Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16](Cl)=[N:17][C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2.[OH-:21].[Na+]>C(O)CCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16]([O:21][CH2:4][CH2:3][CH2:12][CH3:11])=[N:17][C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)-c1cc(Cl)nc(=O)n1CC2
Reactant: [OH-]
Agent: [Na+]
Solvent: CCCCO
Product: CCCCOc1cc2n(c(=O)n1)CCc1cc(OC)c(OC)cc1-2
Yield: 85 %

Procedure:
1.46 g of 9,10-dimethoxy-6,7-dihydro-2-chloro-4H-pyrimido(6,1-a)-isoquinolin-4-one are added to a mixture of 1.0 g of sodium hydroxide and 50.0 ml of n-butanol. The reduction mixture is refluxed for 6 hours. The solent is removed under reduced pressure. The residue is treated with water and extracted with chloroform. The extract is dried over anhydrous Na2SO4 and evaporated to give a white solid. After crystallization from a chloroform-ether mixture, 0.7 g of the title compound is obtained, m.p. 158°-159° C.
Reaction SMILES: [CH3:1][C:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)([CH3:4])[CH3:3].[P:11](=[O:19])([N:16]=[C:17]=[O:18])([S:14][CH3:15])[O:12][CH3:13]>CCOCC>[CH3:1][C:2]([N:5]1[CH2:10][CH2:9][N:8]([C:17]([NH:16][P:11](=[O:19])([S:14][CH3:15])[O:12][CH3:13])=[O:18])[CH2:7][CH2:6]1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)N1CCNCC1
Reactant: COP(=O)(N=C=O)SC
Solvent: CCOCC
Product: COP(=O)(NC(=O)N1CCN(C(C)(C)C)CC1)SC
Yield: 86 %

Procedure:
To a stirred solution of 2.85 grams (g) of 1-(1,1-dimethylethylpiperazine in 60 milliliters (ml) of ether was added dropwise at ambient temperature 3.4 g of O,S-dimethyl phosphoroisocyanatidothioate. A precipitate began to form almost immediately. After a short time this precipitate was collected by filtration, extracted with ether, and dried to obtain 5.34 g of the title compound (86 percent of theory) as white crystals melting at 133-135° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)(OC)=[O:2].C1COCC1.[BH4-].[Na+]>O>[OH:2][CH2:1][C:5]1[N:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc2c(cn1)[nH]c1ccccc12

Procedure:
3-carbomethoxy-β-carboline or a derivative thereof (J in Scheme VII above) is dissolved in a polar solvent (e.g., THF), and a reducing agent (e.g., NaBH4) is added to the solution. The mixture is stirred for a few hours and cooled. An excess of water is then added, and the mixture is stirred for another few hours. The solvent is thereafter evaporated and the resulting residue is dissolved in water, washed several times with one or more non-polar solvents such as dichloromethane and ethyl acetate, and the combined organic extracts are then evaporated. The remaining residue is purified by column chromatography (e.g., on a silica gel with elution by a 9:1 mixture of ethylacetate and methanol), to give a 3-hydroxymethyl-β-carboline intermediate.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([O:24][CH3:25])=[C:17]([O:22][CH3:23])[CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:28][CH3:29])=[C:7]([O:26][CH3:27])[CH:8]=2)[N:3]=1.[NH3:30]>C(O)C>[NH2:30][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([O:24][CH3:25])=[C:17]([O:22][CH3:23])[CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:28][CH3:29])=[C:7]([O:26][CH3:27])[CH:8]=2)[N:3]=1
Reactant: N
Reactant: COc1cc2c(cc1OC)CN(c1nc(Cl)nc3cc(OC)c(OC)cc13)CC2
Solvent: CCO
Product: COc1cc2c(cc1OC)CN(c1nc(N)nc3cc(OC)c(OC)cc13)CC2
Temperature: 25 °C

Procedure:
The product of (A), viz, 2-chloro-6,7-dimethoxy-4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline (5.0 g.) and a saturated solution of ammonia in ethanol (60 ml.) were heated together in an autoclave at 100° C. for a period of approximately 16 hours. After the reaction mixture had been allowed to cool to room temperature (~25° C.), the solvent was removed by means of evaporation under reduced pressure and the resulting brown residue (5.0 g.) was partitioned between methylene chloride and water. The separated organic layer thus obtained was then evaporated in vacuo and the residue (3.0 g.) was subsequently converted into the hydrochloride salt by conventional means. Recrystallization of the crude material from a mixture of ethanol and isopropanol then afforded 1.0 g. of pure final product as the hydrochloride hemihydrate, m.p. 245° C.
Reaction SMILES: O=[C:2]([CH2:6][C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)[CH2:3][C:4]#[N:5].[NH2:14][NH2:15]>CCO>[CH3:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[CH2:6][C:2]1[CH:3]=[C:4]([NH2:5])[NH:14][N:15]=1
Reactant: Cc1cccc(CC(=O)CC#N)c1
Reactant: NN
Solvent: CCO
Product: Cc1cccc(Cc2cc(N)[nH]n2)c1

Procedure:
3-Oxo-4-m-tolyl-butyronitrile (2.5583 gms.) is then suspended in 50 mL of anhydrous EtOH. This suspension is treated with 1.0 mL of anhydrous hydrazine, and subsequently heated to refluxing temperature for 1 day. The reaction mixture is concentrated in vacuo. The residue is then triturated with isopropanol to precipitate out the 5-(3-methyl-benzyl)-2H-pyrazol-3-ylamine.
Reaction SMILES: CC1(C)[O:6][C@H:5]([C:7]([N:9]2[CH2:14][CH2:13][C:12]([C:15]3[C:20]([F:21])=[CH:19][C:18]([N:22]4[CH2:26][C@H:25]([CH2:27][N:28]([C:36]5[O:40][N:39]=[C:38]([CH3:41])[CH:37]=5)C(OC(C)(C)C)=O)[O:24][C:23]4=[O:42])=[CH:17][C:16]=3[F:43])=[CH:11][CH2:10]2)=[O:8])[CH2:4][O:3]1.FC(F)(F)C(O)=O.O>ClCCl>[OH:6][C@@H:5]([CH2:4][OH:3])[C:7]([N:9]1[CH2:14][CH2:13][C:12]([C:15]2[C:20]([F:21])=[CH:19][C:18]([N:22]3[CH2:26][C@H:25]([CH2:27][NH:28][C:36]4[O:40][N:39]=[C:38]([CH3:41])[CH:37]=4)[O:24][C:23]3=[O:42])=[CH:17][C:16]=2[F:43])=[CH:11][CH2:10]1)=[O:8]
Reactant: Cc1cc(N(C[C@H]2CN(c3cc(F)c(C4=CCN(C(=O)[C@@H]5COC(C)(C)O5)CC4)c(F)c3)C(=O)O2)C(=O)OC(C)(C)C)on1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(NC[C@H]2CN(c3cc(F)c(C4=CCN(C(=O)[C@@H](O)CO)CC4)c(F)c3)C(=O)O2)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
3-(4-(1-(2,2-Dimethyl-1,3-dioxolan-4(S)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-5(R)-(N-(t-butoxycarbonyl)-3-methylisoxazol-5-ylaminomethyl)oxazolidin-2-one (400 mg, 0.65 mM) was dissolved in dichloromethane (6 ml) and treated with trifluoroacetic acid (6 ml) at 0°. After stirring for 30 minutes at ambient temperature, water (1.2 ml) was added, and stirring continued for 1 hour. Solvent was removed, the residue dissolved in methanol (20 ml), and treated with aqueous ammonia to bring the pH to 7-8; solvent was removed, and the residue chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 5% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (181 mg ). NMR (DMSO-d6) δ: 2.02 (s, 3H); 2.29 (m, 1H); 2.35 (m, 1H); 3.41 (t, 2H); 3.47 (m, 1H); 3.54 (m, 1H); 3.71 (m, 1H); 3.75 (dd, 1H); 4.04 (dd, 1H); 4.08 (m, 1H); 4.13 (t, 1H); 4.24 (m, 1H); 4.36 (t, 1H); 4.66 (t, 1H); 4.82 (m, 1H); 4.95 (t, 1H); 4.99 (s, 1H); 5.85 (s, 1H); 7.30 (d, 2H); 7.36 (t, 1H). MS (ESP): 479 (MH+) for C22H24F2N4O6
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])=[CH:17][C:16]=2[OH:27])=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CC(C)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])=[CH:17][C:16]=2[O:27][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CC(C)=CCOc1ccc(C(=O)C=Cc2ccc(C(C)(C)C)cc2)c(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(OCC=C(C)C)ccc1C(=O)C=Cc1ccc(C(C)(C)C)cc1
Reaction time: 0.08 h
Yield: 85.4 %

Procedure:
To a solution of 45.1 g of 4-t-butyl-2'-hydroxy-4'-(3-methyl-2-butenyloxy)chalcone in 500 ml of acetone was added 10.6 g of potassium hydroxide, and the mixture was stirred for 5 minutes. Then, 21.5 g of ethyl bromoacetate was added, and the mixture was stirred for 45 minutes. After neutralization with dilute hydrochloric acid, the precipitated solid was collected by filtration, washed with water, dried and recrystallized from ethanol to give 47.6 g of 4-t-butyl-2'-ethoxycarbonylmethoxy-4'-(3-methyl-2-butenyloxy)chalcone as a pale yellow powder.
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[CH3:20])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[ClH:31]>CO.[OH-].[OH-].[Pd+2]>[ClH:31].[CH:22]1([CH2:21][N:19]([CH3:20])[C:17]2[CH:16]=[N:15][C:13]3[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=3[N:18]=2)[CH2:23][CH2:24]1
Reactant: CN(CC1CC1)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(CC1CC1)c1cnc2c(n1)OCCNC2
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 67 %

Procedure:
To a solution of 8-benzyl-N-(cyclopropylmethyl)-N-methyl-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (0.36 g) in methanol (10 mL) was added 20% Pd(OH)2/C (70 mg), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 2.5 hr. The reaction mixture was filtered, and the filtrate was concentrated. To a solution of the obtained crude product in ethyl acetate (10 mL) was added a 4 N hydrogen chloride-ethyl acetate solution (300 μL), and the mixture was stirred for 30 min. The reaction mixture was filtered, and the obtained crystals were purified by recrystallization (methanol-ethyl acetate) to give the title compound (197 mg, 67%) as a colorless powder.
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)#[N:32].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2ccc(C#N)cc2)CC1
Yield: 11 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 4-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown solid (11%).
Reaction SMILES: [N:1]1([CH2:4][C@:5]23[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:6]2[C@@H:7]2[C@@:20]([CH3:23])([CH2:21][CH2:22]3)[C@@:19]3([CH3:24])[C@@H:10]([C@:11]4([CH3:40])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]3[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][CH:28]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[CH3:47][S:48]([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)(=[O:50])=[O:49]>CC(C)=O>[CH3:23][C@:20]12[C@@:19]3([CH3:24])[C@@H:10]([C@:11]4([CH3:40])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:25])([CH3:26])[C:14]([C:27]3[CH:28]=[CH:29][C:30]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[CH:38][CH:39]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:41]([C:44]([CH3:46])=[CH2:45])[CH2:42][CH2:43][C@:5]1([CH2:4][NH:1][CH2:2][CH2:3][N:54]1[CH2:55][CH2:56][N:51]([S:48]([CH3:47])(=[O:50])=[O:49])[CH2:52][CH2:53]1)[CH2:22][CH2:21]2
Reactant: C=C(C)[C@@H]1CC[C@]2(CN3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: CC(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(CNCCN3CCN(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
A mixture of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aziridin-1-ylmethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (30 mg, 0.048 mmol) and 1-(methylsulfonyl)piperazine (78.7 mg, 0.48 mmol) in acetone (5 mL) was heated at reflux in a sealed tube for 18 h. The desired compound was detected by LCMS (M+1=790.7, 2.96 min, method 9).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][C:17]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[NH:19][C:18]2=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:37]([N:39]([CH2:55][CH3:56])[C:40]([N:42]1[C:50]2[C:45](=[CH:46][C:47]([S:51](Cl)(=[O:53])=[O:52])=[CH:48][CH:49]=2)[CH2:44][CH2:43]1)=[O:41])[CH3:38].O>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][NH:16][C:17]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[N:19]([S:51]([C:47]3[CH:46]=[C:45]4[C:50](=[CH:49][CH:48]=3)[N:42]([C:40]([N:39]([CH2:55][CH3:56])[CH2:37][CH3:38])=[O:41])[CH2:43][CH2:44]4)(=[O:52])=[O:53])[C:18]2=[O:27])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(CC)C(=O)N1CCc2cc(S(=O)(=O)Cl)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(CCNC2(c3ccccc3Cl)C(=O)Nc3ccc(Cl)cc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)C(=O)N1CCc2cc(S(=O)(=O)N3C(=O)C(NCCC4CCN(C(=O)OC(C)(C)C)CC4)(c4ccccc4Cl)c4cc(Cl)ccc43)ccc21
Reaction time: 0.5 h
Yield: 126.8 %

Procedure:
A solution of 1 g of 3-[[2-(1-tert-butoxycarbonylpiperid-4-yl)ethyl]amino]-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one in 5 ml of DMF is cooled to +4° C. under an argon atmosphere and 0.087 g of sodium hydride as a 60% dispersion in oil is added. After stirring for 30 minutes at +4° C., 0.627 g of 1-(diethyl-aminocarbonyl)indoline-5-sulfonyl chloride is added and the mixture is stirred for 3 hours at RT. 50 ml of water are added to the reaction mixture, extraction is carried out with AcOEt, the organic phase is washed with a saturated solution of NaCl and with water and dried over sodium sulfate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using DCM and then a DCM/AcOEt mixture (88/12; v/v) as the eluent to give 1.97 g of the expected product after crystallization from a DCM/iso ether mixture. M.p.=139° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21](CC4C=CC(OC)=CC=4)[C:22]4[CH:27]=[CH:26][N:25]=[CH:24][N:23]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([O:37][CH3:38])[CH:3]=1.[F:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[F:39][C:40]1[CH:45]=[CH:44][C:43]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:17]4[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]5[CH:27]=[CH:26][N:25]=[CH:24][N:23]=5)(=[O:20])=[O:19])=[CH:15][CH:16]=4)[CH:11]=[CH:10][N:9]=3)=[C:4]([O:37][CH3:38])[CH:3]=2)=[CH:42][CH:41]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(-c4ccc(Cl)cc4OC)nccc3c2)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1cc(-c2ccc(F)cc2)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Reaction time: 0.75 h
Yield: 75.6 %

Procedure:
A vial was charged with 1-(4-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (INTERMEDIATE BBBBB, 42.9 mg, 0.078 mmol), (4-fluorophenyl)boronic acid (21.95 mg, 0.157 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (1.610 mg, 3.92 μmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (2.97 mg, 3.92 μmol), and potassium phosphate (49.9 mg, 0.235 mmol). The vial was flushed with Ar (g), then THF (0.4 mL) and water (0.04 mL) were added in sequence. The vial was sealed and placed in a 110° C. heating bath overnight, then the mixture was cooled and extracted with EtOAc (3×). The combined organic extracts were concentrated. The residue was taken up in DCM (1 mL), TFA (0.5 mL), and triflic acid (0.05 mL) (8:40 am). After 45 min, the mixture was concentrated. The residue was taken up in EtOAc. The organic solution was washed with saturated aq. sodium bicarbonate solution (2×), dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (25-g Interchim 15 micron column, 10% MeOH/DCM) to give 1-(4′-fluoro-3-methoxy-[1,1′-biphenyl]-4-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (28.7 mg, 0.059 mmol, 75% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=13.04 (s, 1H), 8.69 (d, J=5.8 Hz, 1H), 8.64 (d, J=1.5 Hz, 1H), 8.56 (s, 1H), 8.23 (d, J=6.2 Hz, 1H), 8.09 (d, J=5.4 Hz, 1H), 7.95 (dd, J=1.9, 8.9 Hz, 1H), 7.91-7.83 (m, 2H), 7.78 (d, J=8.9 Hz, 1H), 7.46-7.39 (m, 3H), 7.38-7.31 (m, 2H), 7.02 (d, J=6.4 Hz, 1H), 3.75 (s, 3H). m/z (ESI) 487.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]=[C:4]2[CH2:14][CH2:15][CH2:16][C:3]=12.CC1(C)C(C)(C)OB([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35]C)=[O:34])=[CH:28][CH:27]=2)O1.C([O-])([O-])=O.[Na+].[Na+].[Cl-]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.O1CCOCC1>[CH:9]1([O:8][C:6]2[N:5]=[C:4]3[CH2:14][CH2:15][CH2:16][C:3]3=[C:2]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([CH2:32][C:33]([OH:35])=[O:34])=[CH:30][CH:31]=3)[CH:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)Cc1ccc(CB2OC(C)(C)C(C)(C)O2)cc1
Reactant: Clc1cc(OC2CCCC2)nc2c1CCC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)Cc1ccc(Cc2cc(OC3CCCC3)nc3c2CCC3)cc1
Temperature: 25 °C

Procedure:
A 20-mL sealed tube, with stirrer bar, was charged with 4-chloro-2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.103 g, 0.43 mol), methyl 2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate (0.126 g, 0.43 mmol), Pd(dppf)Cl2 (0.035 g, 0.043 mmol), and powdered Na2CO3 (0.184 g, 1.74 mmol). Dioxane (4 mL) and water (2 mL) were added. The resulting mixture was stirred under Ar at 90° C. for 24 h. until the starting chloride was consumed. After this time, the mixture was cooled to room temperature and the reaction mixture absorbed onto silica (4 g). Purification by chromatography on silica using dichloromethane/methanol (10:0 to 8:2) as eluent to afford 2-(4-((2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)acetic acid. MW=351.44. MS: ESI+, m/z 352 [M+H]+. This product was dissolved in methanol and treated with 4M HCl/methanol and stirred for 3 days. The reaction was concentrated under reduced pressure. The residue (0.154 g) was treated with minimum saturated sodium bicarbonate then purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 1:1) as eluent to afford the title compound (0.038 g, 24%) as a colorless oil. MW=365.47. 1H NMR (CDCl3, 300 MHz) δ 7.23-7.17 (m, 2H), 7.14-7.08 (m, 2H), 6.22 (s, 1H), 5.35-5.26 (m, 1H), 3.81 (s, 2H), 3.69 (s, 3H), 3.60 (s, 2H), 2.89 (t, J=8.0 Hz, 2H), 2.72 (t, J=7.5 Hz, 2H), 2.06 (quin, J=7.5 Hz, 2H), 1.98-1.88 (m, 2H), 1.85-1.68 (m, 4H), 1.66-1.53 (m, 2H); APCI MS 366 [M+H]+.
Reaction SMILES: CON(C)[C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5].[CH2:17]([Mg]Br)[CH:18]([CH3:20])[CH3:19].O1CCCC1.C([Mg]Br)C(C)C.[Cl-].[NH4+]>O1CCCC1>[CH3:17][CH:18]([CH3:20])[CH2:19][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5]
Reactant: CON(C)C(=O)c1oc2ccccc2c1C
Reactant: CC(C)C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(C(=O)CC(C)C)oc2ccccc12
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution (20 mL) of N-methoxy-N,3-dimethyl-1-benzofuran-2-carboxamide (1.00 g) synthesized above in tetrahydrofuran was added dropwise a 1.0M solution (6.84 mL) of isobutylmagnesium bromide in tetrahydrofuran at 0° C., and the mixture was stirred for 1 hr. In addition, 1.0M isobutylmagnesium bromide tetrahydrofuran solution (6.84 mL) was added, and the mixture was stirred at 0° C. for 1 hr then at room temperature for 2 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9, volume ratio) to give the title object compound (873 mg, 89%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][Cl:12].[N:14]([O-])=O.[Na+]>Cl.O>[Cl:12][CH2:11][CH2:10][CH2:9][C:8]1[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[NH:1][N:14]=1
Reactant: Nc1ccccc1C(=O)CCCCl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: ClCCCc1n[nH]c2ccccc12
Reaction time: 1 h
Yield: 24.9 %

Procedure:
To a suspension of 1-(2-aminophenyl)-4-chloro-1-butanone (508 mg, 2.6 mmol) in concentrated HCl (3.5 mL) at −5° C. was added a solution of NaNO2 (193 mg, 2.8 mmol) in H2O (0.75 mL), and the reaction mixture was stirred for 1 h. A solution of SnCl2-2H2O (1.37 g, 6.07 mmol) in concentrated HCl (1.9 mL) was added at −5° C. to the solution, and this stirred for 1 h under ice cooling. The reaction was quenched with H2O and extracted into Et2O (100 mL). The organic solution was washed with H2O (50 mL) and brine (50 mL), dried over MgSO4 and concentrated in vacuo. Purification by column chromatography afforded 3-(3-chloropropyl)-1H-indazole (126 mg, 25%) as a yellow solid. The title compound was isolated as a yellow oil (38 mg, 77%) according to the method of Example 286, Step C from (8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole (30 mg, 0.12 mmol) and 3-(3-chloropropyl)-1H-indazole (44 mg, 0.24 mmol). 1H NMR (CDCl3) δ1.83-2.19 (m, 7H), 2.23-2.35 (m, 1H), 2.43-2.54 (m, 2H), 2.72-2.79 (m, 1H), 2.81-2.88 (m, 1H), 2.92-3.11 (m, 4H), 3.12-3.21 (m, 1H), 3.24-3.29 (m, 1H), 3.51-3.62 (m, 1H), 3.80-3.92 (m, 1H), 6.61 (t, 1H, J=7.5 Hz), 6.84 (d, 1H, J=6.6 Hz), 6.94 (dd, 1H, J=1.1, 7.7 Hz), 7.11-7.16 (m, 1H), 7.34-7.48 (m, 2H), 7.70 (d, 1H, J=8.0 Hz) ppm.