Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([C:21]3([CH3:24])[CH2:23][CH2:22]3)=[O:20])[CH2:15][CH2:14]2)=[N:4][CH:3]=1.C1COCC1.ClC(Cl)(Cl)C[O:33][C:34](=O)[NH:35][C:36]1[N:37]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)[N:38]=[C:39]([C:41]2([CH3:44])[CH2:43][CH2:42]2)[CH:40]=1>>[CH3:24][C:21]1([C:19]([N:16]2[CH2:17][CH2:18][CH:13]([O:12][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2]([NH:1][C:34]([NH:35][C:36]4[N:37]([C:45]5[CH:46]=[CH:47][C:48]([CH3:51])=[CH:49][CH:50]=5)[N:38]=[C:39]([C:41]5([CH3:44])[CH2:42][CH2:43]5)[CH:40]=4)=[O:33])=[CH:3][N:4]=3)[CH2:14][CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CC1(C(=O)N2CCC(Oc3ncc(N)c4ccccc34)CC2)CC1
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)Nc2cnc(OC3CCN(C(=O)C4(C)CC4)CC3)c3ccccc23)cc1
Temperature: 46.5 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
Add [4-(4-Amino-isoquinolin-1-yloxy)-piperidin-1-yl]-(1-methyl-cyclopropyl)-methanone (Preparation 23, 331.00 g, 1.02 moles), THF (3.97 L, 48.79 moles), [5-(1-Methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (Preparation 18, 410.00 g, 1.02 moles), and DIPE (159.00 g, 1.22 moles) to a 12 L Morton flask equipped with overhead stirrer, thermocouple, and reflux condenser. Reflux the mixture for 22 hours. Cool reaction to <50° C. and treat with carbon (Darco G-60; 33.00 g, 2.75 moles). Stir the slurry for 30 minutes at 43-50° C., then filter over micro fiber paper and Hyflo Super Cel® (27.00 g). Seed the filtrate and allow to cool at ambient temperature during precipitation. Pack the resulting slurry in ice and stir overnight. Filter the solids, wash with THF (300.00 mL, 3.69 moles), and dry under reduced pressure at 40° C. Subject residue to silica gel chromatography eluting with 1:3 acetone/DCM, then 30% acetone in DCM to obtain 401 g (68%) 1-{1-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yloxy]-isoquinolin-4-yl}-3-[5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-urea as a white solid 1H NMR (300 MHz, DMSO-d6): δ 0.56 (t, J=6.0 Hz, 2H), 0.73 (t, J=6.0 Hz, 2H), 0.84 (t, J=6.0 Hz, 2H), 0.92 (t, J=6.0 Hz, 2H), 1.27 (s, 3H), 1.41 (s, 3H), 1.73-1.81 (m, 2H), 1.99-2.08 (m, 2H), 2.41 (s, 3H), 3.52-3.65 (m, 2H), 3.83-3.96 (m, 2H), 5.47-5.58 (m, 1H), 6.22 (s, 1H), 7.37 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.65-7.71 (m, 1H), 7.78-7.83 (m, 2H), 8.12 (s, 1H), 8.27 (d, J=8.4 Hz, 1H), 8.58 (s, 1H), 8.69 (s, 1H).
Reaction SMILES: [Cl-:1].[OH:2][CH:3]([CH2:9]O)[CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6].S(Cl)([Cl:13])=O>CN(C)C=O>[Cl-:13].[Cl:1][CH2:9][CH:3]([OH:2])[CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: C[N+](C)(C)CC(O)CO
Agent: [Cl-]
Solvent: CN(C)C=O
Product: C[N+](C)(C)CC(O)CCl
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 96.6 %

Procedure:
There was suspended 9.20 g of 2,3-dihydroxypropyltrimethylammonium chloride (chemical purity: 100%) in 50 ml of dimethylformamide, and thereto 6.80 g of thionyl chloride was added at a temperature from 5° to 10° C. After stirring for 20 minutes, it was heated at 100° C. for 5 hours. Finally, after cooling the reaction mixture to room temperature, 9.85 g of 3-chloro-2-hydroxypropyltrimethylammonium chloride was obtained by evaporating the reaction mixture to dryness.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([O:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[CH:28]([CH3:30])[CH3:29])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:32])[C:19](=[O:31])[NH:20][N:21]=2)([CH3:12])[CH2:9]1)=O)(C)(C)C.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[CH:28]([C:27]1[CH:26]=[C:25]2[C:16]([N:17]3[C:22]([CH2:23][O:24]2)=[N:21][NH:20][C:19](=[O:31])[CH:18]3[CH3:32])=[CH:15][C:14]=1[O:13][C:10]1([CH3:12])[CH2:9][NH:8][CH2:11]1)([CH3:30])[CH3:29]
Reactant: CC(C)c1cc2c(cc1OC1(C)CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1cc2c(cc1OC1(C)CNC1)N1C(=NNC(=O)C1C)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 3-(7-isopropyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.049 g, 0.110 mmol) in DCM (2 mL) was added TFA (0.35 mL) and the mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo. The residue was purified by preparative HPLC (Table 3, Method 7) to give 7-isopropyl-4-methyl-6-(3-methyl-azetidin-3-yloxy)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid as a pale solid (0.042 g, 82%). LC/MS (Table 1, Method 5) Rt=2.233 min.; MS m/z: 345 [M+H]+
Reaction SMILES: CC([CH2:5][N:6]([CH2:10][CH2:11][NH:12][C:13]1[N:14]=[C:15]([C:32]2[CH:37]=[C:36]([C:38]([NH:40][C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=3)=[O:39])[CH:35]=[CH:34][C:33]=2[CH3:48])[C:16]2[CH2:21][NH:20][C:19](=[O:22])[N:18]([C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=3[F:30])[C:17]=2[N:31]=1)C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:29][C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([F:30])[C:23]=1[N:18]1[C:17]2[N:31]=[C:13]([NH:12][CH2:11][CH2:10][NH:6][CH3:5])[N:14]=[C:15]([C:32]3[CH:37]=[C:36]([CH:35]=[CH:34][C:33]=3[CH3:48])[C:38]([NH:40][C:41]3[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=3)=[O:39])[C:16]=2[CH2:21][NH:20][C:19]1=[O:22]
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(NCCN(CC(C)(C)C)C(=O)[O-])nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCNc1nc(-c2cc(C(=O)Nc3ccc(F)cc3)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
To a solution of 1,1-dimethylethyl(2-{[8-(2,6-difluorophenyl)-4-(5-{[(4-fluorophenyl)amino]carbonyl}-2-methylphenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]amino}ethyl)methylcarbamate (20 mg, 0.030 mmol) in DCM (5 mL) was added TFA (0.06 mL). The reaction mixture was stirred at room temperature overnight, quenched with triethylamine (0.2 mL) at −78° C. The residue was mixed with H2O (5.0 mL). The organic layer was separated and the aqueous layer was extracted with DCM (3×15 mL). The combined organic phases were washed with saturated aq. NaCl, dried over Na2SO4, filtered, and concentrated. Purification via a CombiFlash system (90% CH2Cl2/7% MeOH/3% NH4OH) then afforded the title compound (11 mg, 65%). LC-MS (ES) m/z 562 (M+H)+; 1H-NMR(MeOD) δ 2.27 (s, 3H), 2.34 (s, 3H), 2.57 (m, 2H), 3.26 (m, 2H), 4.11 (s, 2H), 7.15 (m, 4H), 7.52 (m, 2H), 7.71 (m, 2H), 7.82 (s, 1H), 7.97 (d, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>ClCCl>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([S:27]([C:24]3[CH:25]=[CH:26][C:21]([Br:20])=[CH:22][CH:23]=3)(=[O:29])=[O:28])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1CCN(c2ccncc2)CC1
Reaction time: 2 h
Yield: 73.2 %

Procedure:
A solution of 1-(4-pyridyl)piperazine (0.49 g) and triethylamine (0.7 ml) in dry dichloromethane (20 ml) was treated slowly with a solution of 4-bromophenylsulphonyl chloride (0.77 g) in dry dichloromethane (10 ml). The reaction mixture was then stirred under argon for 2 hours. The dichloromethane solvent was removed by evaporation and the residue dissolved in ethyl acetate. The organic extracts were washed with water, brine, dried (MgSO4) and evaporated to yield a white crystalline solid which was recrystallised from ethyl acetate to give 1-(4-pyridyl)-4-(4-bromophenylsulphonyl)piperazine (0.84 g) as a solid, m.p. 199-200° C.: microanalysis, found: C, 47.3; H, 4.1; N, 10.9%; C15H16BrN3O2S requires: C, 47.1; H, 4.22; N, 11.0%; NMR: (CDCl3) 3.13(t,4H), 3.42(t,4H), 6.62(dd,2H), 7.67(q,4H), 8.29(d,2H): MS: m/z 382 (MH)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH2:19]([N:22]([CH2:26][CH:27]=[CH2:28])[C:23](Cl)=[O:24])[CH:20]=[CH2:21]>C(Cl)Cl.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:23]([N:22]([CH2:26][CH:27]=[CH2:28])[CH2:19][CH:20]=[CH2:21])=[O:24])=[N:6][CH:7]=1
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: NNc1ccc(F)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: C=CCN(CC=C)C(=O)NNc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (for reference procedure see WO 2010/022076, which is incorporated herein by reference in its entirety; 2.54 g, 20.0 mmol) in DCM (150 mL) and DIPEA (3.87 g, 30.0 mmol) was added N,N-di-2-propen-1-yl-carbamic chloride (for reference procedure see for example Tetrahedron 1996, 52, 13739-13750, which is incorporated herein by reference in its entirety; 4.13 g, 26.0 mmol) and the reaction mixture was stirred at RT for 18 h. The reaction mixture was diluted with MeOH (50 mL) and loaded onto an SCX cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3 in MeOH. The compound containing fractions were concentrated in vacuo and the resulting residue was purified by FCC on silica, using a gradient of 0-6% [2M NH3 in MeOH] in DCM, to afford the title compound (2.30 g, 46%) as a yellow solid. LCMS (Method 1): Rt 2.26 min, m/z 251 [MH+].
Reaction SMILES: C([O:3][P:4]([CH2:9][S:10][C:11]1[NH:15][C:14]2[CH:16]=[C:17]([Cl:28])[C:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([CH3:27])[CH:21]=3)=[CH:19][C:13]=2[N:12]=1)(=[O:8])[O:5]CC)C.Br[Si](C)(C)C>C(Cl)Cl.C[Si](C)(C)N[Si](C)(C)C>[Cl:28][C:17]1[C:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([CH3:27])[CH:21]=2)=[CH:19][C:13]2[N:12]=[C:11]([S:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])[NH:15][C:14]=2[CH:16]=1
Reactant: CCOP(=O)(CSc1nc2cc(-c3ccc(Cl)c(C)c3)c(Cl)cc2[nH]1)OCC
Agent: C[Si](C)(C)Br
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: ClCCl
Product: Cc1cc(-c2cc3nc(SCP(=O)(O)O)[nH]c3cc2Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [6-Chloro-5-(4-chloro-3-methyl-phenyl)-1H-benzoimidazol-2-ylsulfanylmethyl]-phosphonic acid diethyl ester 12-1 (140 mg, 0.29 mmol) in CH2Cl2 (0.8 mL) and hexamethyldisilazane (0.8 mL) was added bromotrimethylsilane (0.40 mL, 3.0 mmol). After stirring overnight at room temperature, the volatiles were removed from the mixture via a rotary evaporator. The resulting residue was dissolved in EtOAc (2 mL) and filtered through a 0.45 μm syringe filter. The filtrate was evaporated to dryness, and anhydrous MeOH was added. The mixture was triturated by sonication from MeOH to give a suspension of a fine white solid. The solid was isolated by centrifugation followed by decanting the MeOH. The resulting solid was furthered purified by a second trituration in MeOH, and then dried under vacuum at 40° C. overnight to afford the title compound 12-2. LRMS (API-ES) m/e for C15H13Cl2N2O3PS (M+H)+, calcd 403.23. found 403.1. Anal. Calcd for C15H13Cl2N2O3PS: C, 44.68; H, 3.25; N, 6.95. Found: C, 44.44; 1-1, 3.43; N, 6.68.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:20][CH:19]=1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][N:26]([CH3:27])[CH3:28])=[CH:20][CH:19]=2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)CCc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Product: CN(C)CCc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)cc1
Yield: 71.6 %

Procedure:
Following general procedure D, (6-bromo-4-(4-(2-(dimethylamino)ethyl)phenylamino)quinolin-3-yl)(cyclopropyl)methanone (100 mg, 0.23 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (93 mg, 0.34 mmol) to afford the desired product (83 mg, 72%) as a yellow-brown solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.46 (s, 1H), 8.21 (dd, J=8.8, 1.9 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.89 (s, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.04 (m, 2H), 3.41 (m, 2H), 3.21 (m, 2H), 2.99 (s, 7H), 2.90 (m, 1H), 1.23 (m, 4H); ESI MS m/z 504 [C29H27ClFN3O2+H]+; HPLC 97.0% (AUC), tR=10.95 min.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]=[C:16]=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[NH2:18]/[C:19](/[CH3:27])=[C:20](/[F:26])\[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:19]([CH3:27])=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[F:26])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: CCOC(=O)/C(F)=C(/C)N
Reactant: CC(C)OC(=O)c1cc(N=C=O)c(F)cc1Cl
Product: CCOC(=O)C(F)=C(C)NC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F

Procedure:
using isopropyl 2-chloro-4-fluoro-5-isocyanatobenzoate and ethyl 3-amino-2-fluorocrotonate there is obtained isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-2-fluoro-1-methylvinyl]ureido}-benzoate, m.p. 150°-152° C.,
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:13][S:14](Cl)(=[O:16])=[O:15].O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:14]([CH3:13])(=[O:16])=[O:15])[C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)n1ccc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (600 mg, 3.06 mmol) in dry THF (30 mL) was added NaH (246 mg, 6.12 mmol) at room temperature. The suspension was stirred for 30 min before addition of methanesulfonyl chloride (540 mg, 4.80 mmol). The solution was stirred at room temperature for another 30 min and poured into water (50 mL). The aqueous solution was extracted with ethyl acetate (2×30 mL), the combined organic layers were dried over MgSO4 and filtered, the filtrate was evaporated under vacuum to afford white solid (780 mg, 93%). The crude product was used directly for the next reaction. LC/MS: Rt 3.26 mis.; (m/e=275.0, 276.9 (M+H, M+2+H).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:15][C:16]#[N:17])=[CH:3][CH:2]=1.CCCCC.[H-].[Na+].Br[CH2:26][C:27]1[C:31]2[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:30]=2[S:29][CH:28]=1>CN(C=O)C>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]2[S:29][CH:28]=[C:27]([CH2:26][N:12]3[C:13]4[CH:1]=[CH:2][CH:3]=[C:4]([O:14][CH2:15][C:16]#[N:17])[C:5]=4[C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:31]=2[CH:32]=1
Reactant: N#CCOc1cccc2[nH]c3ccccc3c12
Reactant: Clc1ccc2scc(CBr)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: N#CCOc1cccc2c1c1ccccc1n2Cc1csc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.7 %

Procedure:
2-(9H-Carbazol-4-yloxy)acetonitrile (0.146 g, 0.66 mmol)) is added to a slurry of pentane-washed NaH (0.0441 g, 0.0011 mol) in DMF (1 mL) and allowed to stir for 20 min at room temperature. 3-(Bromomethyl)-5-chlorobenzothiophene (0.229 g, 0.88 mmol) is added and after stirring for 1 h the mixture is partitioned between ethyl acetate and water. The combined organic layers are dried over magnesium sulfate and concentrated to an oil. The oil is chromatographed on silica gel (75 mL) using ethyl acetate/hexane (20/80) and solids are precipitated using dichloromethane/hexane to give 0.148 g (56%) of the title compound; MS (ESI+) for C23H15ClN2OS m/z 425.2 (M+Na); IR (drift) 1581, 1460, 1439, 1332, 1279, 1232, 1221, 1155, 1148, 1115, 1079, 833, 780, 752, 717 cm−1; 1H NMR (CDCl3) δ5.10, 5.70, 6.72, 6.80, 7.12, 7.28-7.47, 7.80, 7.87, 8.36. Anal. Calcd for C23H15ClN2OS: C, 68.57; H, 3.75; N, 6.95. Found: C, 68.87; H, 4.22; N, 6.56.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[O:5][CH2:6][CH2:7][CH2:8][C:9](=[O:11])[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccccc1OCCCC(=O)O
Solvent: Cc1ccccc1
Product: COc1cccc2c1OCCCC2=O
Reaction time: 8 h
Yield: 10 %

Procedure:
To PPA in toluene at 100° C., was added 4-(2-methoxyphenoxy)butanoic acid and the mixture stirred overnight. The mixture was poured onto ice-water, and extracted with ether (3 times). The combined organic phase was washed with water and dried over anhydrous sodium sulfate. Evaporation of the organic phase afforded a light yellow oil in 10% yield: 1H NMR δ 7.33 (dd, 1H, J=4.4, 5.1 Hz), 7.03 (d, 2H, J=4.3 Hz), 4.31 (t, 2H, J=6.6 Hz), 3.90 (s, 3H), 2.90 (t, 2H, J=6.9 Hz), 2.22 (p, 2H, J=6.8 Hz).
Reaction SMILES: C([O:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:23](=[O:24])[CH:22]=[C:21]3[C:16]([CH:17]=[C:18]([C:25]#[C:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:19]=[CH:20]3)=[CH:15]2)=[CH:9][CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O>>[O:24]=[C:23]1[CH:22]=[C:21]2[C:16]([CH:17]=[C:18]([C:25]#[C:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:19]=[CH:20]2)=[CH:15][N:14]1[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([OH:34])=[O:5])=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Cn2cc3cc(C#CCc4ccccc4)ccc3cc2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(Cn2cc3cc(C#CCc4ccccc4)ccc3cc2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-[3-oxo-7-(3-phenyl-prop-1-ynyl)-2H-isoquinolin-2-ylmethyl]benzoic acid tert-butyl ester [0.20 g, 0.44 mmol, Example 1A, Step (2)] is treated with trifluoroacetic acid (5 mL) and the reaction mixture stirred at room temperature for 30 minutes. The solution is evaporated to dryness, the residue is dissolved in ethyl acetate, washed with water, brine, dried over MgSO4 and evaporated to dryness. The brown solid is triturated with acetonitrile, the solid collected by filtration, and washed with acetonitrile. The solid is then dissolved in hot ethyl acetate, evaporated onto silica gel, and purified on a 2.5×10 cm silica gel column eluted with hexanes/ethyl acetate 1:1, followed by ethyl acetate. Drying will afford the purified product.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[N:15]1[CH:27]([CH2:28][CH:29]=[O:30])[C:26]2[C:17](=[CH:18][C:19]([CH2:31][C:32]3[CH:33]=[N:34][C:35]([Cl:38])=[CH:36][CH:37]=3)=[C:20]3[C:25]=2[N:24]=[CH:23][CH:22]=[CH:21]3)[C:16]1=[O:39])(C(C)(C)C)(C)C.[BH4-].[Na+]>ClCCl.CO.Cl.C(=O)(O)[O-].[Na+]>[Cl:38][C:35]1[N:34]=[CH:33][C:32]([CH2:31][C:19]2[CH:18]=[C:17]3[C:16](=[O:39])[N:15]([C@H:10]4[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]4[OH:8])[CH:27]([CH2:28][CH2:29][OH:30])[C:26]3=[C:25]3[C:20]=2[CH:21]=[CH:22][CH:23]=[N:24]3)=[CH:37][CH:36]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCCC[C@@H]1N1C(=O)c2cc(Cc3ccc(Cl)nc3)c3cccnc3c2C1CC=O
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: ClCCl
Solvent: CO
Product: O=C1c2cc(Cc3ccc(Cl)nc3)c3cccnc3c2C(CCO)N1[C@H]1CCCC[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of {8-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-5-[(6-chloropyridin-3-yl)methyl]-7-oxo-8,9-dihydro-7H-pyrrolo[3,4-h]quinolin-9-yl}acetaldehyde (see Example 22, 0.030 g, 0.053 mmol) in a mixture of 0.4 mL of dichloromethane and 0.1 mL of methanol at 0° C. was added sodium borohydride (2.0 mg, 0.053 mmol). The mixture was allowed to warm to ambient temperature and after 15 hr, hydrochloric acid (3 N aqueous, 5 drops) was added. After 24 hr, the mixture was diluted with saturated aqueous sodium bicarbonate and extracted 3× with ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the titled compound that gave a mass ion (ES+) of 452.1735 for [M+H]+ [calc'd for C25H27ClN3O3, [M+H]+=452.1735]: 1H NMR (400 MHz, CD3OD) δ 9.00-8.98 (m, 1H), 8.62-8.59 (m, 1H), 8.31-8.30 (m, 1H), 7.69 (s, 1H), 7.65-7.62 (m, 2H), 7.37 (d, J=8.3 Hz, 1H), 5.44-5.41 (m, 2H), 4.60 (s, 2H), 4.42-4.36 (m, 1H), 3.76-3.66 (m, 1H), 3.15-3.01 (m, 2H), 2.58-2.51 (m, 1H), 2.16-2.13 (m, 1H), 1.97-1.93 (m, 2H), 1.82-1.79 (m, 2H), 1.46-1.40 (m, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]#[C:10][CH:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]1.[CH3:23]C([O-])(C)C.[K+].CI.Cl>CN1C(=O)CCC1.O>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]([CH3:23])[C:10]([CH:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]1)=[CH:9]2
Reactant: CC(C)(C)OC(=O)N1CCC(C#Cc2cc(Br)ccc2N)C1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN1CCCC1=O
Product: Cn1c(C2CCN(C(=O)OC(C)(C)C)C2)cc2cc(Br)ccc21
Temperature: 780 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
To degassed with argon solution of tert-butyl 3-((2-amino-5-bromophenyl)ethynyl)pyrrolidine-1-carboxylate (5.69 g, 15.58 mmol) in NMP (30 mL) was added t-BuOK (3.9 g, 34.75 mmol). Mixture was heated at 780° C. for 45 min before it was cooled to 0° C. in an ice-bath. MeI (3.0 mL, 48.08 mmol) was added dropwise and reaction was allowed to warm to room temperature and stirred 30 min. Then reaction was diluted with H2O (100 mL) and acidified with 1M aqueous HCl to pH˜2. Product was extracted with EtOAc (3×150 mL). Combined organics were washed with NaCl (aqueous saturated) and dried over Na2SO4. Upon solvent removal residue was purified by column chromatography using EtOAc/hexanes (gradient 0-40%) to afford tert-butyl 3-(5-bromo-1-methyl-1H-indol-2-yl)pyrrolidine-1-carboxylate (5.17 g) in 87% yield.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=1[OH:19])=[O:8].[CH3:20]CCCCCC>C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:7](=[O:8])[C:9]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=2)[O:19][CH:20]=1
Reactant: COc1cc(O)c(C(=O)CCCCCBr)cc1OC
Reactant: CCCCCCC
Solvent: Cc1ccccc1
Product: COc1cc2occ(CCCCBr)c(=O)c2cc1OC
Reaction time: 5 h
Yield: 53 %

Procedure:
2nd method: A solution of 500 mg (1.5 mmol) of the compound of the above Step, 6-bromo-1-(2-hydroxy-4,5-dimethoxyphenyl)-hexan-1-one, in 30 ml of dry toluene is refluxed, with stirring, with 0.6 ml (4.5 mmol) of DMF dimethylacetal. Reflux is continued for 5 h. After concentration, and purification by flash chromatography with a gradient of pure heptane to heptane-ACOEt 80-20, 270 mg (yield=53%) of 3-(4-bromobutyl)-6,7-dimethoxychromen-4-one are obtained, after evaporation, in the form of white crystals identical to those obtained by the 1st method. TLC SiO2 hept-AcOEt 70-30 Rf=0.3. 1H NMR (DMSO): 8.19 (s, 1H), 7.36 (s, 1H), 7.16 (s, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.65 (t, 2H, J=6.3 Hz), 2.38 (t, 2H, J=7.3 Hz), 1.72 (m, 2H), 1.64 (m, 2H), 1.55 (m, 2H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[N:9]=[N:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Br[CH2:14][CH2:15]Br>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.C(#N)C>[Cl:3][C:4]1[N:9]=[N:8][C:7]([C:10]2([C:11]#[N:12])[CH2:15][CH2:14]2)=[CH:6][CH:5]=1
Reactant: N#CCc1ccc(Cl)nn1
Reactant: BrCCBr
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Product: N#CC1(c2ccc(Cl)nn2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Aqueous NaOH solution (50%, 5 mL) was added to a solution of (6-chloro-pyridazin-3-yl)-acetonitrile (0.21 g), 1,2-dibromoethane (0.14 mL), and benzyltributylammonium chloride (0.43 g) in acetonitrile (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 4 h and was then extracted with ethyl acetate. The combined extracts were washed with brine and dried (MgSO4). The solvent was evaporated and the residue was chromatographed on silica gel (cyclohexane/ethyl acetate 1:1→0:1) to give the title compound as a solid. Yield: 0.14 g (57% of theory); LC (method 1): tR=1.12 min; Mass spectrum (ESI+): m/z=180/182 (Cl) [M+H]+.