Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)[C:2]#[CH:3].C([Mg]Br)C.[O:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1>C1COCC1>[OH:21][C:18]1([C:3]#[C:2][CH2:1][O:4][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][O:6]2)[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1
Reactant: C#CCOC1CCCCO1
Reactant: O=C1CCOCC1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: OC1(C#CCOC2CCCCO2)CCOCC1
Temperature: -20 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
Tetrahydro-2-(2-propynyloxy)-2H-pyran (21 g, 150 mmol) was converted to the corresponding magnesium anion by deprotonation with ethyl magnesium bromide (75 mL of a 2M solution, 150 mmol) according to the method described in Org. Synth., 60: 81, 7 (1981). The resulting anion was cooled to -20° C. and tetrahydro-4H-pyran-4-one (14.8 g, 148 mmol) in dry THF (30 mL) was added dropwise and the resulting solution stirred for three hours. The reaction was quenched by addition of crushed ice and saturated aqueous NH4Cl. The resulting two-layered mixture was extracted with ether (3×150 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Purification by chromatography on silica gel (200 g, 20% ethyl acetate: hexanes) provided 4-hydroxy-4-[3-(tetrahydropyran-2-yloxy)prop-1-ynyl]tetrahydropyran(31.4 g, 88%).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:13]=[C:12]([N:14]2[C:22]3[C:17](=[C:18]([N:23]4[CH:27]=[C:26]([C:28]5[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=5)[N:25]=[CH:24]4)[CH:19]=[CH:20][CH:21]=3)[C:16]([CH:34]([CH3:36])[CH3:35])=[N:15]2)[CH:11]=[CH:10][C:7]=1[C:8]#[N:9])([CH3:4])([CH3:3])[CH3:2].[OH-:37].[Na+].OO.O>CS(C)=O>[C:1]([NH:5][C:6]1[CH:13]=[C:12]([N:14]2[C:22]3[C:17](=[C:18]([N:23]4[CH:27]=[C:26]([C:28]5[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=5)[N:25]=[CH:24]4)[CH:19]=[CH:20][CH:21]=3)[C:16]([CH:34]([CH3:36])[CH3:35])=[N:15]2)[CH:11]=[CH:10][C:7]=1[C:8]([NH2:9])=[O:37])([CH3:4])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(C)c1nn(-c2ccc(C#N)c(NC(C)(C)C)c2)c2cccc(-n3cnc(-c4cccnc4)c3)c12
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)c1nn(-c2ccc(C(N)=O)c(NC(C)(C)C)c2)c2cccc(-n3cnc(-c4cccnc4)c3)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
To a solution of compound (1b) in DMSO (4.41 mL) were added 4N aqueous sodium hydroxide solution (160 μL) and 30% aqueous hydrogen peroxide solution (60 μL), and the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, water was poured into the reaction solution, and the precipitated solid was collected by filtration to obtain compound (1) (150 mg, yield 96%) as a white solid.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.C(N(CC)CC)C.[OH-].[Na+]>ClCCl>[O:4]=[C:2]1[N:20]([CH:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]2)[C@@H:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]2[NH:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(N[C@@H]2CCCC[C@H]2N)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)N[C@@H]3CCCC[C@H]32)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 141.8 %

Procedure:
A solution of triphosgene (7.2 g, 24.2 mmol) in dichloromethane (300 mL) was added with a solution of tert-butyl 4-{[(1R,2R)-2-aminocyclohexyl]amino}piperidine-1-carboxylate (18 g, 60 mmol) and triethylamine in dichloromethane (600 mL) drop wise over a period of 1 h and stirred at room temperature for 22 h. An additional amount of triphosgene (8 g) and triethylamine (13 mL) were added and stirred at room temperature for another 22 h. An aqueous solution of sodium hydroxide (0.5N 200 mL) was added to the reaction mixture, layers were separated, and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to afford the crude product which was triturated with diethylether (80 mL) to give the title compound as white solid (11.1 g, 56%). 1H NMR (300 MHz, METHANOL-D4): δ ppm 4.25-4.05 (m, 2H), 3.80-3.65 (m, 1H), 3.10-2.90 (m, 2H), 2.85-2.65 (m, 2H), 2.20-1.90 (m, 2H), 1.90-1.55 (m, 4H), 1.55-1.30 (m, 11H)
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:5]=[C:4]([C:18]([NH2:20])=O)[N:3]=1.P(Cl)(Cl)([Cl:23])=O>C(OCC)(=O)C>[Cl:23][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:5]=[C:4]([C:18]#[N:20])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: NC(=O)c1nc(O)cc(-c2cccc(C(F)(F)F)c2)n1
Solvent: CCOC(C)=O
Product: N#Cc1nc(Cl)cc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
4-Hydroxy-6-(3-trifluoromethyl-phenyl)-pyrimidine-2-carboxylic acid amide (340 mg) was heated to reflux in ethyl acetate (2 ml) and phosphorous oxychloride (8 ml) for four hours. Solvent was evaporated under reduced pressure and the remaining residue dissolved in ethyl acetate (30 ml) and washed with saturated sodium chloride (20 ml). Organics were separated, dried over sodium sulphate and solvent was removed to yield product 4-chloro-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile (362 mg) as a brown solid. This product was used for next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>C(Cl)Cl>[F:28][C:27]([F:30])([F:29])[C:25]([OH:31])=[O:26].[N:19]1([C:17]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:16]3)=[O:18])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C(=O)N3CCOCC3)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc2c(c1)CNC2)N1CCOCC1

Procedure:
A solution of N-t-butoxycarbonyl-5-[(morpholin-4-yl)carbonyl] isoindoline (D19) (300 mg) in DCM (5 ml) at rt was treated with TFA (2 ml) for 1 h and then evaporated. The residue was re-evaporated from DCM/toluene to give the title compound (D20) (305 mg). MS electrospray (+ion) 233 (MH+). 1H NMR δ (CDCl3): 10.10 (1H, m), 7.25 (3H, m), 4.64 (2H, m), 4.53 (2H, m), 3.54 (8H, m).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([OH:8])=O.Cl.[CH3:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][O:28][CH3:29])[N:21]=[CH:20][N:19]=[C:18]2[NH:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[C:33]([CH3:44])[CH:32]=1>CN(C)C=O>[CH3:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][O:28][CH3:29])[N:21]=[CH:20][N:19]=[C:18]2[NH:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]2[CH2:39][CH2:40][N:41]([C:6]([CH:2]3[CH2:3][CH2:4][CH2:5][O:1]3)=[O:8])[CH2:42][CH2:43]2)=[C:33]([CH3:44])[CH:32]=1
Reactant: O=C(O)[C@H]1CCCO1
Reactant: COCCOc1cc2ncnc(Nc3ccc(OC4CCNCC4)c(C)c3)c2cc1OCCOC
Agent: Cl
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(Nc3ccc(OC4CCN(C(=O)C5CCCO5)CC4)c(C)c3)c2cc1OCCOC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,1′-carbonyldiimidizole (35 mg, 0.221 mmol) in N,N-dimethylformamide (2 mL) was added (R)-(+)-tetrahydrofuroic acid (25 mg, 0.221 mmol). The reaction was stirred at room temperature for 30 minutes then [6,7-Bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-[3-methyl-4-(piperidin-4-yloxy)-phenyl]-amine hydrochloride (100 mg, 0.193 mmol) was added. The reaction was then stirred at room temperature overnight. The following day, the reaction was filtered through a 0.45 μm PTFE membrane filter and purified by preparatory HPLC. 1H NMR (300 MHz, DMSO-d6) δ 9.38(bs, 1H), 8.39(s, 1H), 8.15(s, 1H), 7.85(s, 1H), 7.52(d, J=8.39 Hz, 1H), 7.19(s, 1H), 7.04(d, J=8.71 Hz, 1H), 4.70(t, J=7.46, 1.55 Hz, 1H), 4.64(t, J=18.66, 3.42 Hz, 1H), 4.84(t, J=4.97, 3.75 Hz, 2H), 3.77(m, 8H), 3.43(m, 2H), 3.38(s, 3H), 3.36(s, 3H), 2.21(s, 3H), 2.05(m, 4H), 1.90(m, 2H), 1.66(m, 2H), LRMS (M+): 581.1, (M−): 579.2.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: O=C(O)c1cc(F)ccc1Br
Reactant: CNOC
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a suspension of 2-bromo-5-fluorobenzoic acid (2.0 g, 9.13 mmol) in DCM (90 mL) at room temperature was added N,O-dimethylhydroxylamine hydrochloride (1.069 g, 10.96 mmol), N-(3-dimethylaminopropyl)-K-ethylcarbodiimide hydrochloride (2.276 g, 11.87 mmol), hydroxybenzotriazole (1.818 g, 11.87 mmol) and triethylamine (2.55 mL, 18.26 mmol). The resulting mixture was stirred at room temperature for 5.5 h after which time the reaction was quenched by addition of sat. aq. NaHCO3 solution and the layers separated. The organic layer was then washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO2, 0-40% EtOAc/Hexanes) to afford 2-bromo-5-fluoro-N-methoxy-N-methylbenzamide as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.54 (dd, J=8.8, 4.9 Hz, 1H), 7.05 (dd, J=8.2, 3.0 Hz, 1H), 7.00 (td, J=8.4, 3.0 Hz, 1H), 3.50 (s, 2H), 3.38 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:7][C:8]([C:10]1[NH:11][C:12]([C:15]2[CH:20]=[C:19]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:18]=[C:17]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])[CH:16]=2)=[CH:13][CH:14]=1)=[O:9])[C@H:4]([OH:6])[CH3:5].[CH:38]([Si:41]([CH:46]([CH3:48])[CH3:47])([CH:43]([CH3:45])[CH3:44])Cl)([CH3:40])[CH3:39].C(N(CC)CC)C.[Cl-].[NH4+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[OH:6][C@H:4]([CH3:5])[C@H:3]([NH:7][C:8]([C:10]1[NH:11][C:12]([C:15]2[CH:20]=[C:19]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:23]([CH3:24])[CH3:25])[CH:26]([CH3:27])[CH3:28])[CH:18]=[C:17]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])[CH:16]=2)=[CH:13][CH:14]=1)=[O:9])[CH2:2][O:1][Si:41]([CH:46]([CH3:48])[CH3:47])([CH:43]([CH3:45])[CH3:44])[CH:38]([CH3:40])[CH3:39]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)N[C@H](CO)[C@@H](C)O)[nH]2)c1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)N[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)[C@@H](C)O)[nH]2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.8 %

Procedure:
N-[(2R,3R)-1,3-Dihydroxybutan-2-yl]-5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tripropan-2-ylsilyl)oxy]phenyl)-1H-pyrrole-2-carboxamide (2.10 g, 3.93 mmol) synthesized in Example (110a) was dissolved in methylene chloride (50 mL), and triisopropylchlorosilane (1.50 mL, 7.01 mmol), 4-dimethylaminopyridine (1.50 g, 12.27 mmol) and triethylamine (5.00 mL, 35.87 mmol) were added, followed by stirring at room temperature for 1 day under nitrogen atmosphere. To the reaction solution, a saturated aqueous ammonium chloride solution (50 mL) was added, and extraction was carried out with methylene chloride (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=25-40%) to afford the desired compound (2.52 g, yield 93%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9](Br)[CH:8]=1)[CH3:6])[CH3:2].C(O[C:19]([S-:21])=[S:20])C.[K+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]2[NH:13][C:19](=[S:20])[S:21][C:9]=2[CH:8]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)c1ccc(N)c(Br)c1
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)c1ccc2[nH]c(=S)sc2c1
Temperature: 25 °C

Procedure:
To a stirred solution of 2-(4-Amino-3-bromo-phenyl)-propionic acid ethyl ester (1.58 g) in DMF was added potassium ethylxanthate (1.86 g) at room temperature. After stirred with reflux for 14 h, the reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was chromatographed on silica gel (n-Hex:EtOAc=6:1 to 4:1) to afford the product as yellow oil. (595 mg, 38.3%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][C:17]=1[C:26]([OH:28])=[O:27].C(N(CC)CC)C>CC(C)=O>[OH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:6][CH:7]=2)(=[O:24])=[O:23])=[CH:18][C:17]=1[C:26]([OH:28])=[O:27]
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: N#CC=CS(=O)(=O)c1ccc(NS(=O)(=O)c2ccc(O)c(C(=O)O)c2)cc1

Procedure:
is prepared by dissolving 10.4 grams (0.05 mol) of 3-(4-aminobenzenesulfonyl)acrylonitrile and 14 g (0.05 mol + 15% excess) of 4-hydroxy-3-carboxybenzenesulfonyl chloride in 200 ml acetone, cooling in an ice bath and slowly adding thereto 8 ml (0.055 mol) of triethylamine diluted with 25 ml acetone. After filtration and evaporation of the acetone the remaining semi-solid is dissolved in dimethylformamide, dispersed in water and the emulsion extracted with chloroform. After work-up the above sulfonamide is recovered.
Reaction SMILES: ClC1C(C(O)=O)=CN=C(Cl)C=1C.BrC1C=CC(NC2C(C(O)=O)=CN3C=CN=C3C=2C)=C(Cl)C=1.[N-:35]=[N+:36]=[N-:37].[Na+].[CH3:39][O:40][C:41](=[O:59])[C:42]1[C:47]([NH:48][C:49]2[CH:54]=[CH:53][C:52]([Br:55])=[CH:51][C:50]=2[Cl:56])=[C:46]([CH3:57])[C:45](Cl)=[N:44][CH:43]=1>>[CH3:39][O:40][C:41](=[O:59])[C:42]1[C:47]([NH:48][C:49]2[CH:54]=[CH:53][C:52]([Br:55])=[CH:51][C:50]=2[Cl:56])=[C:46]([CH3:57])[C:45]([N:35]=[N+:36]=[N-:37])=[N:44][CH:43]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cnc(Cl)c(C)c1Nc1ccc(Br)cc1Cl
Agent: Cc1c(Cl)ncc(C(=O)O)c1Cl
Agent: Cc1c(Nc2ccc(Br)cc2Cl)c(C(=O)O)cn2ccnc12
Agent: [Na+]
Product: COC(=O)c1cnc(N=[N+]=[N-])c(C)c1Nc1ccc(Br)cc1Cl
Temperature: 50 °C

Procedure:
4,6-Dichloro-5-methylnicotinic acid (J. Heterocyclic Chemistry 1999, 36, 953-957) was converted to 7-(4-bromo-2-chloro-phenylamino)-8-methylimidazo[1,2-a]pyridine-6-carboxylic acid according to the steps described in the alternate synthesis of Step D, Example 9. It was determined that addition of sodium azide to the 4-(4-bromo-2-chloro-phenylamino)-6-chloro-5-methylnicotinic acid methyl ester intermediate required heating to 50° C., which results in a separable mixture of the desired methyl ester, 6-azido-4-(4-bromo-2-chlorophenylamino)-5-methylnicotinic acid methyl ester, and the corresponding carboxylic acid. MS ESI (+) m/z 380, 382 (M+, Cl, Br pattern) detected. 1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 9.40 (br s, 1H), 8.25 (d, 1H), 8.12 (d, 1H), 7.79 (m, 1H), 7.42 (dd, 1H), 6.80 (d, 1H), 2.07 (s, 3H).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[N:5][S:6][C:7]=1[CH3:8].[NH2:9][CH2:10][CH2:11][SH:12]>>[NH2:9][CH2:10][CH2:11][S:12][CH2:2][C:3]1[N:4]=[N:5][S:6][C:7]=1[CH3:8]
Reactant: NCCS
Reactant: Cc1snnc1CO
Product: Cc1snnc1CSCCN

Procedure:
Reacting 4-hydroxymethyl-5-methyl-1,2,3-thiadiazole with cysteamine by the procedure of Example 1 gives 4-[ (2-aminoethyl)thiomethyl]-5-methyl-1,2,3-thiadiazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:15])=[C:11]([CH:14]=1)[CH:12]=[O:13].C(=O)([O-])[O-].[Na+].[Na+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CC(C)=O>[CH3:1][O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:15][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:11]([CH:14]=1)[CH:12]=[O:13]
Reactant: COc1c(C)c(Cc2ccc(O)c(C=O)c2)c(OC)c(OC)c1OC
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C=O)c2)c(OC)c(OC)c1OC
Yield: 75.2 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzaldehyde (0.100 g, 0.290 mol) was dissolved in acetone (10 ml) and, after addition of anhydrous sodium carbonate (0.080 g, 0.579 mmol) and benzyl bromide (0.059 g, 0.347 mmol), the mixture was heated to reflux for 3 hours. The reaction solution was filtered and the residue obtained by concentration of the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (0.114 g, 0.261 mmol, 90%).
Reaction SMILES: Br[C:2]1[C:7]([C:8](OC)=[O:9])=[C:6]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[CH:4][N:3]=1.O.[NH2:21][NH2:22].CN1CCCC1=O>O>[C:14]1([CH2:13][CH2:12][C:6]2[CH:5]=[CH:4][N:3]=[C:2]3[NH:21][N:22]=[C:8]([OH:9])[C:7]=23)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1c(CCc2ccccc2)ccnc1Br
Reactant: NN
Solvent: O
Solvent: CN1CCCC1=O
Product: Oc1n[nH]c2nccc(CCc3ccccc3)c12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 2-bromo-3-methoxycarbonyl-4-(2-phenylethyl)pyridine (1.42 g), hydrazine monohydrate (0.65 mL) and N-methylpyrrolidone (10 mL) was stirred at 100° C. for 2 hours. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration, washed with water and dried under reduced pressure to give the title compound (0.74 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([N:14]3[CH2:18][CH2:17]C[C@H:15]3[CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[C:4](=[O:27])[C:3]1=[O:28].O(C[C@@H]1CCN1S(C1C=C2C(=CC=1)NC(=O)C2=O)(=O)=O)C1C=CC=CC=1.BrC[C:57]1[CH:58]=[CH:59][C:60]([F:63])=[N:61][CH:62]=1>>[F:63][C:60]1[N:61]=[CH:62][C:57]([CH2:1][N:2]2[C:10]3[C:5](=[CH:6][C:7]([S:11]([N:14]4[CH2:18][CH2:17][C@H:15]4[CH2:19][O:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)(=[O:13])=[O:12])=[CH:8][CH:9]=3)[C:4](=[O:27])[C:3]2=[O:28])=[CH:58][CH:59]=1
Reactant: Fc1ccc(CBr)cn1
Reactant: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Agent: O=C1Nc2ccc(S(=O)(=O)N3CC[C@H]3COc3ccccc3)cc2C1=O
Product: O=C1C(=O)N(Cc2ccc(F)nc2)c2ccc(S(=O)(=O)N3CC[C@H]3COc3ccccc3)cc21
Yield: 62 %

Procedure:
(S)-1-(6-Fluoropyridin-3-ylmethyl)-5-(2-phenoxymethylazetidine-1-sulfonyl)-1H-indole-2,3-dione (18g) was prepared according to the same procedure for compound 11a, except using compound 17 and 5-(bromomethyl)-2-fluoropyridine, and purified with ether to afford 74 mg (62%) of 18g as an orange solid, mp 176.8-178.3° C. 1H NMR (300 MHz, CDCl3) δ 8.27 (d, J=2.4 Hz, 1H), 8.07 (d, J=2.1 Hz, 1H), 8.01 (dd, J=8.25 Hz, J=2.1 Hz, 1H), 7.79 (td, J=8.1 Hz, J=2.4 Hz, 1H), 7.22 (m, 2H), 7.00-6.77 (m, 5H), 4.92 (s, 2H), 4.49 (m, 1H), 4.09 (m, 2H), 3.85 (m, 2H), 2.35-2.23 (m, 2H). Anal. Calcd for C24H20FN3O5S: C, 59.87, H, 4.19; N, 8.73. Found: C, 59.81, H, 4.16; N, 8.62.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]1([C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:19][CH:18]2[C:20]#N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(=O)(=O)(O)[OH:29]>CCCCCC.C1(C)C=CC=CC=1>[C:11]1([C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:19][CH:18]2[CH:20]=[O:29])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#CC1CC1(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=CC1CC1(c1ccccc1)c1ccccc1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
A solution of diisobutylaluminum hydride in hexane (25%; 212 mL) was added over 30 minutes to a solution of 2,2-diphenylcyclopropanecarbonitrile (45.4 g) in dry toluene (400 mL) maintained at -40° C. during the addition. After the reaction had been stirred at room temperature for 1 hour, it was rechilled to 0°-5° C. and 2N sulfuric acid (400 mL) was added dropwise. The two phase system was stirred at ambient temperature for 1 hours then the layers were separated and the aqueous phase was extracted with ethyl acetate (2×300 mL). The organic layers were washed with Rochelle salt solution (5%; 2×200 mL), then were dried (Na2SO4) and evaporated to give 2,2-diphenylcyclopropanecarboxaldehyde as a solid, mp 71°-73° C. A sample was crystallized from benzene-hexane to provide the purified aldehyde, mp 75°-76° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:22][CH2:21][N:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)[CH:8]=[CH:7][C:5]=1[NH2:6].Cl[C:28]1[N:29]=[C:30]([NH:47][C:48]2[CH:56]=[CH:55][CH:54]=[C:53]([F:57])[C:49]=2[C:50](N)=[O:51])[C:31]2[CH:36]=[CH:35][N:34]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C:32]=2[N:33]=1.Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:57][C:53]1[CH:54]=[CH:55][CH:56]=[C:48]2[C:49]=1[C:50](=[O:51])[N:29]1[C:28]([NH:6][C:5]3[CH:7]=[CH:8][C:9]([N:11]4[CH2:16][CH2:15][CH:14]([N:17]5[CH2:18][CH2:19][N:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:21][CH2:22]5)[CH2:13][CH2:12]4)=[CH:10][C:4]=3[O:3][CH3:2])=[N:33][C:32]3[N:34]([S:37]([C:40]4[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=4)(=[O:38])=[O:39])[CH:35]=[CH:36][C:31]=3[C:30]1=[N:47]2
Reactant: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1N
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(F)c4C(N)=O)nc(Cl)nc32)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1Nc1nc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c2nc3cccc(F)c3c(=O)n12
Temperature: 25 °C
Yield: 89.1 %

Procedure:
A solution of 2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline hydrochloride (3 g, 7.41 mmol) and 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (3 g, 6.52 mmol) in trifluroroethanol (200 mL) and HCl in dioxane (14.16 ml, 56.6 mmol) and KI (300 mg, 1.807 mmol) was stirred at 90° C. in a 300 mL pressure vessel behind a blast shield for 15 hours. After cooling to rt, the solution was neutralized with aqueous NaHCO3 (400 mL), the black suspension was added to CH2Cl2 (500 mL), and the layers separated. Addition of brine (200 mL) helped to separate the organic and aqueous layers. The organic layers were concentrated under reduced pressure and then suspended in CH2Cl2 (20 mL) and Et2O (150 mL). The solid was filtered to obtain 8-fluoro-5-[(2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one as brown powder (4.5 g, 5.81 mmol, 89% yield). This material was used without further purification. ESIMS (M+H)+=775.32 (100%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].[C:11](Cl)(=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>C1COCC1>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)c1ccc(N)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2ccc(C(C)=O)cc2)cc1
Yield: 74.5 %

Procedure:
Reaction of 4-aminoacetophenone (74 mg, 0.55 mmol) in THF (6 mL) with p-anisoyl chloride (90 mg, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave N-(4-acetyl-phenyl)-4-methoxy-benzamide (110 mg, 0.41 mmol, 75% yield) as a white powder after washing by dichloromethane.