Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4]1)#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:39]=[CH:40][CH:41]=1)[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36](=[O:38])[CH3:37])[N:34]=2)[N:31]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C=O.CN1CCCC1=O>[C:36]([NH:35][C:33]1[N:34]=[C:29]2[CH:28]=[CH:27][C:26]([O:25][C:24]3[CH:23]=[C:22]([NH:21][C:9](=[O:11])[C:8]4[CH:12]=[CH:13][CH:14]=[C:6]([C:3]5([C:1]#[N:2])[CH2:4][CH2:5]5)[CH:7]=4)[CH:41]=[CH:40][CH:39]=3)=[N:31][N:30]2[CH:32]=1)(=[O:38])[CH3:37]
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Reactant: CC(=O)Nc1cn2nc(Oc3cccc(N)c3)ccc2n1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C5(C#N)CC5)c4)c3)ccc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.6 %

Procedure:
To a solution of 3-(1-cyanocyclopropyl)benzoic acid (1.50 g, 8.01 mmol) in tetrahydrofuran (30 mL) were added N,N-dimethylformamide (2 drops) and oxalyl chloride (1.16 mL, 13.3 mmol), and the mixture was stirred at room temperature for 1.5 hr. The solvent was evaporated under reduced pressure, and the residue and N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]acetamide (1.89 g, 6.67 mmol) were dissolved in N-methylpyrrolidone (30 mL), and the mixture was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0) to give the title compound (2.25 g, 75%) as a pale-brown powder.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6]CC)=[O:5].O.[OH-].[Na+]>C(OC)(C)(C)C>[NH2:1][C@H:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)CC(N)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Product: N[C@@H](CC(=O)O)c1ccccc1

Procedure:
9.2 mmol of the racemic compound ethyl rac-3-amino-3-phenylpropionate (1.79 g) are taken up in 50 ml of a two-phase solvent mixture composed of 25 ml of water and 25 ml of methyl tert-butyl ether (MTBE) as the organic solvent component and set to a pH of 8.2 by automatic pH adjustment through adding 1 M sodium hydroxide solution (obtained through Merck). On reaching a reaction temperature of 20° C., 200 mg of lipase PS (Pseudomonas cepacia; obtained through Amano Enzymes, Inc.) are added to start the reaction. After a reaction time of 3, 5 and 24 hours, the conversion rate of the (S)-3-amino-3-phenylpropionic acid formed is determined. A conversion of 23.5% after 3 hours or a quantitative conversion of approximately 50% after 15 hours and an enantioselectivity of 89.0% ee (after 15 hours) are determined. The conversion and enantioselectivity are determined by means of HPLC.
Reaction SMILES: [CH2:1]([Sn:5](=O)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH2:11]([OH:15])[CH2:12][CH2:13][CH3:14].O.[C:17]1([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:24]1([O:23][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1.[O-:15][CH2:11][CH2:12][CH2:13][CH3:14].[O-:15][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:1]([Sn+2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: CCCC[Sn](=O)CCCC
Solvent: O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCC[O-]
Product: CCCC[Sn+2]CCCC

Procedure:
Dibutyltin oxide was heated to 190° C. in diphenyl ether and then butanol was dropwise added thereto. Water produced by the reaction and excess butanol were distilled out, whereby a diphenyl ether solution of dibutyltin dibutoxide was prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:11][CH2:12][CH3:13])[C:9]=1[OH:10])[CH2:5][OH:6].Br[CH:15]([C:20]1[CH:25]=[CH:24][C:23]2[O:26][CH2:27][O:28][C:22]=2[CH:21]=1)[C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([CH2:11][CH2:12][CH3:13])[C:9]=1[O:10][CH:15]([C:20]1[CH:25]=[CH:24][C:23]2[O:26][CH2:27][O:28][C:22]=2[CH:21]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C(Br)c1ccc2c(c1)OCO2
Reactant: CCCc1cc(CO)cc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1cc(CO)cc(Cl)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 81 %

Procedure:
To a solution of 0.280 g (1.40 mmol) of the product of step C and 0.762 g () of methyl α-bromo-3,4-methylenedioxyphenylacetate in 3.0 mL of acetone was added 0.386 g (2.80 mmol) of finely powdered potassium carbonate and the mixture was stirred and heated at reflux for 2 hours. At this point, the reaction mixture was cooled to room temperature, filtered, and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 30% EtOAc-hexane. Evaporation of the purified fractions and solvent removal in vacuo afforded 0.445 g (81%) of the title compound.
Reaction SMILES: O.[NH2:2][CH:3]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7]2[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=2[C:5]2[CH:24]=[CH:25][CH:26]=[CH:27][C:4]1=2.C([O-])([O-])=O.[K+].[K+].Cl[C:35]([O:37][CH:38]1[CH:43]([CH:44]([CH3:46])[CH3:45])[CH2:42][CH2:41][C@@H:40]([CH3:47])[CH2:39]1)=[O:36]>C1COCC1>[CH:44]([C@@H:43]1[CH2:42][CH2:41][C@@H:40]([CH3:47])[CH2:39][C@H:38]1[O:37][C:35](=[O:36])[NH:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[C:7]2[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=2[C:5]2[CH:24]=[CH:25][CH:26]=[CH:27][C:4]1=2)([CH3:45])[CH3:46]
Reactant: CC(C)C1CC[C@@H](C)CC1OC(=O)Cl
Reactant: COc1ccc(CN2C(=O)C(N)c3ccccc3-c3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)O[C@@H]3C[C@H](C)CC[C@H]3C(C)C)c3ccccc3-c3ccccc32)cc1
Reaction time: 0.25 h
Yield: 41.7 %

Procedure:
Water (40 mL) was added to a yellow solution of 7-amino-5-(4-methoxy-benzyl)-5H,7H-dibenzo[b,d]azepin-6-one (7.45 g) in THF (40 mL) at room temperature forming a light yellow suspension. To this suspension were added K2CO3 (5.53 g) in one portion and, after 15 minutes of stirring, (−)-(1R)-menthyl chloroformate (4.96 g) was added within 30 minutes. The dropping funnel was washed with THF. The emulsion was stirred for 105 minutes at room temperature. Heptane (486 mL) was added within 40 minutes and, after 60 more minutes of stirring, the precipitate was filtered off, washed with heptane, water, and then heptane in that order and dried under vacuum at 55° C. to afford [(S)-5-(4-methoxy-benzyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-carbamic acid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (4.75 g, 45%), d.e=99.8:0.2 (HPLC), as a white powder.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[N:23]=[CH:22][C:21]([CH:24]3[CH2:29][CH2:28][N:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>ClCCl>[C:30]([N:27]1[CH2:28][CH2:29][CH:24]([C:21]2[CH:22]=[N:23][C:18]([N:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[NH:8][CH2:9][CH2:10]3)=[CH:19][CH:20]=2)[CH2:25][CH2:26]1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C3CCN(C(C)(C)C)CC3)cn2)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)N1CCC(c2ccc(N3CCNc4ccccc43)nc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.5 %

Procedure:
4-(1′-(tert-Butyl)-1′,2′,3′,4′,5′,6′-hexahydro-3,4′-bipyridinyl-6-yl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester (0.166 g, 0.37 mmol) is placed in 0.65 ml of dichloromethane at 0° C. and then 4N HCl in dioxane (1.4 ml, 5.59 mmol) is added. The reaction medium is stirred at ambient temperature for 18 h. After concentrating to dryness, the reaction medium is hydrolysed with 20 ml of H2O and then K2CO3 is added until a pH of 10 is reached. The aqueous phase is extracted with ethyl acetate. The organic phase is then washed with a saturated aqueous sodium chloride solution, then dried over MgSO4 and concentrated to dryness. 0.12 g of 1-(1′-(tert-butyl)-1′,2′,3′,4′,5′,6′-hexahydro-3,4′-bipyridinyl-6-yl)-1,2,3,4-tetrahydroquinoxaline is obtained.
Reaction SMILES: [Br:1]Br.[CH3:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:13].C([O-])(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[Br:1][C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[C:4]([CH3:3])[C:5](=[O:13])[N:6]=2)[CH:11]=1
Reactant: CC1C(=O)Nc2ccccc21
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1=c2cc(Br)ccc2=NC1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 93.7 %

Procedure:
Under an atmosphere of nitrogen, bromine (0.96 g, 6.0 mmol) in acetic acid (5 cm3) was added drop wise to a solution of 3-methyl-2-indolinone (0.8749 g, 6.0 mmol) (Kende, et al, Synth. Commun., 12, 1, 1982) and sodium acetate (0.50 g, 6.0 mmol) in acetic acid (10 cm3). The reaction was stirred at room temperature for 3.5 h. Saturated sodium carbonate was added to quench the reaction. The water layer was extracted with EtOAc (×3), dried (MgSO4), filtered, and evaporated to give the title compound (1.26 g, 93%), Mp=119-120° C.; 1H NMR (DMSO) δ 1.32 (d, 3H, J=7.66 Hz), 3.45 (q, 1H, J=7.62 Hz), 6.77 (d, 1 H, J=8.23 Hz), 7.46 (s, 1H), 7.36-7.33 (m, 1H), 10.4 (s, 1H); IR (KBr) 3200, 1725 cm−; MS (EI) m/z 224/226 (M−H)−; CHN calculated for C9H8BrNO: C, 47.82; H, 3.57; N, 6.20; Found: C, 47.44; H, 3.42; N, 6.04.
Reaction SMILES: I[C:2]1[C:3]([CH3:16])=[C:4]2[C:8]3=[C:9]([CH2:11][NH:12][CH2:13][C:14](=[O:15])[N:7]3[CH:6]=[CH:5]2)[CH:10]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[C:23]([C:2]2[C:3]([CH3:16])=[C:4]3[C:8]4=[C:9]([CH2:11][NH:12][CH2:13][C:14](=[O:15])[N:7]4[CH:6]=[CH:5]3)[CH:10]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1c(I)cc2c3c1ccn3C(=O)CNC2
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: Cc1c(-c2cccc(C(F)(F)F)c2)cc2c3c1ccn3C(=O)CNC2
Reaction time: 0.03 h
Yield: 81 %

Procedure:
Using the procedure described in Example 50(b), the title compound was synthesized from 6-iodo-7-methyl-3,4-dihydro-2H-[1,4]diazepino[6,7,1-hi]indol-1-one (Example 50(a)) and 3-trifluoromethylphenylboronic acid in 81% yield after purification by preparative HPLC. A gradient mobile phase, starting with 90% 0.1M NH4OAc, 10% CH3CN up to 2 min, then reaching 100% CH3CN after 22 min, was used. Rt=17.59 min. The title compound was obtained in the form of a white solid: 1H NMR (DMSO-d6) δ 2.25 (s, 3H), 3.44-3.48 (m, 2H), 4.13-4.16 (m, 2H), 7.19 (t, 1H, J=7.5 Hz), 7.77-7.88 (m, 6H), 8.32-8.36 (m, 1H). HRMS calcd. for C19H15N2OF3 (M+) 344.136, found 344.1136. Anal. HPLC Rt=14.9 min.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]=O.[CH2:19]([NH:22][CH2:23][CH:24]=[CH2:25])[CH:20]=[CH2:21]>>[CH2:10]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[O:9][CH2:17][N:22]([CH2:23][CH:24]=[CH2:25])[CH2:19][CH:20]=[CH2:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Reactant: C=O
Reactant: C=CCNCC=C
Product: C=CCN(CC=C)CON(Cc1ccccc1)Cc1ccccc1

Procedure:
The procedure of Example I is repeated using 21.33 g of dibenzylhydroxylamine, 9.73 g of aqueous formaldehyde (37%) solution and 9.72 g of diallylamine, to afford the title compound.
Reaction SMILES: N([O:3][C:4](C)(C)[CH3:5])=O.ClC1C=C2C(=O)N(O)C(=O)C2=CC=1.C1(=NO)CCCCC1.[N+](C1CCCCC1)([O-])=O.[C:38]1(=[O:44])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>C(O)(=O)C.C1CCCCC1>[C:4]([O:44][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)(=[O:3])[CH3:5]
Reactant: CC(C)(C)ON=O
Reactant: O=C1CCCCC1
Agent: O=C1c2ccc(Cl)cc2C(=O)N1O
Agent: O=[N+]([O-])C1CCCCC1
Agent: ON=C1CCCCC1
Solvent: C1CCCCC1
Solvent: CC(=O)O
Product: CC(=O)OC1CCCCC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Cyclohexane (1 ml), t-butyl nitrite (1 mmol), 4-chloro-N-hydroxyphthalimide (0.2 mmol), and acetic acid (1 ml) were placed in a flask and were stirred at 80° C. in an atmosphere of argon gas (1 atm=0.101 MPa) for 20 hours. The resulting reaction mixture was analyzed to find that cyclohexanone oxime, nitrocyclohexane, cyclohexanone, and cyclohexyl acetate were formed in yields of 13%, 9%, 2%, and 2%, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][C:9]3[S:10][CH:11]=[CH:12][C:8]=3[C:7](=[N:15]O)[C:6]=2[CH:17]=1.[Cl-].[NH4+:19].N>[Zn].C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][C:9]3[S:10][CH:11]=[CH:12][C:8]=3[CH:7]([N:15]=[C:5]3[CH2:6][CH2:17][CH2:2][CH2:3][CH2:4][NH:19]3)[C:6]=2[CH:17]=1
Reactant: [NH4+]
Reactant: ON=C1c2cc(Cl)ccc2CCc2sccc21
Agent: N
Agent: [Cl-]
Agent: [Zn]
Solvent: CCO
Product: Clc1ccc2c(c1)C(N=C1CCCCCN1)c1ccsc1CC2
Temperature: 25 °C

Procedure:
80.5 g of 6-chloro-9,10-dihydro-4-hydroxyimino-4H-benzo-[4,5]cyclohepta[1,2-b]thiophene, 105 g of zinc dust and 14 g of ammonium chloride are stirred with 1750 ml of 25% ammonia solution and 350 ml of ethanol for 3 hours at the boiling temperature. Upon cooling to room temperature, the undissolved portion is filtered off and is washed with benzene. 200 ml of concentrated caustic soda solution are added to the filtrate which is extracted with a mixture of ether/benzene 1:1. The organic phase is washed with saturated common salt solution, dried over magnesium sulphate and the solvent is removed by evaporation. The remaining 4-amino-6-chloro-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophene is converted in ethanol into the hydrochloride. M.Pt. decomp. from 234°.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([NH2:11])([CH3:10])([CH3:9])[CH3:8]>C(OCC)C.CCCCC.[Ti](Cl)(Cl)(Cl)Cl>[C:7]([N:11]=[C:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)N
Reactant: O=C1CCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCCCC
Product: CC(C)(C)N=C1CCCC1
Temperature: -55 °C
Reaction time: 6 h
Yield: 76.1 %

Procedure:
Cyclopentanone (13.3 mL, 150 mmol) and tert-butylamine (47.4 mL, 450 mmol) were combined in 110 mL diethyl ether under a nitrogen atmosphere and were then cooled to −55° C. in a dry ice/acetonitrile bath. Titanium tetrachloride (8.2 mL, 75 mmol) was taken up in 70 mL pentane and added dropwise to the above solution, being careful to maintain the temperature at −40° C. the reaction was then stirred at −40° C. for 6 h and was then allowed to warm to room temperature overnight. The reaction mixture was filtered through a short plug of celite and washed with diethyl ether. The filtrate was evaporated in vacuo to yield 15.9 g (76%) of the title product as a clear oil.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[CH:15]=3)=[C:7](I)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:26][CH3:27].[CH3:28][O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([O:38][CH3:39])[C:35]=1[O:36][CH3:37].[C:43]([O-])([O-])=[O:44].[K+].[K+]>C1(OC)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[CH:15]=3)=[C:7]([C:43](=[O:44])[C:32]3[CH:31]=[C:30]([O:29][CH3:28])[C:35]([O:36][CH3:37])=[C:34]([O:38][CH3:39])[CH:33]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:26][CH3:27]
Reactant: COc1ccc(Cn2cc(-c3oc4c(F)c(OC)ccc4c3I)cn2)cc1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: O=C([O-])[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: COc1ccccc1
Product: COc1ccc(Cn2cc(-c3oc4c(F)c(OC)ccc4c3C(=O)c3cc(OC)c(OC)c(OC)c3)cn2)cc1
Temperature: 85 °C
Reaction time: 30 h
Yield: 50.3 %

Procedure:
A suspension of 4-(7-fluoro-3-iodo-6-methoxy-benzofuran-2-yl)-1-(4-methoxybenzyl)-1H-pyrazole (0.087 g, 0.182 mmol), 3,4,5-trimethoxyphenyl boronic acid (0.058 g, 0.27 mmol), dry K2CO3 (0.075 g, 0.55 mmol) and Pd(PPh3)2Cl2 (0.016 g, 0.014 mmol) in anhydrous anisole (8 ml) was placed in Parr mini bench top reactor (series 4561, 300 ml. The reactor was degassed under reduced pressure and flashed with dry N2 than flashed three times with CO by pressurizing the reactor up to 180 psi and depressurizing. Finally, the reactor was pressurized to 180 psi and stirred at 85±5° C. (the temperature of external oil bath) for ˜30 h. The reactor was cooled down to room temperature and the reaction mixture was diluted to 20 ml with CH2Cl2 and filtered through celite. The celite pad was washed with fresh portion of CH2Cl2 (3×20 ml) and combined filtrates were evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica-gel, eluted with CH2Cl2/ethyl acetate 9:1) giving the product of Step 1 as a creamy solid (0.05 g, 50.25%) 1H NMR (300 MHz, CDCl3) 7.98 (s, 1H), 7.97 (s, 1H), 7.08 (s, 2H), 6.9-6.97 (m, 1H), 6.82-6.86 (m, 1H), 5.21 (s, 2H), 3.7-3.96 (m, 15H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([OH:14])=O)=[CH:2]1.[CH:15]([NH:18][NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:17])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([N:18]([CH:15]([CH3:17])[CH3:16])[NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:14])=[CH:2]1
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: O=C(O)/C=C/c1c[nH]c2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)/C=C/c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1H-indol-3-yl)acrylic acid (200 mg, 1.06 mmol), N′-isopropylbenzohydrazide (283.4 mg, 1.59 mmol) and HATU (604.6 mg, 1.59 mmol) dissolved in DMF (7.0 ml), N,N-diisopropylethylamine (DIPEA)(0.277 ml, 1.59 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc:methanol=15:3:1) and dried so that white solid form of (E)-N′-(3-(1H-indol-3-yl)acryloyl)-N′-isopropylbenzohydrazide was obtained (327 mg, 88%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]3[CH2:18][CH2:17][CH2:16][C@H:15](O)[C:10]=3[CH:11]=2)[CH2:6]1)=[O:4].C1C=CC(P([N:36]=[N+:37]=[N-:38])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1.Cl>C1(C)C=CC=CC=1>[N:36]([C@H:15]1[C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][C:9]=2[CH2:18][CH2:17][CH2:16]1)[CH2:6][N:5]([C:3](=[O:4])[C:2]([F:21])([F:20])[F:1])[CH2:14][CH2:13]3)=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(N1CCc2cc3c(cc2C1)CCC[C@@H]3O)C(F)(F)F
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=N[C@@H]1CCCc2cc3c(cc21)CCN(C(=O)C(F)(F)F)C3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-2,2,2-trifluoro-1-(6-hydroxy-3,4,6,7,8,9-hexahydrobenzo[g]isoquinolin-2(1H)-yl)ethanone (3.0 g, 10 mmol) in 30 mL of toluene at −10° C. was added DPPA (2.6 mL, 12 mmol). To this stirred solution was then added DBU (1.8 mL, 12 mmol) dropwise while keeping the temperature below 0° C. After stirring at room temperature overnight, 7 mL of 10% HCl was added and the resulting solution was evaporated to dryness and directly submitted to flash chomatography (SiO2, hexane/EtOAc=100:10 to 100:15 to 100:20) to afford (R)-1-(6-azido-3,4,6,7,8,9-hexahydrobenzo[g]-isoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone as a colorless oil which was directly used in the next step.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:41][C:15]3[N:16]=[C:17]([C:26]4[C:27]5[C:31]([CH:32]=[CH:33][CH:34]=4)=[N:30][N:29](C4CCCCO4)[CH:28]=5)[N:18]=[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].CO.S(=O)(=O)(O)O>O>[NH:30]1[C:31]2[C:27](=[C:26]([C:17]3[N:18]=[C:19]([N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[C:14]4[CH:13]=[C:12]([CH2:11][N:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH2:7]5)[S:41][C:15]=4[N:16]=3)[CH:34]=[CH:33][CH:32]=2)[CH:28]=[N:29]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cccc5nn(C6CCCCO6)cc45)nc3s2)CC1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cccc5[nH]ncc45)nc3s2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 112.2 %

Procedure:
4-(6-((4-(Methylsulfonyl)piperazin-1-yl)methyl)-2-(2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl)thieno[2,3-d]pyrimidin-4-yl)morpholine 21 (500 g, 0.836 mole) was charged to a sizable reactor, followed by methanol (9.5 L) and water (250 ml). The resulting slurry was cooled to 0° C. and stirred for 0.5 h. A cold solution of concentrated sulfuric acid (H2SO4, 5.54 ml, assay 95-98%, 1.004 mole, 1.20 equiv.) and water (250 ml) was slowly added while maintaining the temperature below 10° C. The mixture was allowed to warm up to the ambient temperature and stirred for 20 hours. The slurry was cooled to 5° C., filtered and rinsed with cold methanol (2 L). The cake was charged to a reactor and stirred in a mixture of methanol (9.5 L) and water (25 ml) at 50° C. for 3 hours. The slurry was cooled 0-5° C., filtered and rinsed with cold methanol (2 L). The cake was dried in a vacuum oven at 50° C. for 24 hours to afford 4-(2-(1H-Indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-4-yl)morpholine II sulfate salt as a light yellow solid (482 g, 94%). 1H NMR (300 MHz, DMSO-d6) δ 3.00-4.00 (br, 8H), 3.01 (s, 3H), 3.85-3.87 (m, 4H), 4.00-4.02 (m, 4H), 4.69 (s, 2H), 7.46-7.52 (t, 7.8 Hz, 1H), 7.70-7.73 (d, 8.3 Hz, 1H), 7.91 (br, 1H), 8.22-8.25 (d, 7.2 Hz, 1H), 8.82 (s, 1H). LCMS (ESI pos) m/e 514 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5]N1CCCCC1.[CH:16]1[CH:17]=[CH:18]C2N(O)N=[N:22][C:20]=2[CH:21]=1.[CH:26]1([C:31]([OH:33])=O)[CH2:30][CH:29]=[CH:28][CH2:27]1.CCN=C=NCCCN(C)C>ClCCl.CN(C1C=CN=CC=1)C.O>[CH:26]1([C:31]([N:22]2[CH2:18][CH2:17][CH:16]([O:5][C:4]3[CH:12]=[CH:13][C:14]([Cl:15])=[C:2]([Cl:1])[CH:3]=3)[CH2:21][CH2:20]2)=[O:33])[CH2:27][CH:28]=[CH:29][CH2:30]1
Reactant: O=C(O)C1CC=CC1
Reactant: On1nnc2ccccc21
Reactant: Clc1ccc(ON2CCCCC2)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(C1CC=CC1)N1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 60 h
Yield: 79.6 %

Procedure:
3,4-Dichlorophenoxypiperidine (3.09 g) was dissolved in dichloromethane (80 mL). HOBT (1.77 g) and DMAP (0.44 g) were added followed by a solution of 3-cyclopentene-1-carboxylic acid (1.45 g) in dichloromethane (5 mL). EDCI (2.45 g) was added and the solution was stirred for 60 h. Water (100 mL) was added and the phases were separated. The aqueous phase was extracted with dichloromethane (2×40 mL). The organic phases were combined, dried (MgSO4), filtered and evaporated to give subtitle compound (3.40 g) that was used without further purification.