Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH3:21][CH:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26].[BH4-].[Na+]>CO>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:26][CH2:25][CH2:24][CH2:23][CH:22]([CH3:27])[CH3:21])[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Reactant: CC(C)CCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCCC(C)C)ccc1Oc1ccc(C(N)=O)cn1
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.100 g, 0.367 mmol), 4-methylpentylamine (Part A, 0.0409 g, 0.404 mmol) and 3 Å molecular sieves in a vial. Add methanol (3.6 mL), cap and stir overnight. Add NaBH4 (in excess over two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 5 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 10 g ISCO® column with (2.0 M NH3 in methanol) in ethyl acetate to give 6-{2-methoxy-4-[(4-methylpentylamino)methyl]phenoxy}nicotinamide (0.131 g, 71.8%). Dissolve the compound in dichloromethane (2.5 mL) and add 1 equivalent of 0.50M methanesulfonic acid in dichloromethane. Stir the solution for a short time before concentrating to give the title compound (0.124 g, ˜100%): TOF MS ES+ 358.2 (M+H)+, HRMS calcd for C20H28N3O3 358.2131 (M+H)+, found 358.2119, time 0.39 min; HPLC [Waters XTerra™ MS C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 15 min], tR=8.2 min, 100% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>O>[Cl:1][C:2]1[C:3]([S:13]([Cl:12])(=[O:15])=[O:14])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2o1
Reactant: O=S(=O)(O)Cl
Solvent: O
Product: O=c1[nH]c2cc(Cl)c(S(=O)(=O)Cl)cc2o1

Procedure:
5-Chloro-3H-benzooxazol-2-one (10.0 g, 59 mmol) was added in portions to chlorosulfonic acid (30 mL) at −20° C. with stirring. The mixture was stirred at room temperature for 2.5 hours and at 70° C. for 1.5 hours. The cooled reaction mixture was poured slowly into iced-water (300 mL) and stirred for 1 hour. The precipitate was collected and washed with water. The dried precipitate was stirred in chloroform (500 mL) for 3 hours at room temperature, filtered off and dried to give 12.3 g of a pale pink solid.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:3].Br[C:20]1[C:21](=[O:38])[N:22]([C:27]2[CH:28]=[C:29]([CH:34]=[CH:35][C:36]=2[CH3:37])[C:30]([O:32][CH3:33])=[O:31])[CH:23]=[C:24]([Br:26])[N:25]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1.O>[CH3:33][O:32][C:30](=[O:31])[C:29]1[CH:34]=[CH:35][C:36]([CH3:37])=[C:27]([N:22]2[CH:23]=[C:24]([Br:26])[N:25]=[C:20]([NH:3][C:2]([CH3:18])([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:1])[C:21]2=[O:38])[CH:28]=1
Reactant: COC(=O)c1ccc(C)c(-n2cc(Br)nc(Br)c2=O)c1
Reactant: CC(C)(N)c1ccccc1OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C)c(-n2cc(Br)nc(NC(C)(C)c3ccccc3OCc3ccccc3)c2=O)c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 68.8 %

Procedure:
A solution of α,α-dimethyl-2-(phenylmethoxy)-benzenemethanamine (Example 198d, 1.5 g) dissolved in dioxane (52.2 mL) was treated with methyl 3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-4-methylbenzoate (Example 1b, 2.499 g) and N-ethyldiisopropylamine (1.083 mL) under nitrogen. The resulting solution was stirred at 100° C. for 10 h. After cooling to room temperature, the reaction mixture was diluted with water (50 mL), and extracted with ethyl acetate (100 mL×2). The organic was dried (MgSO4), filtered and evaporated. The crude product was trituated with 50% diethyl ether in iso-hexane for 3 h. The solid was filtered off to afford the subtitle compound (2.405 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([CH2:11][C:12](OCC)=[O:13])[C:5]=2[CH:4]=[CH:3]1.[OH-].[Na+]>C1COCC1>[CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([CH2:11][CH2:12][OH:13])[C:5]=2[CH:4]=[CH:3]1
Reactant: CCOC(=O)CC1CCCc2c1ccn2C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1ccc2c1CCCC2CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of ethyl 2-(1-methyl-4,5,6,7-tetrahydro-1H-indol-4-yl)acetate (0.22 g, 1.00 mmol) in THF anh. is added slowly over a suspension of AlLiH4 (0.1 g, 2.63 mmol) in THF anh. (10 mL) cooled in an ice bath. The mixture is maintained under stirring at room temperature for 1 hour and then is refluxed for 3 hours. The mixture is hydrolyzed with ice and NaOH (10%), filtered and the solvent is evaporated under reduced pressure. The residue is dissolved in ethyl acetate and washed with water. The organic phase is removed at reduced pressure and the resulting crude is purified by column chromatography, giving 2-(1-methyl-4,5,6,7-tetrahydro-1H-indol-4-yl)ethanol (0.15 g, 0.84 mmol, 84%, oil). 1H NMR (300 MHz, CDCl3): δ 1.37 (m, 1H), 1.68 (m, 3H), 1.92 (m, 3H), 2.49 (m, 2H), 2.78 (m, 1H), 3.46 (s, 3H), 3.81 (m, 2H), 5.99 (d, J=2.5 Hz, 1H), 6.50 (d, J=2.5 Hz, 1H).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:32]=[CH:31][C:9]3[C:10]4[C:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)=[CH:13][N:12]([C:18]2[N:19]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.[CH3:33][C:34]1([CH3:37])[CH2:36][O:35]1>>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[N:19]1[C:18]([N:12]2[N:11]=[C:10]3[C:14]([CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([CH:4]5[CH2:3][N:2]([CH2:33][C:34]([CH3:37])([OH:35])[CH3:36])[CH2:5]5)[CH:32]=[CH:31][C:9]=43)=[CH:13]2)=[N:22][CH:21]=[N:20]1
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2ccc(C4CNC4)cc2OCC3)c(F)c1
Reactant: CC1(C)CO1
Agent: Cl
Product: CC(C)(O)CN1CC(c2ccc3c(c2)OCCc2cn(-c4ncnn4-c4ccc(F)cc4F)nc2-3)C1

Procedure:
Following the procedure for 177, 8-azetidin-3-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride was reacted with 2,2-dimethyl-oxirane to give 183 as a white solid. 1H NMR (400 MHz, DMSO-d): δ 8.45 (s, 1H); 8.31 (s, 1H); 8.17 (s, 1H); 7.84 (td, J=8.75, 5.92 Hz, 1H); 7.66 (ddd, J=10.33, 9.02, 2.79 Hz, 1H); 7.40-7.34 (m, 1H); 7.31 (d, J=8.17 Hz, 1H); 7.00 (d, J=1.69 Hz, 1H); 6.93 (dd, J=8.25, 1.78 Hz, 1H); 4.26 (t, J=5.06 Hz, 2H); 3.79 (t, J=7.52 Hz, 2H); 3.64 (t, J=7.75 Hz, 1H); 3.35 (t, 2H); 3.08 (t, J=5.05 Hz, 2H); 2.35 (t, 2 H); 1.10 (s, 6H). LCMS: RT=7.45 min, M+H+=493
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].O>C(Cl)Cl>[CH2:21]([O:20][C:18](=[O:19])[NH:9][CH2:8][CH2:7][C:5]1[O:6][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH3:22]
Reactant: Cc1ccc(CCN)o1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)NCCc1ccc(C)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
2-(5-Methylfuran-2-yl)ethylamine (1.0 g) prepared in the step 2 and 2.2 mL of triethylamine were dissolved in 25 mL of methylene chloride, 0.87 g of ethyl chloroformate was slowly dropped thereinto under cooling with ice and the mixture was stirred at room temperature for 8 hours. To the reaction solution was added 200 mL of water followed by extracting with methylene chloride. The organic layer was washed with water and a saturated solution of sodium chloride successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo. The residue was purified by silica gel column chromatography to give 0.61 g of the objective compound as yellow liquid.
Reaction SMILES: Br.[CH3:2][C:3]1[N:4](S(C2C=CC=CC=2)(=O)=O)[CH:5]=[C:6]([C:8]2[N:9]=[C:10]([NH:13][C:14]([NH2:16])=[NH:15])[S:11][CH:12]=2)[CH:7]=1.[OH-].[K+]>CO>[CH3:2][C:3]1[NH:4][CH:5]=[C:6]([C:8]2[N:9]=[C:10]([NH:13][C:14]([NH2:16])=[NH:15])[S:11][CH:12]=2)[CH:7]=1
Reactant: Cc1cc(-c2csc(NC(=N)N)n2)cn1S(=O)(=O)c1ccccc1
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(-c2csc(NC(=N)N)n2)c[nH]1
Yield: 95.8 %

Procedure:
A mixture of 12.1 g (25 mmole) of N-[4-(2-methyl-1-phenylsulfonylpyrrol-4-yl)thiazol-2-yl]guanidine hydrobromide, 12.1 g 85% potassium hydroxide and 400 ml methanol was heated at reflux for 18 hours. The mixture was cooled, evaporated to dryness, and the residue triturated with water. The resulting precipitate was collected, washed with water, and dried in vacuo to give 5.3 g (96%) of the product as its free base; m.p. 235°-237° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1(Cl)[C:14]([Cl:15])=[C:13]([Cl:16])[C:12]([Cl:17])=[C:11]1[Cl:18].[Cl-:20].[Al+3].[Cl-].[Cl-].Cl>ClC(Cl)=C(Cl)Cl.O>[Cl:20][C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[C:14]1([Cl:15])[C:10]([Cl:9])=[C:11]([Cl:18])[C:12]([Cl:17])=[C:13]1[Cl:16]
Reactant: ClC1=C(Cl)C(Cl)(Cl)C(Cl)=C1Cl
Reactant: [Cl-]
Reactant: Clc1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Solvent: O
Solvent: ClC(Cl)=C(Cl)Cl
Product: ClC1=C(Cl)C(Cl)(c2ccc(Cl)cc2Cl)C(Cl)=C1Cl
Reaction time: 0.5 h

Procedure:
A mixture of 294 grams (2.0 moles) of paradichlorobenzene, 819 grams (3.0 moles) of hexachlorocyclopentadiene, and 15 grams of aluminum chloride, in 300 grams of perchloroethylene was heated at 80°-92° centigrade for two hours during which time a total of 103 grams of hydrogen chloride was evolved. Ten milliliters of water and 20 grams of Superfiltrol absorbent were added and the reaction mixture was stirred at 60° centigrade for 30 minutes and then filtered with suction. The filtrate was distilled at reduced pressure and the fraction boiling at 131°-160° centigrade at 0.5 to 2.3 millimeters of mercury pressure was collected and refractionated through a one foot long heated Vigreux column to give pure 2,4-dichlorophenyl pentachlorocyclopentadiene as a pale yellow viscous oil of boiling point of 146°-147° centigrade at 0.4-0.6 millimeters of mercury.
Reaction SMILES: CC(=O)CCC(=O)C.CN1CC=C([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22](N)[CH:23]=3)[N:18](S(C3C=CC=CC=3)(=O)=O)[CH:17]=2)CC1.C(O)(=O)C>C(O)C>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3ccc(N)cc23)CC1
Agent: CC(=O)CCC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hexane-2,5-dione (2 mL) was added to a solution of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-1H-indol-5-amine (300 mg, 0.82 mmol) in ethanol (50 mL). Acetic acid (2 mL) was added, and the resulting solution was stirred at room temperature overnight. The solvent was concentrated, followed by column chromatography purification using a 1:10 methanol/dichloromethane solvent system provided 30 mg (8%) of 5-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-phenylsulfonyl)-1H-indole as a yellow solid. 1H NMR (CDCl3) δ 8.05 (d, 1H), 7.95 (d, 2H), 7.62 (s, 1H), 7.50 (d, 2H), 7.26 (2H), 6.84 (d, 2H), 6.11 (s, 1H), 5.90 (s, 2H), 3.46 (d, 2H), 3.07 (t, 2H), 2.74 (s, 2H), 2.62 (s, 2H), 1.98 (s, 6H). LC/MS (EI) tR 2.46, m/z 446.0 (M++1)
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][OH:5].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C1COCC1>[N:13]1([C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[CH2:4][OH:5])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)c(CO)c1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(CO)c1
Yield: 99.2 %

Procedure:
2-Fluoro-5-nitrobenzyl alcohol (1 g, 5.84 mmol) and morpholine (1.03 mL, 11.68 mmol) were heated at 115° C. for 1 h. The reaction mixture was then diluted with 40 mL of THF and washed with a saturated aqueous solution of Na2CO3 and then with brine. The organic layer was dried over MgSO4, filtered and evaporated to yield expected compound as yellow oil (1.38 g, 99% yield). MALDI-TOF: m/z 239.2 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10](/[C:14](/[CH3:25])=[CH:15]/[CH:16]=[CH:17]/[C:18](/[CH3:24])=[CH:19]/[C:20]([O:22]C)=[O:21])=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[CH3:3].[OH-].[Na+].Cl>C(O)C>[CH3:3][CH:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10](/[C:14](/[CH3:25])=[CH:15]/[CH:16]=[CH:17]/[C:18](/[CH3:24])=[CH:19]/[C:20]([OH:22])=[O:21])=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[CH3:1]
Reactant: COC(=O)/C=C(C)/C=C/C=C(\C)c1ccc2c(c1)CCCN2C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(/C=C/C=C(\C)c1ccc2c(c1)CCCN2C(C)C)=C\C(=O)O
Temperature: 60 °C

Procedure:
330 mg of methyl (E,E,E)-7-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-3-methylocta-2,4,6-trienoate was dissolved in 10 ml of ethanol, followed by the addition of 1.0 ml of a 5N aqueous solution of sodium hydroxide. The obtained mixture was heated at 60° C. for one hour and adjusted to pH5 by adding 6N hydrochloric acid under cooling with ice. The crystals thus precipitated were recovered by filtration and recrystallized from ethanol to give 100 mg of the title compound as orange crystals.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Br)=[CH:5][C:4]=1[CH2:11]Br.C[O:14][P:15]([O:18][CH3:19])[O:16][CH3:17]>C1(C)C=CC=CC=1>[C:3]1([CH2:2][P:15](=[O:14])([O:18][CH3:19])[O:16][CH3:17])[CH:8]=[CH:7][C:6]([CH2:9][P:15](=[O:14])([O:18][CH3:19])[O:16][CH3:17])=[CH:5][C:4]=1[CH2:11][P:15](=[O:14])([O:18][CH3:19])[O:16][CH3:17]
Reactant: BrCc1ccc(CBr)c(CBr)c1
Reactant: COP(OC)OC
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1ccc(CP(=O)(OC)OC)c(CP(=O)(OC)OC)c1)OC

Procedure:
A solution of 1,2,4-tris(bromomethyl)benzene (Preparation 4, 0.532 g, 0.0015 M) and trimethylphosphite (15 mL, 0.126 M) in dry toluene (25 mL) is stirred and heated at reflux temperature for 80 hours. Solvent and excess trimethylphosphite are removed under reduced pressure and the oily residue is chromatographed over silica gel (50 g, 40-63 μm, 10% CH3OH--CHCl3, 8 mL fractions) using 10% CH3OH--CHCl3 to elute the column. Fractions 16-22 contain the title compound (0.587 g, 0.00132 M, 88%), which is a viscous oil.
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[C:11](OS(C4C=CC(C)=CC=4)(=O)=O)=[C:12]([CH3:17])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=3[N:6]([C:29]3[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=3[F:36])[C:5]2=[O:37])[CH2:3][CH2:2]1.[NH2:38][C:39]1[CH:40]=[C:41]([CH:46]=[CH:47][CH:48]=1)[NH:42][C:43](=[O:45])[CH3:44].CN(C)C(=O)C.N1C(C)=CC=CC=1C>CO>[CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[C:11]([NH:38][C:39]4[CH:40]=[C:41]([NH:42][C:43](=[O:45])[CH3:44])[CH:46]=[CH:47][CH:48]=4)=[C:12]([CH3:17])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=3[N:6]([C:29]3[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=3[F:36])[C:5]2=[O:37])[CH2:2][CH2:3]1
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(C)c(=O)n(C)c3c2c(=O)n(C2CC2)c(=O)n3-c2ccc(I)cc2F)cc1
Solvent: Cc1cccc(C)n1
Solvent: CO
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1cccc(Nc2c(C)c(=O)n(C)c3c2c(=O)n(C2CC2)c(=O)n3-c2ccc(I)cc2F)c1
Temperature: 130 °C
Reaction time: 4 h
Yield: 93.2 %

Procedure:
To p-toluenesulfonic acid 3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester 77 (28.0 g) and 3′-aminoacetanilide 57 (13.2 g) were added N,N-dimethylacetamide (84.0 ml) and 2,6-lutidine (15.3 ml), and the mixture was stirred at 130° C. for 4 hrs. After allowing to cool with stirring, methanol (196 ml) was added dropwise, and the mixture was stirred at room temperature. The crystals were collected by filtration and dried to give N-{3-[3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]-phenyl}-acetamide 58 (25.2 g, yield 93%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]([CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])=[CH:3][CH2:4][O:5][C:6](=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10]CCCCC=C.CC(=CCC/C(=C/CO)/C)C.C(O)(=O)CCCCCCCCC=C>>[CH3:1][C:2]([CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])=[CH:3][CH2:4][O:5][C:6](=[O:17])[CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCCCCCCCC(=O)OCC=C(C)CCC=C(C)C
Agent: C=CCCCCCCCCC(=O)O
Agent: CC(C)=CCC/C(C)=C/CO
Product: C=CCCC(=O)OCC=C(C)CCC=C(C)C

Procedure:
According to the same procedure, undec-10-enoic acid 3,7-dimethyl-oct-2,6-dienyl ester was prepared from geraniol and 10-undecenoic acid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([OH:19])=[C:10]([C:16]([OH:18])=O)[N:11]=[C:12]2[Cl:15])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl.C[O:22][C:23](=[O:27])[C@@H:24]([CH3:26])[NH2:25]>>[CH:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([OH:19])=[C:10]([C:16]([NH:25][C@H:24]([CH3:26])[C:23]([OH:27])=[O:22])=[O:18])[N:11]=[C:12]2[Cl:15])=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](C)N
Reactant: CC(C)Oc1ccc2c(O)c(C(=O)O)nc(Cl)c2c1
Agent: Cl
Product: CC(C)Oc1ccc2c(O)c(C(=O)N[C@H](C)C(=O)O)nc(Cl)c2c1

Procedure:
Analogously to Example A-56, 0.040 g of 7-isopropoxy-1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid were allowed to react with D-Alanine methyl ester hydrochloride. The intermediate ester product was hydrolyzed as in Example A-56 to give 0.042 g of a white solid: MS-(−)-ion, M−1=353.0 amu.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C@H:3]([CH3:20])[C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([N+:15]([O-])=O)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]>C(OCC)(=O)C.[Pd]>[CH3:1][N:2]([CH3:21])[C@H:3]([CH3:20])[C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([NH2:15])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)[C@@H](C)N(C)C)CC2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N)N(C(=O)[C@@H](C)N(C)C)CC2
Yield: 70.9 %

Procedure:
To a solution of (2R)-N,N-dimethyl-1-[5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]-1-oxo-2-propanamine (2.2 g, 7.50 mmol) in ethyl acetate (250 mL) was added Pd/C (0.798 g, 0.750 mmol) and the reaction maintained under 50 psi of H2(g) overnight on the Fisher-Porter. The crude material was filtered through a celite pad, washed with ethyl acetate, concentrated on the rotovap, and placed under high vacuum overnight to afford 1-[(2R)-2-(dimethylamino)propanoyl]-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine (1.4 g, 71%). ESIMS (M+H)+=264.
Reaction SMILES: [C:1]1([CH:7]2[C:12]3=[N:13][NH:14][C:15](=[O:20])[C:16]4[CH:17]=[CH:18][CH:19]=[C:10]([C:11]=43)[NH:9][C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCOCC1.CCN(CC)CC>C1COCC1>[C:1]1([CH:7]2[C:12]3=[N:13][NH:14][C:15](=[O:20])[C:16]4[CH:17]=[CH:18][CH:19]=[C:10]([C:11]=43)[NH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1Nc2cccc3c(=O)[nH]nc(c23)C1c1ccccc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=c1[nH]nc2c3c(cccc13)NCC2c1ccccc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 1.4 %

Procedure:
A mixture of 9-phenyl-2H-pyrido[4,3,2-de]phthalazine-3,8(7H,9H)-dione (80 mg, 2.2 mmol), BH3 (0.7 mL, 1 mol/L in THF), dioxane (4 mL) in sealed tube was stirred for 2 h at 95° C. under nitrogen atmosphere. Then the mixture was treated with MeOH˜HCl (g) (0.2 mL), stirred for 20 min at 95° C. Then the mixture was cooled and adjusted to pH=8 with Et3N. The solvent was removed under vacuum and the crude was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20:1 to 1:1) to obtain the title compound as a yellow solid (l 8.3 mg, yield 24%). LC-MS (ESI) m/z: 264 (M+1)+. 1H-NMR (400 MHz, CD3OD) δ (ppm): 3.60-3.64 (m, 1H), 3.68-3.72 (m, 1H), 4.21 (t, J=5.2 Hz, 1H), 7.09-7.11 (d, J=8 Hz, 1H), 7.16-7.29 (m, 5H), 7.53-7.61 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][CH2:15][CH:16]([C:17]([O:19]C(C)C)=[O:18])[C:11]3=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:11]3=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)OC(=O)C1CCCn2c(C(=O)c3ccc(F)cc3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(c1ccc(F)cc1)c1ccc2n1CCCC2C(=O)O
Temperature: 25 °C

Procedure:
A solution of isopropyl 3-p-fluorobenzoyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate in methanol is treated under an atmosphere of nitrogen with a solution of sodium hydroxide in water, maintaining the reaction mixture at room temperature for 1.5 hours. The methanol is then removed under reduced pressure and the basic solution which remains is diluted with water and extracted with ether to remove any unsaponifiable product. The aqueous solution is acidified with 10% hydrochloric acid and extracted three times with ethyl acetate. The combined extracts are dried and evaporated to dryness under reduced pressure, and the residue crystallized from ethyl acetate-hexane, to give 3-p-fluorobenzoyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylic acid, identical to the product obtained in Example 8.
Reaction SMILES: [CH:1]1([C:4]2[CH:36]=[CH:35][C:7]([CH2:8][O:9][C:10]3[CH:15]=[CH:14][C:13]([CH:16]4[CH2:19][N:18]([C:20]([C:22]5[CH:27]=[C:26]([O:28][CH2:29][C@H:30]6C[O:31]6)[CH:25]=[CH:24][N:23]=5)=[O:21])[CH2:17]4)=[CH:12][C:11]=3[O:33][CH3:34])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.O.[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.[C:45](#N)C>>[CH:1]1([C:4]2[CH:36]=[CH:35][C:7]([CH2:8][O:9][C:10]3[CH:15]=[CH:14][C:13]([CH:16]4[CH2:17][N:18]([C:20]([C:22]5[CH:27]=[C:26]([O:28][CH2:29][C@H:30]([OH:31])[CH2:38][N:39]6[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]6)[CH:25]=[CH:24][N:23]=5)=[O:21])[CH2:19]4)=[CH:12][C:11]=3[O:33][CH3:34])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: CN1CCNCC1
Reactant: CC#N
Reactant: COc1cc(C2CN(C(=O)c3cc(OC[C@H]4CO4)ccn3)C2)ccc1OCc1ccc(C2CC2)cc1
Solvent: O
Product: COc1cc(C2CN(C(=O)c3cc(OC[C@H](O)CN4CCN(C)CC4)ccn3)C2)ccc1OCc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
To a mixed solution of {3-[4-(4-cyclopropylbenzyloxy)-3-methoxyphenyl]azetidin-1-yl}-[4-((R)-1-oxiranylmethoxy)-pyridin-2-yl]-methanone (0.45 g) prepared in (1) in acetonitrile (4.0 mL)/water (1.0 mL) was added 1-methylpiperazine (1.0 mL). The reaction mixture was stirred at RT for 12 hr. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (Developing solvent: chloroform/methanol=9/1) to give the title compound (0.43 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:14][CH2:15][CH2:16][O:17][CH3:18].C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1cc(Cl)c(C=O)cc1O
Reactant: COCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCCOc1cc(C=O)c(Cl)cc1OC
Temperature: 0 °C

Procedure:
A mixture of crude 2-chloro-5-hydroxy-4-methoxy-benzaldehyde (1.79 g, 8.15 mmol), 1-bromo-3-methoxypropane (1.53 g, 9.79 mmol) and anhydrous K2CO3 (1.69 g, 12.2 mmol) in MeCN (30 mL) is refluxed overnight. Ice water is added to the mixture, followed by extraction with AcOEt. The combined organics are washed with brine, dried (Na2SO4) and concentrated. The title compound is obtained after purification by RP-HPLC on a PrepC18 OBD column (dimensions: 30×100 mm; 5 μM particle size, SunFire Ltd), and using a 95-5% gradient of MeCN/H2O 5:95 (containing 0.1% TFA) to MeCN/H2O 95:5 (containing 0.1% TFA) over 20 min, as white solid. TLC, Rf (hexane/AcOEt 1:1)=0.42. MS: 259.0 [M+H]+. ]+. tR (HPLC, Nucleosil C18HD column, 20-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 4.15 min. 1H-NMR (CDCl3): δ 2.15 (m, 2H), 3.39 (s, 3H), 3.59 (m, 2H), 3.99 (s, 3H), 4.19 (m, 2H), 6.91 (s, 1H), 7.45 (s, 1H), 10.4 (s, 1H) ppm.