Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:24][C:23]2[C:25](=[O:26])[C:18](=[CH:19][C:20]([C:22]=2OC)=[O:21])[NH:17][C:15](=[O:16])[C:14]([CH3:29])=[CH:13][CH:12]=[CH:11][C@H:10]([O:30][CH3:31])[C@@H:9]([O:32][C:33]([NH2:35])=[O:34])[C:8]([CH3:36])=[CH:7][C@H:6]([CH3:37])[C@@H:5]([OH:38])[C@@H:4]([O:39][CH3:40])[CH2:3]1.[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44][NH2:45].[ClH:47]>C(Cl)Cl.O1CCOCC1>[CH3:1][C@@H:2]1[CH2:24][C:23]2[C:25](=[O:26])[C:18](=[CH:19][C:20]([C:22]=2[NH:45][CH2:44][CH2:43][N:42]([CH3:46])[CH3:41])=[O:21])[NH:17][C:15](=[O:16])[C:14]([CH3:29])=[CH:13][CH:12]=[CH:11][C@H:10]([O:30][CH3:31])[C@@H:9]([O:32][C:33]([NH2:35])=[O:34])[C:8]([CH3:36])=[CH:7][C@H:6]([CH3:37])[C@@H:5]([OH:38])[C@@H:4]([O:39][CH3:40])[CH2:3]1.[ClH:47]
Reactant: CN(C)CCN
Reactant: COC1=C2C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)C=C(C)[C@H](OC(N)=O)[C@@H](OC)C=CC=C(C)C(=O)NC(=CC1=O)C2=O
Agent: COC1=C2C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)/C=C(\C)[C@H](OC(N)=O)[C@@H](OC)/C=C\C=C(/C)C(=O)NC(=CC1=O)C2=O
Agent: CO[C@H]1/C=C\C=C(/C)C(=O)NC2=CC(=O)C(NCCN(C)C)=C(C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)/C=C(\C)[C@@H]1OC(N)=O)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CO[C@H]1C=CC=C(C)C(=O)NC2=CC(=O)C(NCCN(C)C)=C(C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)C=C(C)[C@@H]1OC(N)=O)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of geldanamycin (15 g, 26.75 mmol) (SAIC-Frederick, Lot No. 3155-28-1) and N,N-dimethyl-ethylenediamine (15 mL, 37.83 mmol) (Aldrich, Lot No. HN04216AL) in dry methylene chloride (300 mL) (Mallinckrodt, Lot No. 4881KVJP) was stirred at room temperature for 1 hour and subsequently poured into ice water (500 mL). After the organic layer and aqueous layer became visually separated, the aqueous layer was extracted with methylene chloride (2×100 mL). The combined methylene chloride solution was washed with water (2×100 mL), dried with MgSO4 (Spectrum, Lot No. HJ302), and evaporated in a diaphragm pump. The remaining residue (16.5 g, 26.75 mmol) was dissolved in methylene chloride (130 mL). Dissolved hydrogen chloride (1.1 eq, 29.43 mmol) (Matheson, Lot No. T410242) in dioxane (Aldrich, Lot No. 16619CQ) was added to the solution resulting in immediate precipitation. After stirring for 30 minutes, the solids were collected, rinsed with methylene chloride (50 mL), and air-dried for 18 hours to give the crude hydrochloride salt (17.2 g). A solution of the crude product (17.2 g) in aqueous alcohol (50% v/v, 200 mL) (Aaper Alcohol, Lot. No. 97A28UARAT) was heated to reflux, filtered, and allowed to cool for 30 minutes. After cooling on ice for an additional 30 minutes, the solids were collected, washed with cold anhydrous alcohol (50 mL), and air-dried for 1 hour. The product was dried further at 70° C./0.1 mmHg for 17 hours to give pure target compound. Approximately 13.4 g of 17-Demethoxy-17-[[2(dimethylamino)ethyl]amino]geldanamycin hydrochloride (82%) was isolated as a violet crystalline solid and used in Examples 1 and 2.
Reaction SMILES: CC1C(N=C=O)=CC([N:8]=C=O)=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.COC1C=CC(O)=CC=1.[C:40]([O:44][CH2:45][CH2:46]O)(=[O:43])[CH:41]=[CH2:42]>>[C:40]([OH:44])(=[O:43])[CH:41]=[CH2:42].[NH2:8][C:40]([O:44][CH2:45][CH3:46])=[O:43]
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Reactant: C=CC(=O)OCCO
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: COc1ccc(O)cc1
Product: C=CC(=O)O
Product: CCOC(N)=O
Temperature: 70 °C
Reaction time: 7 h

Procedure:
In a flask equipped with a stirring blade, 348 parts (2 mol) of TDI (2,4-tolylene diisocyanate) was charged and 2000 parts (1 mol) of polypropylene glycol (number-average molecular weight of 2000) and 2 parts of dibutyltin diacetate were added while stirring. After heating to 70° C. while paying attention to heat generation, 0.2 parts of p-methoxyphenol and 1 part of 2,6-tertiary butyl-4-methylphenol were added. The reaction was conducted at the same temperature for 7 hours. Then, 232 parts (2 mol) of HEA (2-hydroxyethyl acrylate) was charged and the reaction was further reacted at the same temperature for 7 hours. After confirming the disappearance of absorption of NCO by infrared absorption spectrum, the reaction product was taken out to obtain a urethane acrylate (OS-1) as a radical polymerizable oligomer (A1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([O:10][CH3:11])[CH2:7][CH2:6][CH:5]([O:8][CH3:9])[O:4]1.C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[C:19]([NH:1][CH2:2][C:3]1([O:10][CH3:11])[CH2:7][CH2:6][CH:5]([O:8][CH3:9])[O:4]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC1CCC(CN)(OC)O1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC1CCC(CNC(=O)c2ccccc2)(OC)O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 103.4 %

Procedure:
10 g (62 mmol) of 2-aminomethyl-2,5-dimethoxytetrahydrofuran and 17 ml (123 mmol) triethylamine were dissolved in 100 ml of anhydrous tetrahydrofuran. At 0° C., 7.2 ml (62 mmol) of benzoyl chloride were added dropwise, and the mixture was stirred at 0° C. for 1 h and then filtered, and the filtrate was concentrated under reduced pressure to yield 17 g of the crude product which was immediately reacted further.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:10]=3)[C@:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:32]1[CH:37]=[N:36][CH:35]=[CH:34][N:33]=1)CCC.O1CCOCC1>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:17]([O:16][C:8]1[CH:9]=[CH:10][C:11]2[O:12][C:13]3[C:4](=[CH:3][C:2]([C:32]4[CH:37]=[N:36][CH:35]=[CH:34][N:33]=4)=[CH:15][CH:14]=3)[C@@:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:6]=2[CH:7]=1)[C:18]([CH3:19])([CH3:21])[CH3:20]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: CC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(Br)ccc1O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cnccn3)ccc1O2

Procedure:
A vial was charged with (R)-2′-bromo-7′-(neopentyloxy)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (55.6 mg, 0.133 mmol), tetrakis(triphenylphosphine)palladium (0) (15.40 mg, 0.013 mmol), 2-(tributylstannyl)pyrazine (148 mg, 0.400 mmol), and dioxane (0.7 mL). The vial was sealed under a blanket of Ar gas and placed in a 100° C. oil for 16 h. The mixture was then cooled and filtered through celite. The filtrate was evaporated, and the residue was purified by chromatography on a 12-g Redi-Sep column, eluting with 0-10% MeOH/DCM to give a brown oil. This oil was dissolved in MeOH and filtered through a 2 micron filter, then purified further by reverse-phase HPLC (10-90% CH3CN/H2O with 0.1% TFA). The product containing fractions were combined in saturated aqueous sodium bicarbonate solution with the aid of MeOH. The mixture was extracted with DCM (2×), and the combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give (S)-2′-(neopentyloxy)-7′-(pyrazin-2-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as a white solid. MS m/z=417.2 [M+H]+. Calc'd for C24H25N4O3: 417.19.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]2[CH2:13][S:14][CH2:15][C:3]=12.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1>C(O)CCC>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:8](=[O:10])[C:7]3[C:2]([C:3]4[CH2:15][S:14][CH2:13][C:4]=4[NH:5][CH:6]=3)=[N:24]2)=[CH:19][CH:18]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(c1Cl)CSC2
Solvent: CCCCO
Product: O=c1c2c[nH]c3c(c-2nn1-c1ccc(Cl)cc1)CSC3

Procedure:
A mixture of 0.6 g of ethyl 4-chloro-5,7-dihydrothieno[3,4-b]pyridine-3-carboxylate, p-chlorophenylhydrazine(0.35 g) and 10 ml of n-butanol is heated at reflux for 24 hours, then evaporated to dryness. To the residue is added additional p-chlorophenylhydrazine (0.35 g) and 10 ml of N-methyl-2-pyrrolidone, and the mixture is heated at 150° for 18 hours, then evaporated to dryness. The residue is treated with 20 ml of 2N NaOH and 40 ml of ether. Alkaline layer is separated and pH adjusted to 6.5 depositing solid which is dissolved in methanol; the solution is decolorized with charcoal and concentrated to deposit crystals. Recrystalization from methanol affords 2-(p-chlorophenyl)-2,3,6,8-tetrahydrothieno[3,4-b]pyrazolo[3,4-d]pyridin-3(5H)-one, mp>330°; IR(cm-1)1600, 1570, 1470, 1000, 931, 835, 830 and 762; (the compound of formula IA wherein R1 =p-chlorophenyl, R2 and R3 =H and A represents ##STR27## The starting material is prepared as follows:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5](=[CH:8][CH:9]=1)[CH:6]=O.[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:16]([CH2:17][S:18]([CH2:21][C:22](O)=[O:23])(=[O:20])=[O:19])=[CH:15][C:14]=1[N+:27]([O-:29])=[O:28]>C(O)(=O)C>[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:16]([CH2:17][S:18]([C:21]2[C:22](=[O:23])[O:10][C:4]3[C:5]([CH:6]=2)=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=3)(=[O:19])=[O:20])=[CH:15][C:14]=1[N+:27]([O-:29])=[O:28]
Reactant: COc1ccc(CS(=O)(=O)CC(=O)O)cc1[N+](=O)[O-]
Reactant: O=Cc1ccc(O)cc1O
Solvent: CC(=O)O
Product: COc1ccc(CS(=O)(=O)c2cc3ccc(O)cc3oc2=O)cc1[N+](=O)[O-]
Yield: 62 %

Procedure:
A solution of 4-hydroxysalicylaldehyde (1 mmol) and 2-(4-methoxy-3-nitrobenzylsulfonyl)acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 2, Method A to generate a 62% yield of the title compound; m.p. 126-128° C.
Reaction SMILES: N[C:2]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)=[CH:3][C:4]#[N:5].Cl.C[OH:13]>>[O:13]=[C:2]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[CH2:3][C:4]#[N:5]
Reactant: N#CC=C(N)c1ccsc1
Reactant: CO
Agent: Cl
Product: N#CCC(=O)c1ccsc1
Reaction time: 3 h

Procedure:
A 1.2 g. portion of β-amino-3-thiopheneacrylonitrile is added to 10 ml. of 1 N hydrochloric acid. A 40 ml. portion of methanol is added and the mixture is stirred for 3 hours. The mixture is evaporated in vacuo to a residue which is dissolved in 35 ml. of hot methanol and treated with charcoal. After cooling, petroleum ether is added, the mixture is filtered and the solid collected is discarded. The filtrate is allowed to evaporate and the residue is dissolved in 35 ml. of hot isopropanol and isoluble material filtered and discarded The filtrate is cooled and the solid is collected giving the desired product as white plates, m.p. 87°-88° C.
Reaction SMILES: [C:1](=[S:3])=S.C1(N=C=NC2CCCCC2)CCCCC1.[Cl:19][C:20]1[CH:33]=[CH:32][C:23]([CH:24]([NH2:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:22][CH:21]=1>CCOCC>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH:24]([N:31]=[C:1]=[S:3])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:32][CH:33]=1
Reactant: S=C=S
Reactant: NC(c1ccccc1)c1ccc(Cl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: S=C=NC(c1ccccc1)c1ccc(Cl)cc1
Temperature: -35 °C
Reaction time: 3 h

Procedure:
A mixture of 80 ml of carbon disulfide and 39.82 g (0.193 mole) of dicyclohexylcarbodimide in 100 ml of anhydrous ether, under dry N2, is cooled with stirring to -35° C. Then 42.23 g (0.194 mole) of p-chlorobenzhydrylamine in 500 ml of dry ether is added over about 5 min such that the temperature within the reaction vessel does not rise above -20° C. The temperature is allowed to rise slowly over 3 hrs. to ca.25° C and stirring is continued overnight. Dicyclohexylthiourea was removed by filtration and the filtrate is taken to dryness in vacuo. The cloudy oil is treated with 500 ml of pentane which dissolves the product and precipitates more insoluble impurities. Filtration through filter aid (diatomaceous earth) and solvent removal in vacuo gives p-chlorobenzhydryl isothiocyanate as an oil; IR (neat) 2140 cm-1.
Reaction SMILES: C([O:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH:20]([CH3:22])[CH3:21])[CH:10]=1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[OH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH:20]([CH3:21])[CH3:22])[CH:10]=1
Reactant: CCOC(=O)c1ccc(OCc2ccccc2)cc1C(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(O)cc1C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of N-methylformanilide (9.92 g) and phosphoryl chloride (11.3 g) was stirred at room temperature for 30 minutes, and benzyloxy-3-isopropylbenzene (16.6 g) was added to the mixture. After being stirred at room temperature overnight, ice was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford 4-benzyloxy-2-isopropylbenzaldehyde (19.4 g) as a crude product. An aqueous solution (200 mL) of sodium chlorite (33.2 g) was added dropwise to an ice-cooled suspension of the crude 4-benzyloxy-2-isopropylbenzaldehyde and potassium dihydrogenphosphate (50.0 g) in tert-butylalcohol (200 mL)/2-methyl-2-butene (100 mL) with stirring. The mixture was stirred at room temperature for 3 hrs. To the resulting mixture was added water, and the insoluble materials were removed by filtration. The filtrate was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford 4-benzyloxy-2-isopropylbenzoic acid (23.3 g) as a crude product. A suspension of the crude 4-benzyloxy-2-isopropylbenzoic acid, ethyl iodide (13.7 g) and potassium carbonate (15.2 g) in N,N-dimethylformamide (300 mL) was stirred at room temperature for30 minutes. The reaction mixture was partitioned between diethyl ether and water. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to afford ethyl 4-benzyloxy-2-isopropylbenzoate (16.8 g). A suspension of ethyl 4-benzyloxy-2-isopropylbenzoate and 10% palladium-carbon (0.1 g) in ethanol (100 mL) was stirred at room temperature for 30 minutes under an atmosphere of hydrogen. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to afford the title compound (1.1 g).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]([NH2:7])=[O:6])[CH3:4].[C:8]([O:12][C:13](=[O:30])[C@H:14]([CH3:29])[N:15]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:16][CH:17]=O)([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.C([BH3-])#N.[Na+]>CO>[C:8]([O:12][C:13](=[O:30])[C@H:14]([CH3:29])[N:15]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:16][CH2:17][NH:2][C@@H:3]([C:5]([NH2:7])=[O:6])[CH3:4])([CH3:9])([CH3:10])[CH3:11]
Reactant: C[C@@H](N)C(N)=O
Reactant: C[C@@H](C(=O)OC(C)(C)C)N(CC=O)C(=O)OCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@@H](NCCN(C(=O)OCc1ccccc1)[C@@H](C)C(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The D-alanine amide hydrochloride, (45) (2.5 g) (20.18 mmol) was dissolved in methanol, followed by the aldehyde (44) (3.30 g, 10.27 mmol) and triethylamine (1.40 mL, 1.0 g, 10.07 mmol). Sodium cyanoborohydride (0.86 g, 13.7 mmol) was added and the solution was kept stirring at room temperature overnight. The solution was evaporated under vacuum. The residue was taken up in chloroform:methanol (98:2) and flash chromatographed silica gel to yield the titled product (46): (2.48 g, 61%). 1H-NMR CDCl3) δ7.33 (s, 5H), 6.00 (br s, 1H), 5.20 (d, 2H), 4.67-3.00 (m, 4H), 2.77 (t, 2H), 1.83-1.23 (s/m, 13H).
Reaction SMILES: NC(N)=O.[CH:5]1([NH:10][S:11]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([NH2:21])[C:15]=2[OH:22])(=[O:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1.[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>>[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31]([NH:21][C:16]1[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([S:11]([NH:10][CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9]2)(=[O:13])=[O:12])[C:15]=1[OH:22])=[O:32]
Reactant: Nc1ccc(Cl)c(S(=O)(=O)NC2CCCC2)c1O
Reactant: O=C=Nc1ccccc1Br
Agent: NC(N)=O
Product: O=C(Nc1ccccc1Br)Nc1ccc(Cl)c(S(=O)(=O)NC2CCCC2)c1O
Yield: 39.3 %

Procedure:
Following the general procedure for urea formation outlined in example 15, (N-cyclopentyl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide (0.15 g, 0.52 mmol) and 2-bromophenylisocyanate (64 μL, 0.52 mmol) were coupled to form the desired urea (0.1 g, 39%). LC-MS m/z 488(M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([Cl:12])[CH:3]=1.[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCO>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[C:4]([Cl:12])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1Cl
Reactant: c1ccccc1
Solvent: CCO
Solvent: O
Product: O=S(=O)(c1ccccc1)c1ccc(Br)cc1Cl

Procedure:
A 500 mL round-bottomed flask was charged with 4-bromo-2-chlorobenzene-1-sulfonyl chloride (10.0 g, 34.5 mmol, Sigma-Aldrich, St. Louis, Mo.), ferric chloride (2.80 g, 17.2 mmol), and 200 mL of benzene. The mixture was heated at reflux for 12 h then diluted with water (100 mL) and extracted with CH2Cl2 (2×300 mL). The combined organic layers were dried (MgSO4) and concentrated to give a brown solid that was slurried with EtOH (100 mL) to give 4-bromo-2-chloro-1-(phenylsulfonyl)benzene (7.50 g).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][N:21]3[C:29]([C:32]([NH:34][CH2:35][C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)=[O:33])=[CH:30][CH:31]=[C:20]3[CH2:19]2)=[O:17])=[CH:12][CH:11]=1)#[N:2].[N-:42]=[N+:43]=[N-:44].[Na+].[Cl-].[NH4+].O>CS(C)=O>[N:38]1[CH:39]=[CH:40][CH:41]=[C:36]([CH2:35][NH:34][C:32]([C:29]2[N:21]3[C:20]([CH2:19][N:18]([C:16]([C:13]4[CH:12]=[CH:11][C:10]([C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[CH2:3][C:1]5[NH:44][N:43]=[N:42][N:2]=5)=[CH:15][CH:14]=4)=[O:17])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[CH2:22]3)=[CH:31][CH:30]=2)=[O:33])[CH:37]=1
Reactant: N#CCc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3ccccc3Cc3nnn[nH]3)cc1)C2
Temperature: 50 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
A mixture of 0.537 g (0.001 mol) of 10-{[2′-(cyanomethyl)-1,1′-biphenyl-4-yl]carbonyl}-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 17, 0.32 g (0.005 mole) of sodium azide and 0.26 g (0.005 mole) of ammonium chloride in 20 mL of dimethyl sulfoxide was heated with stirring at 50° C. for three hours. The reaction mixure was poured into 100 mL of water, and the precipitated crude product was subjected to chromatographic purification giving 0.46 g of title compound, m.p. 164-167° C.
Reaction SMILES: [S:1]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[O:2].[C:17](=[O:20])([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30]>CS(C)=O.C(OCC)(=O)C.CN(C)CCN(C)C>[S:1]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:20][CH3:17])=[CH:12][CH:11]=1)([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:5][CH:4]=1)=[O:2]
Reactant: O=S(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: O=C([O-])[O-]
Reactant: COCCOCCBr
Agent: CN(C)CCN(C)C
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COCCOCCOc1ccc(S(=O)c2ccc(OCCOCCOC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85098.1 %

Procedure:
4,4′-sulfinyldiphenol (20.0 g, 85.0 mmol), potassium carbonate (26.6 g, 0.192 mol, 2.26 eq) and tetramethylethylenediamine (0.495 g, 4.25 mmol, 0.05 eq) were dissolved in DMSO (100 mL) and stirred at r.t. for 30 minutes. Then 1-bromo-2-(2-methoxyethoxy)ethane (32.67 g, 0.179 mmol, 2.1 eq) was added, the solution heated to 90° C. for 18 h and cooled to r.t. The reaction mixture was diluted with ethyl acetate (600 mL), washed with water (5×500 mL), dried (Na2SO4) and concentrated in vacuo to afford the title compound (33.40 g, 90%) as an orange oil. 1H NMR (500 MHz, (CD3)2CO) δ: 7.59 (d, J=8.5 Hz, 4H), 7.07 (d, J=8.5 Hz, 4H), 4.17 (t, J=4.5 Hz, 4H), 3.80 (t, J=5 Hz, 4H), 3.63 (t, J=4.5 Hz, 4H), 3.48 (t, J=4.5 Hz, 4H), 3.28 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29](O)=[O:30])[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[CH3:35][NH:36][CH3:37]>>[CH3:35][N:36]([CH3:37])[C:29](=[O:30])[CH:28]([N:26]1[CH:27]=[C:23]([C:21]2[CH:20]=[N:19][N:18]3[C:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:1])([F:34])[F:33])=[O:6])[CH:9]=4)=[CH:15][N:16]=[C:17]3[CH:22]=2)[CH:24]=[N:25]1)[CH3:32]
Reactant: CNC
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Product: CC(C(=O)N(C)C)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and dimethylamine (2.0 N in THF). LCMS (M+H)+: m/z=501.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([CH3:41])([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:30])([F:29])[F:28])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:40])[C:18](=[O:39])[N:19]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.CO.[BH3-][C:47]#N.[Na+]>CC(O)C.CC(O)=O>[CH3:41][C:10]1([N:12]([CH3:47])[C:13]2[C:26]([C:27]([F:29])([F:28])[F:30])=[CH:25][C:24]3[O:23][CH2:22][C:21]4=[N:20][N:19]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:37])[CH3:38])[C:18](=[O:39])[CH:17]([CH3:40])[N:16]4[C:15]=3[CH:14]=2)[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11]1
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(NC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: CO
Product: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(N(C)C4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 110 °C
Reaction time: 48 h
Yield: 52.7 %

Procedure:
A mixture of 3-methyl-3-[4-methyl-3-oxo-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-azetidine-1-carboxylic acid tert-butyl ester (Example #100, Step A, 0.250 g, 0.417 mmol) and paraformaldehyde (neat, 0.250 g, 8.34 mmol) in iPrOH (5 mL) and AcOH (0.5 ml) was stirred at 110° C. for 2 days. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. Then, MeOH (5 mL), AcOH (2.5 mL) and NaBH3CN (0.524 g, 8.34 mmol) were added. The mixture was stirred at 60° C. for 1 h. The reaction mixture was cooled to ambient temperature and solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5-10% EtOAc in petroleum ether) to give tert-butyl 3-methyl-3-(methyl(1-methyl-2-oxo-8-(trifluoromethyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)amino)azetidine-1-carboxylate (0.135 g, 53%). 1H NMR (CDCl3, 400 MHz): δ 7.25 (s, 1H), 6.72 (s, 1H), 5.10 (m, 2H), 4.65 (m, 1H), 4.66 (q, J=13.2 Hz, 2H), 4.03 (d, J=8.8 Hz, 1H), 3.90 (d, J=12.4 Hz, 1H), 3.66 (t, 2H), 3.58 (t, 2H), 2.68 (s, 3H), 1.48 (s, 3H), 1.47 (d, J=6.4 Hz, 3H), 1.42 (s, 9H), 0.99 (m, 2H), 0.00 (s, 9H).