ml, 3.98 mmol) and 4 A molecular sieve (1.02 g) in dichloromethane (15 mL) was stirred at room temperature for 12 hours. After filtration, the mixture was concentrated and purified by chromatography (silica gel, petroleum:ethyl acetate=10:1) to afford methyl 2-methyl-1-phenyl-1H-indole-3-carboxylate as white solid (272 mg, 39%). 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J=8.0 Hz, 1H), 7.66-7.51 (m, 3H), 7.36 (dd, J=5.3, 3.2 Hz, 2H), 7.30 (s, 1H), 7.21-7.14 (m, 1H), 7.04 (d, J=8.2 Hz, 1H), 4.00 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[Br:11].C([O-])([O-])=O.[K+].[K+].[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1.CC(=O)OCC>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([O:10][CH2:25][C:22]2[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=2)[CH:7]=[CH:6][C:5]=1[Br:11]
Reactant: COC(=O)c1cc(O)ccc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OCc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.7 %

Procedure:
To a solution of 2-Bromo-5-hydroxy-benzoic acid methyl ester (80 g, 347 mmol) and K2CO3 (71.9 g, 520 mmol) in DMF (800 mL) was added BnBr (500 g, 416.2 mmol) at RT. The mixture was stirred at RT under N2 for 5 hr. The reaction mixture was diluted with H2O (500 mL) and extracted with ethyl acetate (100 mL*3). The organic phase was washed with saturated sodium bicarbonate solution 500 mL, dried over Na2SO4. After concentration, the crude product was purified by silica gel chromatography eluted with PE:EA=4:1 to give title product (100 g, 90% yield) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[CH:11][N:12]([CH2:21][CH3:22])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.C([Li])CCC.[CH:28]1([N:34]=[C:35]=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C1COCC1>[CH:28]1([NH:34][C:35]([C:11]2[N:12]([CH2:21][CH3:22])[C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=2)=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCn1cnc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: O=C=NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCn1c(C(=O)NC2CCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1-ethylimidazole (43 mg, 0.12 mmol) from Example 41, Step A (lower Rf isomer) in THF (2 mL) cooled to −70° C. in a dry ice/acetone bath was added 1.6N n-butyl lithium in hexanes (0.092 mL, 0.15 mmol). The reaction was stirred for 1 hr and then cyclohexyl isocyanate (0.032 mL, 0.25 mmol) was added via syringe. The reaction was allowed to warm to rt for 1 hr and was then quenched with aq. sodium bicarbonate and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by Prep TLC (3×1 mm, silica) (25% ethyl acetate in hexanes) to afford the title compound. HPLC/MS: 476 (M+1), 478 (M+3); Rt=4.99 min.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19](O)=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C[N:23](C)S(N)(=O)=O.Cl.CN(C)CCCN=C=NCC.C[C:42]([N:44](C)C)=[O:43]>CN(C1C=CN=CC=1)C>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH2:23])=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][C:7]([C:42]([NH2:44])=[O:43])=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Reactant: CN(C)S(N)(=O)=O
Reactant: CC(=O)N(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: NC(=O)C1=Cc2ccccc2-c2cc3ccc(C(N)=O)cc3n2C1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3-methoxy-6-[[[2-(dimethylamino)-2-oxoethyl]methylamino]carbonyl]- (53 mg, 0.10 mmol), N,N-dimethylsulfamide (62 mg, 0.50 mmol) and DMAP (61 mg, 0.50 mmol) in dimethylacetamide (1.5 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (76 mg, 0.40 mmol). The reaction solution was stirred at 50° C. for 5 h, concentrated under a steam of nitrogen, diluted with MeOH (1 mL) and purified by preparative HPLC (CH3CN/H2O with TFA buffer) to yield 7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxamide, 13-cyclohexyl-N6-[2-(dimethylamino)-2-oxoethyl]-N10-[(dimethylamino)sulfonyl]-3-methoxy-N6-methyl- (13 mg, 0.02 mmol, 20%) as a yellow solid. 1HNMR (500 MHz, CD3OD) δ 8.19 (s, 0.5H), 8.12 (s, 0.5H), 7.91 (d, J=8.1 Hz, 1H), 7.63 (d, J=8.1 Hz, 1H), 7.60-7.50 (m, 1H), 7.20-6.93 (m, 3H), 5.14 (br s, 1H), 4.46-4.11 (m, 2H), 3.96-3.87 (m, 1H), 3.93 (s, 3H), 3.12-2.86 (m, 13H), 2.45 (br s, 3H), 2.20-1.74 (m, 6H), 1.57-1.19 (m, 4H). LCMS: m/e 636 (M+H)+, ret time 2.82 min, column B, 3 minute gradient.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:14](I)[CH3:15].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:14]([N:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:10]=2[NH:9][C:8]1=[O:11])[CH3:15]
Reactant: Cc1cccc2[nH]c(=O)[nH]c12
Reactant: CCI
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)[nH]c2c(C)cccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 17.10 g of 4-methyl-1,3-dihydrobenzimidazol-2-one in 250 ml of anhydrous N,N-dimethylformamide is admixed at 0° C. with 4.070 g of sodium hydride dispersion (60%). The reaction mixture is stirred at 0° C. over a further 30 minutes and 7.5 ml of ethyl iodide are added dropwise. The reaction mixture is stirred at 30° C. over 14 hours, poured onto 500 ml of saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate (2×500 ml). The combined organic phases are washed with 500 ml of brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a brown solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (200:5:1 dichloromethane-methanol-25% conc. ammonia); Rt=3.17.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[S:14][N:13]=[CH:12][C:11]=3[CH:15]=2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[CH3:25][N:26]=[C:27]=[O:28]>C(N(CC)CC)C>[CH3:25][NH:26][C:27]([NH:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[S:14][N:13]=[CH:12][C:11]=3[CH:15]=2)=[CH:4][CH:3]=1)=[O:28]
Reactant: CN=C=O
Reactant: Nc1ccc(Oc2ccc3sncc3c2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CNC(=O)Nc1ccc(Oc2ccc3sncc3c2)cc1
Yield: 85 %

Procedure:
24.2 parts of 5-(4'-aminophenoxy)-benzisothiazole, 400 parts of toluene, 1 part of triethylamine and 11.4 parts of methyl isocyanate were heated at 80° C. for 12 hours, and the reaction mixture was then evaporated down under reduced pressure. 25 parts (85% of theory) of 5-(4'-methylaminocarbonylaminophenoxy)-benzisothiazole of melting point 178° C. were obtained.
Reaction SMILES: [C:1]1(S([O-])(=O)=O)[C:10]2[CH:9]=[CH:8][CH:7]=[C:6](S([O-])(=O)=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Na+].[Na+].[NH2-:21].[Na+].[NH3:23]>>[NH2:21][C:1]1[C:10]2[C:5](=[C:6]([NH2:23])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)([O-])c1cccc2c(S(=O)(=O)[O-])cccc12
Reactant: N
Reactant: [NH2-]
Agent: [Na+]
Product: Nc1cccc2c(N)cccc12
Yield: 84.5 %

Procedure:
In a 200-ml autoclave were placed 26.6 grams (0.08 mole) of anhydrous sodium 1,5-naphthalene disulfonate, 17.6 grams (0.44 mole) of sodium amide and 80 ml of liquid ammonia in the same manner as in Example 1. The resultant mixture was heated at 180° C for 10 hours. The reaction pressure in the autoclave was 160 atm. during the reaction. After the ammonia was removed 30 ml of methanol was added to the reaction mixture for solvolysis. Thereafter the product was treated in the same manner as in Example 2, whereby 10.7 grams of 1,5-diaminonaphthalene was obtained. Yield was 84.5%.
Reaction SMILES: O1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][C:3](=[O:11])[NH:2]1.[C:12](=[O:15])([O-])[O-].[K+].[K+].C[N:19]([CH:21]=O)C>O>[C:21]([C:7]1[CH:6]=[C:5]([CH:4]2[C:3](=[O:11])[NH:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:12]=3[O:15]2)[CH:10]=[CH:9][CH:8]=1)#[N:19]
Reactant: CN(C)C=O
Reactant: O=C1Cc2ccccc2ON1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: N#Cc1cccc(C2Oc3ccccc3NC2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the benzoxazinone (I6) (1.38 g, 4.17 mmol) in DMF (5 mL) was added potassium carbonate (1.40 g, 10.1 mmol), and the solution was stirred at room temperature for 1 hour. The solution was diluted with water and extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with brine (2×100 mL), dried with magnesium sulfate filtered, and evaporated in vacuo. The residue was purified on a silica gel column eluted with 25% ethyl acetate in dichloromethane. The product (I1) was isolated 0.48 g (46%) as a light orange solid.
Reaction SMILES: C(C1[CH:14]=[CH:13][C:12]([CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][N:10]=1)=CC1C=CC=CC=1.[Mn]([O-])(=O)(=O)=[O:29].[K+].C[C:35]([CH3:37])=[O:36]>>[C:16]1([CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:12]2[CH:13]=[CH:14][C:37]([C:35]([OH:29])=[O:36])=[N:10][CH:11]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)=O
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: C(=Cc1ccc(C(c2ccccc2)c2ccccc2)cn1)c1ccccc1
Agent: [K+]
Product: O=C(O)c1ccc(C(c2ccccc2)c2ccccc2)cn1
Reaction time: 15 h

Procedure:
A mixture of 8.2 g. 2-styryl-5-(diphenylmethyl)-pyridine and 120 ml. of acetone is cooled to -10° C. and with vigorous stirring 6.66 g. of finely divided potassium permanganate is added slowly, in a portion-wise fashion, over a 1.5 hour period whilst maintaining the temperature below -5° C. Allow the mixture to stand at -15° C. for 15 hours, filter and wash the solids with chloroform and extract three times with 150 ml. of boiling water. Acidify the aqueous extracts with hydrochloric acid and extract with ether. Discard the ether extracts and basify the aqueous phase to pH 2.5 and filter and dry the precipitated acid which is recrystallized from ethanol to yield the tiltle product (m.p. 189°-191° C.).
Reaction SMILES: COCO[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11](N(CC1C=CC=CC=1)C(C1C=CC=CC=1)C1C=CC=CC=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18]COC.[NH2:43][CH:44]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.CC[O:59][CH2:60][CH3:61].[ClH:62]>C(OCC)(=O)C>[ClH:62].[OH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:5]=[CH:61][C:60]=1[OH:59])([NH:43][CH:44]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOCC
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: COCOc1ccccc1C(c1ccccc1OCOC)N(Cc1ccccc1)C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Oc1ccccc1CC(Cc1ccccc1O)(NC(c1ccccc1)c1ccccc1)c1ccccc1
Reaction time: 0.17 h

Procedure:
At first, 4.88 g of 2-[bis(methoxymethoxyphenyl)methyl-N-(diphenylmethyl)benzylamine was obtained in a similar manner as in Example 77, except that aminodiphenylmethane was used in place of cyclooctylamine. The compound was then dissolved in ethyl acetate saturated with hydrochloric acid. The mixture was stirred for 10 minutes, and then ether was added to the mixture. Precipitates were collected by filtration and then dried to afford 1.3 g of the desired compound of hydrochloride (Compound 87).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]>CCO.N.O.[Ni]>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][NH2:21])=[CH:18][CH:19]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(C#N)cc2)n1
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(CN)cc2)n1
Reaction time: 6 h

Procedure:
A suspension of [6-(4-cyano-phenyl)-pyridin-2-yl]carbamic acid tert-butyl ester (7.0 g, 24 mmol), Raney Ni (1.0 g) in EtOH (500 mL) and NH3.H2O (10 mL) was hydrogenated under H2 (50 psi.) at 50° C. for 6 h. The catalyst was filtered off and the filtrate was concentrated to dryness to give [6-(4-aminomethyl-phenyl)-pyridin-2-yl]-carbamic acid tert-butyl ester, which was used directly in next step. 1H NMR (300 MHz, CDCl3) δ 7.83-7.92 (m, 3H), 7.70 (t, J=7.8 Hz, 1H), 7.33-7.40 (m, 4H), 3.92 (brs, 2H), 1.53 (s, 9 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:18])[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH:16]=O.C[O-].[Na+].Cl>C(=O)(OC)OC.CO>[CH3:1][O:2][C:3]([C:4]1[CH2:5][CH2:6][CH2:7][N:8]([CH3:18])[C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=2[CH:16]=1)=[O:19]
Reactant: COC(=O)CCCCN(C)c1ccc(Br)cc1C=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: COC(=O)OC
Product: COC(=O)C1=Cc2cc(Br)ccc2N(C)CCC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 31.7 %

Procedure:
To a solution of 5-(4-bromo-2-formyl-N-methylanilino)pentanoic acid methylester (3.0 g) in dimethyl carbonate (40 ml), a solution of 28% sodium methoxide in methanol (2.3 g) was added at room temperature, and the resulting mixture was stirred at 50° C. for 2 hours. The mixture was allowed to cool to room temperature, and neutralized with 1N hydrochloric acid. After ethyl acetate extraction, the organic layer was washed with saturated salt water, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography (h-hexane/ethyl acetate=10/1) and the appropriate eluate was concentrated. The precipitated crystal was washed with IPE and collected by filtration. Drying under reduced pressure (40° C., 1 hour) gave yellow crystal of 8-bromo-1-methyl-1,2,3,4-tetrahydro-1-benzazocin-5-carboxylic acid methylester (0.9 g, yield 31%). mp. 88-89° C. 1H-NMR(CDCl3, δ, 300 MHz): 1.44(2H, m), 2.54(2H, t, J=6.2 Hz), 2.87(3H, s), 3.42(2H, t, J=5.6 Hz), 3.78(3H, s), 6.56(1H, d, J=6.0 Hz), 7.19-7.23(2H, m), 7.68(1H, s). Anal. Calcd for C14 H16 NO2 Br: C,54.21; H,5.20; N,4.52; Br,25.76. Found: C,54.19; H,5.29; N,4.37; Br,25.74. IR(KBr, cm−1): 1689, 1189.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[O:4].[C:6](Cl)(=[O:10])[C:7](Cl)=[O:8]>O1CCCC1.O>[CH3:1][N:2]1[C:7](=[O:8])[C:6](=[O:10])[NH:5][C:3]1=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CNC(N)=O
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)NC(=O)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To an ice-cold solution of 1-methylurea (200 mg, 2.70 mmol) in dry tetrahydrofuran (6 mL) was added oxalyl chloride (0.26 mL, 2.97 mmol) dropwise, under a nitrogen atmosphere. The reaction mixture was stirred at 0-5° for 2 h and then allowed to warm to room temperature for 1 h before being diluted with water. The product was extracted with ethyl acetate, and the extracts were washed with water, dried and evaporated to give the product as an off-white solid (326 mg, 94%), mp 146-149° C. (lit. 145-148° C.).