Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:14][N:13](C4CCCCO4)[C:10]3=[CH:11][N:12]=2)[CH:4]=[N:3]1.Cl>CO.O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[N:14][NH:13][C:10]3=[CH:11][N:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc3c(-c4ccccc4)nn(C4CCCCO4)c3cn2)cn1
Agent: Cl
Solvent: O
Solvent: CO
Product: Cn1cc(-c2cc3c(-c4ccccc4)n[nH]c3cn2)cn1
Temperature: 60 °C
Reaction time: 16 h
Yield: 95.6 %

Procedure:
To a stirred solution of 5-(1-methyl-1H-pyrazol-4-yl)-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (54.5 mg, 0.152 mmol) in MeOH (8 mL) was added 6 M HCl in water. The reaction mixture was stirred at 60° C. under N2 for 16 h. The reaction mixture was cooled to room temperature. Volatile solvent was removed under reduced pressure. The crude was redissolved in EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate solution, water and brine, dried over Na2SO4, filtered, and evaporated in vacuo. Crystallization from DCM-heptanes afforded 133 as a solid (40 mg, 95.8%). 1H NMR (400 MHz, DMSO) δ 13.71 (broad s, 1H), 9.04 (s, 1H), 8.32 (s, 1H), 8.24 (s, 1H), 8.09 (d, J=7.3 Hz, 3H), 7.55 (t, J=7.5 Hz, 2H), 7.44 (t, J=7.4 Hz, 1H), 3.90 (s, 3H). LC/MS: m/z 276.1 [M+1]
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]2[CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[C:10]1[C:11]([O:26][CH:27]2[CH2:30][CH2:29][CH2:28]2)=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:20]([CH:22]1[CH2:24][CH2:23]1)=[O:21])[C@@H:15]([CH3:25])[CH2:14][CH2:13]2.[OH-].[Na+].[CH3:33][S:34](Cl)(=[O:36])=[O:35].Cl>O1CCOCC1>[CH:27]1([O:26][C:11]2[C:10]([C:3]3[CH:4]=[N:5][N:6]([CH:7]4[CH2:9][CH2:8]4)[C:2]=3[NH:1][S:34]([CH3:33])(=[O:36])=[O:35])=[CH:19][CH:18]=[C:17]3[C:12]=2[CH2:13][CH2:14][C@H:15]([CH3:25])[N:16]3[C:20]([CH:22]2[CH2:24][CH2:23]2)=[O:21])[CH2:28][CH2:29][CH2:30]1
Reactant: C[C@H]1CCc2c(ccc(-c3cnn(C4CC4)c3N)c2OC2CCC2)N1C(=O)C1CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@H]1CCc2c(ccc(-c3cnn(C4CC4)c3NS(C)(=O)=O)c2OC2CCC2)N1C(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An 8-mL round-bottom flask was charged with ((2S)-6-(5-amino-1-cyclopropyl-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.020 g, 0.05 mmol), 1,4-dioxane (1 mL) and 4 M aqueous sodium hydroxide solution (1 mL). Methanesulfonyl chloride (0.028 g, 0.019 mL, 0.24 mmol) was added, and the resulting solution stirred overnight at room temperature. The pH of the reaction mixture was adjusted to 7 with 1 N aqueous HCl solution, and the mixture was extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative-HPLC with the following conditions (Waters I): Column, SunFire Prep C18, 5 um, 19×100 mm; mobile phase, Water (0.05% ammonium bicarbonate) and acetonitrile (20% to 80% acetonitrile in 10 min, flow rate: 20 mL/min); Detector, UV 220&254 nm. This afforded N-(4-((2S)-5-cyclobutoxy-1-(cyclopropanecarbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-cyclopropyl-1H-pyrazol-5-yl)methanesulfonamide (0.010 g, 42%) as yellow oil. 1H NMR (300 MHz, CD3OD) δ ppm 0.63-0.75 (m, 1H), 0.80-1.00 (m, 2H), 1.00-1.18 (m, 8H), 1.25-1.34 (m, 2H), 1.51-1.68 (m, 1H), 1.85-2.11 (m, 5H), 2.25-2.42 (m, 2H), 2.99-3.08 (m, 1H), 3.13 (s, 3H), 3.65-3.75 (m, 1H), 3.96-4.17 (m, 1H), 4.66-4.74 (m, 1H), 7.15 (d, J=8.10 Hz, 1H), 7.38 (d, J=8.40 Hz, 1H), 7.82 (s, 1H). MS (ESI, pos. ion) m/z 485 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][C:21]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([Cl:29])[CH:24]=2)=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:33]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]([C:21]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([Cl:29])[CH:24]=2)=[O:22])[CH3:33])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2NC(=O)c2ccnc(Cl)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C(=O)c1ccnc(Cl)c1)c1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-{2-[(2-chloro-pyridine-4-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (100 mg, prepared as described in Example 1, Steps A-C) was added to a suspension of sodium hydride (50% in oil, 24 mg) in tetrahydrofuran at 0° C. and the resulting mixture was stirred at 0° C. for 1 hour at which time iodomethane (0.03 ml) was added. The reaction mixture was stirred at room temperature for 3 hours, diluted with ethyl acetate, washed three times with water, dried over sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography (cyclohexane:ethyl acetate 7:3) to afford 4-{2-[(2-Chloro-pyridine-4-carbonyl)-methyl-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester as white crystals. M.p. 59-61° C.; 1H NMR (400 MHz, CDCl3) 1.5 (s, 9H), 2.2 (m, 2H), 2.8 (m, 2H), 3.4 (m, 2H), 3.4 (s, 3H), 3.5 (m, 2H), 6.7 (m, 1H), 6.9 (m, 1H), 7.0-7.3 (m, 4H), 8.1 (m, 1H); MS (ES+) 331 (M+H+—CO2-isobutene), 375 (M+H+-isobutene), 431 (M+H+). This compound was treated according to Example 1 Step D to afford the title product as yellow crystals. M.p. 117-120° C.; 1H NMR (400 MHz, CDCl3) 2.4 (m, 2H), 2.5 (m, 2H), 2.6 (m, 2H), 2.9 (m, 2H), 3.2 (m, 2H), 3.5 (s, 3H), 3.5 (m, 2H), 6.2 (dt, J=18, 9 Hz, 1H), 6.5 (d, J=18 Hz, 1H), 6.8 (d, J=9 Hz, 1H), 6.9 (d, J=5 Hz, 1H), 7.0-7.3 (m, 6H), 8.1 (d, J=5 Hz, 1H); retention Time HPLC 2.17 min; MS (ES+) 481/483 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:23])(=[O:22])[NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)=[C:6]([N+:24]([O-])=O)[CH:5]=1.Cl[Sn]Cl>Cl.CCO>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:23])(=[O:22])[NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)=[C:6]([NH2:24])[CH:5]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Nc2cccc3cccnc23)c([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: COC(=O)c1ccc(S(=O)(=O)Nc2cccc3cccnc23)c(N)c1
Yield: 88.8 %

Procedure:
In a similar fashion using route 1 general procedure 4, 3-nitro-4-(quinolin-8-ylsulfamoyl)-benzoic acid methyl ester (Intermediate 249) (0.65 g, 1.67 mmol), SnCl2 (1.6 g, 8.3 mmol), 4-5 drops of conc. HCl and EtOH (15 ml) at 85° C. for 5 h gave the title compound (0.53 g, 88%).
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1>>[O:4]1[CH2:5][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:26](=[O:27])[C:25]4[CH:29]=[CH:30][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Reactant: COc1ccc(C(=O)O)cc1
Product: COc1ccc(C(=O)Nc2nc3c(OC)ccc(C4COCCOC4)c3s2)cc1

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine and 4-methoxy-benzoic acid, the title compound was prepared as white powder. MS: m/e=415(M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[C:15]([CH3:21])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1>[O-2].[O-2].[Mn+4].O1CCOCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[C:15]([CH3:21])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:29][CH:30]=1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: COc1nc2ccc(C(=O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
To a flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanol (1.51 g, 3.1 mmol, Intermediate 81: step a) was added 1,4-dioxane (50 mL) followed by activated manganese dioxide (1.31 g, 15.1 mmol) and the reaction mixture was heated to reflux. After 1 hour, the contents were filtered while still hot through a pad of Celite® and rinsed with THF. The resulting light yellow solution was concentrated and chromatographed on silica gel (10% acetone-hexane increasing to 25% acetone) to provide the title compound as a light yellowish amorphous solid.
Reaction SMILES: [CH3:1][C:2](=[O:22])[C:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C@H:10]([CH2:11][CH:12]=[CH:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[O:31]1[C@H:12]2[CH2:11][C@H:10]3[C@:15]([CH3:16])([CH2:14][C@@H:13]12)[C@@H:17]1[C@H:7]([C@H:6]2[C@:20]([CH3:21])([CH2:19][CH2:18]1)[C:3]([C:2](=[O:22])[CH3:1])=[CH:4][CH2:5]2)[CH2:8][CH2:9]3
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
5α-Pregna-2,16-dien-20-one (3.0 g.) in chloroform (50 ml.) was treated with m-chloroperbenzoic acid (85%, 2.0 g.). The solution was stirred at room temperature overnight, diluted with more chloroform (50 ml.), washed with dilute potassium bicarbonate solution and with water, dried over sodium sulphate and evaporated to an oil which crystallised on standing. Recrystallisation from ethyl acetate/petrol gave title compound (2.75 g.) as colourless plates, m.p. 145°-149° [α]D + 74.5°, λmax. 238 nm (ε 8970).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=O.[CH:14]1([NH:17][C:18]([NH2:20])=[S:19])[CH2:16][CH2:15]1>C(O)C>[CH:14]1([NH:17][C:18]2[S:19][CH:2]=[C:3]([C:5]3[C:13]4[C:8](=[N:9][CH:10]=[CH:11][CH:12]=4)[NH:7][CH:6]=3)[N:20]=2)[CH2:16][CH2:15]1
Reactant: O=C(CBr)c1c[nH]c2ncccc12
Reactant: NC(=S)NC1CC1
Solvent: CCO
Product: c1cnc2[nH]cc(-c3csc(NC4CC4)n3)c2c1
Temperature: 0 °C
Yield: 124.5 %

Procedure:
A mixture of 2-Bromo-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone (prepared according to Galvez C. et al, J. Het. Chem. 21, 1984, p421-423) (0.90 g, 3.76 mmol) and cyclopropyl-thiourea (prepared according to Marletta, M. et al, J. Med. Chem. 35, 1992, p1137-1144) (0.46 g, 3.96 mmol) was heated in ethanol (20 mL), at reflux for 4 hours. The reaction mixture was cooled to 0° C. with and ice-water bath, then the solids were filtered and dried to give cyclopropyl-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-yl]-amine as a tan solid (1.2 g, 92%). LC/MS MH+ =257.02, LC/MS RT: 1.62 min. 1H NMR (500 MHz, DMSO-d6, ppm) 12.22 (s,1H), 9.20 (bs,1H), 8.42 (d,1H, J=7.82 Hz), 8.36 (dd,1H, J=4.81, 1.22 Hz), 8.00 (s,1H), 7.25 (m,1H), 6.12 (s,1H), 2.77 (t, 1H,J=4.75), 0.86 (m,2H), 0.71 (m,2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[CH2:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH:29]1[CH2:37][NH2:38].C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:19])[NH:38][CH2:37][CH:29]3[CH2:30][C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:28]3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: NCC1Cc2ccccc2C1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCC4Cc5ccccc5C4)cc3)c(Cl)cc21
Reaction time: 16 h
Yield: 99.2 %

Procedure:
4-(6-chloro-4-(ethoxycarbonyl) chroman-7-yloxy)benzoic acid (Preparation 1) (50 mg, 0.133 mmol), suspended in 1.3 ml of dichloromethane, was treated sequentially with (2,3-dihydro-1H-inden-2-yl)methanamine hydrochloride (26.8 mg, 0.146 mmol), N-ethyl-N-isopropylpropan-2-amine (32.4 μl, 0.186 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30.5 mg, 0.159 mmol), and 1-hydroxy-7-azabenzotriazole (5.42 mg, 0.0398 mmol) at ambient temperature. After 16 hours, the reaction was applied directly to a silica gel column and eluted with a gradient (20% to 80%) of ethyl acetate-hexanes to provide the title compound (67 mg, 0.132 mmol, 99.8% yield) as a white solid.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.C(OCC)(=O)C>C1COCC1>[OH:16][CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C[Zn]Br
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(O)c1ccccc1
Yield: 91 %

Procedure:
Under nitrogen atmosphere, 30 mL of THF was added to 3.96 g (6.50 mmol, 0.65 equivalent (equivalent relative to a carbonyl compound as a starting raw material; the same, hereinafter)) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 1.06 g (10 mmol) of benzaldehyde in 5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 0˜5° C. for 3 hours. 25 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 10 mL (×2) of 1N hydrochloric acid, 20 mL of an aqueous saturated sodium chloride solution, 20 mL (×2) of an aqueous saturated sodium bicarbonate solution and 20 mL of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.76 g of the desired product (yield 91%).
Reaction SMILES: [CH2:1]([NH:5][CH3:6])[CH2:2][CH2:3][CH3:4].[CH:7]1([N:13]=[C:14]=[N:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[CH2:1]([N:5]([CH3:6])[C:14]([NH:13][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)=[N:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCCCN(C)C(=NC1CCCCC1)NC1CCCCC1
Yield: 99.7 %

Procedure:
A mixture of 17.78 g of N-butyl-N-methylamine (0.204 mol) and of 21.05 g of dicyclohexylcarbodiimide (0.102 mol) is refluxed for 3 h. The GC analysis then shows a conversion of greater than 99.5% of the dicyclohexylcarbodiimide. The colorless final mixture is concentrated at 60° C. under 1 mbar for 2 h, to give 29.9 g of a colorless and virtually odorless liquid of medium viscosity, corresponding to the expected guanidine (yield 99.7%).
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)N.[CH:12]([C:15]([CH3:17])=O)([CH3:14])[CH3:13]>C(O)(=O)C>[CH3:17][C:15]1[C:12]([CH3:14])([CH3:13])[C:11]2[C:3](=[CH:4][CH:5]=[C:6]([C:7]([OH:9])=[O:8])[CH:10]=2)[N:1]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CC(=O)C(C)C
Solvent: CC(=O)O
Product: CC1=Nc2ccc(C(=O)O)cc2C1(C)C
Temperature: 25 °C
Yield: 80.1 %

Procedure:
A solution of 4-hydrazinobenzoic acid (10.0 g, 65.7 mmol), isopropylmethylketone (21.1 mL, 197 mmol) in acetic acid (35 mL) was heated under reflux in an oil bath for 20 h. After cooling to ambient temperature the solvent was evaporated off under reduced pressure and to it was added a saturated aqueous solution of NaHCO3 (50 mL) and washed with CH2Cl2 (3×40 mL). The pH of the aqueous solution was adjusted with 1 M aqueous HCl to ca. 2, and then extracted with CH2Cl2 (3×50 mL). The combined organic solution was then dried with Na2SO4, filtered and concentrated to dryness under reduced pressure to yield the desired product (10.7 g, 80%) as a brownish solid.
Reaction SMILES: [CH2:1]([CH:3]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][CH:7]=1)[CH3:2].Br[C:19]1[CH:20]=[C:21]([CH:24]=[C:25](Br)[CH:26]=1)[CH:22]=[O:23]>O1CCCC1.C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH2:1]([CH:3]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:19]2[CH:20]=[C:21]([CH:24]=[C:25]([C:13]#[C:12][C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:7][CH:8]=3)[CH:26]=2)[CH:22]=[O:23])=[CH:10][CH:11]=1)[CH3:2]
Reactant: C#Cc1ccc(OCC(CC)CCCC)cc1
Reactant: O=Cc1cc(Br)cc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCC(CC)COc1ccc(C#Cc2cc(C#Cc3ccc(OCC(CC)CCCC)cc3)cc(C=O)c2)cc1
Temperature: 70 °C
Reaction time: 23 h
Yield: 79.3 %

Procedure:
Nitrogen was bubbled through a solution of 1-(2-Ethylhexyloxy)-4-ethynylbenzene (4) (1.69 g, 7.34 mmol) and 3,5-dibromobenzaldehyde (5) (692 mg, 2.62 mmol) in tetrahydrofuran (33 mL) and triethylamine (50 mL) for 5 min. Tetrakis(triphenylphosphine)palladium(0) (218 mg, 0.189 mmol) and copper(I) iodide (65 mg, 0.34 mmol) were added and nitrogen bubbled through the solution for a further 5 min, before stirring at 70° C. for 23 h. Once cool, the solvent was removed and the residue purified by column chromatography over silica with dichloromethane-light petroleum (1:2 to 1:1) as eluent to leave 3,5-bis[4-(2-ethylhexyloxy)phenylethynyl]benzaldehyde (6) (1.17 g, 79%) as a pale brown oil. (Found: C, 83.3; H, 8.2; C39H46O3 requires C, 83.2; H, 8.2%); νmax(film)/cm−1 2211 (C≡C) and 1704 (C═O); δH(400 MHz, CDCl3) 0.93-0.99 (12 H, m, CH3), 1.28-1.56 (16 H, m, CHCH2CH2CH2CH3 and CHCH2CH3), 1.75 (2 H, m, OCH2CH), 3.87 (4 H, d, J 6, OCH2CH), 6.90 (4 H, AA′BB′), 7.48 (4 H, AA′BB′), 7.87 (1 H, dd, J 1.5, 4-H), 7.92 (2 H, d, J 1.5, 2, 6-H) and 10.00 (1 H, s, CHO); δc(100.6 MHz, CDCl3) 11.1, 14.1, 23.1, 23.8, 29.0, 30.4, 39.3, 70.6, 86.0, 91.7, 114.1, 114.6, 125.2, 131.3, 133.5, 136.6, 139.1, 159.9 and 191.0.
Reaction SMILES: [C:1](=O)(O)[O-].[Na+].CI.[CH3:8][N:9]([CH3:27])[C:10]([C@@H:12]1[CH2:16][C@H:15]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:14][NH:13]1)=[O:11]>CN(C)C=O>[CH3:8][N:9]([CH3:27])[C:10]([C@@H:12]1[CH2:16][C@H:15]([S:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:14][N:13]1[CH3:1])=[O:11]
Reactant: O=C([O-])O
Reactant: COc1ccc(CS[C@@H]2CN[C@H](C(=O)N(C)C)C2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N(C)C)N(C)C2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 26.4 %

Procedure:
84 mg of sodium bicarbonate and 41 μl of methyl iodide were added, whilst ice-cooling, to a solution of 163 mg of (2S, 4S)-2-(N,N-dimethylcarbamoyl)-4-(4-methoxybenzylthio)pyrrolidine [prepared as described in step (4) above] dissolved in 1.5 ml of dry dimethylformamide, and the mixture was stirred at room temperature for 4 hours. At the end of this time, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by chromatography using a Lobar column (Merck, LiChroprep Si60, size A). 45 mg of the title compound were obtained, as an oil, from the fractions eluted with a 3:1 by volume mixture of ethyl acetate and methanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:9]([CH3:17])([C:11]1[O:12][C:13]([CH3:16])=[CH:14][CH:15]=1)[CH3:10])C(OC)=O.[Li+].[Cl-].O>CS(C)=O>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:9]([CH3:10])([C:11]1[O:12][C:13]([CH3:16])=[CH:14][CH:15]=1)[CH3:17]
Reactant: COC(=O)C(C(=O)OC)C(C)(C)c1ccc(C)o1
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)CC(C)(C)c1ccc(C)o1
Temperature: 170 °C
Yield: 78 %

Procedure:
Step C To a solution of 2-[1-methyl-1-(5-methyl-furan-2-yl)-ethyl]-malonic acid dimethyl ester (2.5 g, 9.8 mmol) in DMSO (30 mL) was added LiCl (1 g, 23.7 mmol) and H2O (0.17 mL, 9.8 mmol). The reaction mixture was heated at 170° C. for 3 h, then poured into a ice-water, extracted with ethyl acetate. The organic layer were separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:20, 1:20) to give 3-methyl-3-(5-methyl-furan-2-yl)-butyric acid methyl ester as a colorless oil (1.5 g, 78%).
Reaction SMILES: [ClH:1].O1CCOCC1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([C@H:35]2[N:39](C(OC(C)(C)C)=O)[C:38]([CH3:48])([CH3:47])[CH2:37][CH2:36]2)[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:25]4[C@H:32]([CH3:33])[CH2:31][C@@H:30]([OH:34])[C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:20][CH2:19]2)=[O:17])=[C:11]([F:49])[CH:10]=1>C(Cl)Cl>[ClH:1].[ClH:1].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([C@H:35]2[CH2:36][CH2:37][C:38]([CH3:48])([CH3:47])[NH:39]2)[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:25]4[C@H:32]([CH3:33])[CH2:31][C@@H:30]([OH:34])[C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:20][CH2:19]2)=[O:17])=[C:11]([F:49])[CH:10]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Br)cc4F)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Br)cc4F)[C@H]4CCC(C)(C)N4)CC3)c21
Reaction time: 8 h
Yield: 62 %

Procedure:
4.0M HCl/Dioxane (0.121 mL, 0.483 mmol) was added to a solution of (S)-tert-butyl 5-((S)-1-(4-bromo-2-fluorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (0.104 g, 0.161 mmol) in DCM (1 mL). The solution stirred overnight, and the solvent was removed to yield (S)-2-(4-bromo-2-fluorophenyl)-2-((R)-5,5-dimethylpyrrolidin-2-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)ethanone dihydrochloride (0.0618 g, 0.0998 mmol, 62.0% yield). HPLC, 254 nm=1.988 minutes, 99.66% purity, LCMS (APCI+) 547.7 m/z [M+H]+; Retention time=2.45 minutes. 1H NMR (400 MHz, D2O) 8.58 (s, 1H), 7.54 (dd, J1=1.952 Hz, J2=9.761 Hz, 1H), 7.46 (dd, J1=1.562 Hz, J2=8.199 Hz, 1H), 7.35 (t, J=7.809 Hz, 1H), 5.32 (t, J=8.199 Hz, 1H), 4.79 (d, J=9.761 Hz, 1H), 4.40-4.31 (m, 1H), 4.0-3.9 (m, 2H), 3.82-3.62 (m, 3H), 2.30-2.28 (m, 1H), 2.27-2.15 (m, 1H), 2.02-1.84 (m, 4H), 1.58 (s, 3H), 1.44 (s, 3H), 1.29 (d, J=6.637 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.Cl[C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>>[S:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[NH:15][CH:9]1[C:10]2[NH:11][C:12]3[C:4](=[CH:3][C:2]([Br:1])=[CH:14][CH:13]=3)[C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: Clc1nc2ccccc2s1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: Brc1ccc2[nH]c3c(c2c1)CCCC3Nc1nc2ccccc2s1

Procedure:
N-(1,3-Benzothiazol-2-yl)-6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine (75 mg, 0.28 mmol) and 2-chlorobenzothiazole (143 mg, 0.84 mmol) in a similar manner as described in Example 22 to give 11 mg (10%) of a yellow solid. 1H-NMR (CDCl3): δ 9.31 (s, 1H), 7.70-7.62 (m, 3H), 7.39 (t, 1H), 7.29-7.17 (m, 4H), 5.38-5.32 (m, 1H), 2.77-2.75 (m, 2H), 2.45-2.38 (m, 1H), 2.10-1.99 (m, 3H); MS m/z (M−1) 396, 398.