Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]([CH3:13])([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:17]([OH:20])[C:18]#[CH:19]>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:20][CH2:17][CH2:18][CH2:19][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]([CH3:13])([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(Br)c1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)Oc1cccc(CCCO)c1

Procedure:
10d (50 g, 175 mmol) is placed in the presence of 2-propynol (12 ml, 210 mmol) in 400 ml of diisopropylamine, under nitrogen. Pd(PPh3)2Cl2 (3.5 g) and CuI (500 mg) are added and the reaction medium is stirred at reflux for 5 h. The precipitate formed in the course of the reaction is filtered on celite and the reaction medium is dry concentrated. The oil obtained is purified by flash chromatography on silica (petroleum ether:AcOEt 80:20). It is then placed in a solution of 250 ml of THF and 150 ml of EtOH in the presence of Pd/C under hydrogen at 6 bar. This mixture is stirred for 24 h. at ambient temperature. After filtration on celite, the reaction medium is dry concentrated and 12a is isolated in the form of a clear oil (32 g, yield=69%). TLC silica gel 60 F 254 Merck, heptane:AcOEt 80:20, Rf=0.56.
Reaction SMILES: [N+]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[N+](C1C=CC2C(=O)C3C(=CC=CC=3)C(=O)C=2C=1[N+]([O-])=O)([O-])=O>>[CH:11]1[C:10]2[C:9](=[O:19])[C:8]3[C:17](=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:16](=[O:18])[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: O=C1c2ccccc2C(=O)c2c1ccc([N+](=O)[O-])c2[N+](=O)[O-]
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
In general the crude 1-nitroanthraquinone, which is contaminated by dinitroanthraquinone may be produced from anthraquinone by any of the known nitration methods, for example by nitration of anthraquinone in the presence of sulphuric acid or phosphoric acid or by nitration of anthraquinone with concentrated nitric acid alone; the last-named method can be carried out, for example, at -40° C to the boiling point of the reaction medium and in the presence of a great excess of nitric acid of at least 90% strengh. The nitration product can be submitted to the process of this invention as obtained after separation and washing, for example as a moist or dry filtercake, or if desired after intermediate purification.
Reaction SMILES: [CH3:1][O:2][C:3]([O:12][CH3:13])([CH3:11])[C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].C([O-])([O-])=O.[K+].[K+].Br[CH2:21][C:22]([C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[N:26]=[C:27]([NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:28]([CH3:34])=[N:29]2)=[O:23]>CN(C=O)C.C(Cl)Cl>[C:36]([NH:35][C:27]1[C:28]([CH3:34])=[N:29][C:30]2[C:25]([N:26]=1)=[C:24]([C:22](=[O:23])[CH2:21][CH:5]([C:4](=[O:10])[C:3]([O:2][CH3:1])([O:12][CH3:13])[CH3:11])[C:6]([O:8][CH3:9])=[O:7])[CH:33]=[CH:32][CH:31]=2)([CH3:39])([CH3:38])[CH3:37]
Reactant: COC(=O)CC(=O)C(C)(OC)OC
Reactant: Cc1nc2cccc(C(=O)CBr)c2nc1NC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C(CC(=O)c1cccc2nc(C)c(NC(C)(C)C)nc12)C(=O)C(C)(OC)OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of methyl 4,4-dimethoxy-3-oxovalerate (Sigma Aldrich, 0.127 ml, 0.744 mmol), K2CO3 (EMD Biosciences, 0.135 ml, 2.231 mmol), 2-bromo-1-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)ethanone (606) (0.25 g, 0.744 mmol) in DMF (2.97 mL) was stirred at RT for 2 d. Reaction mixture was diluted with DCM and washed with alternating water and brine washes (2×) to remove DMF. The organic layer was concentrated and advanced to the next step. m/z (ESI, +ve) 446.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]([CH3:21])[CH3:20])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.BrC1C=CC2OCCN3C(CN4CCCC4)=C(C(N)=O)N=C3C=2C=1.CNC.[CH3:50][C:51]([OH:55])([C:53]#[CH:54])[CH3:52]>>[CH3:20][N:19]([CH2:18][C:12]1[N:8]2[CH2:9][CH2:10][O:11][C:5]3[CH:4]=[CH:3][C:2]([C:54]#[C:53][C:51]([OH:55])([CH3:52])[CH3:50])=[CH:22][C:6]=3[C:7]2=[N:14][C:13]=1[C:15]([NH2:17])=[O:16])[CH3:21]
Reactant: CN(C)Cc1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Reactant: C#CC(C)(C)O
Agent: CNC
Agent: NC(=O)c1nc2n(c1CN1CCCC1)CCOc1ccc(Br)cc1-2
Product: CN(C)Cc1c(C(N)=O)nc2n1CCOc1ccc(C#CC(C)(C)O)cc1-2
Yield: 34 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-3-((dimethylamino)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (prepared similarly as described in the synthesis of 10-bromo-3-(pyrrolidin-1-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide replacing pyrrolidine with dimethylamine) was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as a grey solid (41 mg, 34%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH2:11])[CH2:8]2.C1N=CN([C:17](N2C=NC=C2)=[O:18])C=1.CCN(C(C)C)C(C)C.[N:33]1([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:37]2([CH2:41][CH2:40][NH:39][CH2:38]2)[CH2:36][CH2:35][CH2:34]1>C(Cl)Cl>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:17]([N:39]1[CH2:40][CH2:41][C:37]3([N:33]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:34][CH2:35][CH2:36]3)[CH2:38]1)=[O:18])[CH2:8]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: CC(C)(C)OC(=O)N1CCCC12CCNC2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC12CCN(C(=O)NC1C3CC4CC(C3)CC1C4)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
A solution of adamantan-2-ylamine (75 mg, 0.38 mmol), CDI (80 mg, 0.46 mmol), i-Pr2NEt (150 mg, 1.14 mmol) in CH2Cl2 (5 mL) was stirred at 0° C. for 1 h, and tert-butyl 1,7-diazaspiro[4.4]nonane-1-carboxylate (100 mg, 0.38 mmol) was added. The reaction mixture stirred at room temperature overnight. The solvent was removed under reduced pressure to give crude product which was purified by preparative TLC to afford tert-butyl 7-(2-adamantylcarbamoyl)-1,7-diazaspiro[4.4]nonane-1-carboxylate (136 mg, 89%). LC-MS Method 3, tR=4.24 min, m/z=404.1; 1H NMR (CDCl3) 1.39 (s, 9H), 1.48-1.52 (m, 4H), 1.62-1.71 (m, 5H), 1.71-1.81 (m, 10H), 1.81-1.88 (m, 3H), 1.89-2.01 (m, 1H), 2.93-3.12 (m, 1H), 3.21 (m, 1H), 3.28-3.49 (m, 2H), 3.55 (m, 1H), 3.68 (m, 1H), 3.88 (m, 1H), 4.46 (m, 1H).
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[CH:4]=[CH:3][CH:2]=1.I[C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+].C1O[CH2:50][CH2:49]OCCOCCOCCOCCOC1>ClC1C=CC=CC=1Cl.[Cu]>[C:17]1([C:21]2[CH:26]=[CH:25][C:24]([N:12]3[C:50]4[CH:49]=[CH:2][CH:3]=[CH:4][C:5]=4[C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=[C:15]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:16]=1
Reactant: Ic1ccc(-c2cccc(I)c2)cc1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1Cl
Product: c1cc(-c2ccc(-n3c4ccccc4c4ccccc43)cc2)cc(-n2c3ccccc3c3ccccc32)c1
Yield: 69.7 %

Procedure:
Carbazole (0.90 g, 5.42 mmol), 3,4′-diiodobiphenyl, K2CO3 (2.72 g, 19.7 mmol), copper powder (0.43 g, 6.77 mmol), and 18-crown-6 (0.13 g, 0.49 mmol) were dissolved in o-dichlorobenzene and heated to reflux for 48 h. The solution was filtered and the solvent removed in vacuo, the residue was recrystallized from MeOH to afford the product (0.83 g, 69.7%). 1H NMR (CDCl3) δ 8.22-8.16 (m, 4H), 7.93-7.65 (m, 8H), 7.56-7.49 (m, 8H), 7.47-7.28 (m, 4H). 13C NMR (CDCl3+DMSO-d6) δ 142.1, 140.8, 140.7, 139.0, 138.3, 137.3, 130.5, 128.5, 127.3, 126.1, 126.0, 125.9, 125.6, 123.4, 120.3, 120.2, 120.0, 109.7. EI MS m/z 484 [M+], m.p.=244-246° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=2)[C:15]([O:17]CC)=[O:16])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(O)C.[OH-].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=2)[C:15]([OH:17])=[O:16])(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc(S(=O)(=O)Nc2cccc(F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc(S(=O)(=O)Nc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the product of Step A was added ethanol (6.4 mL) followed by a solution of NaOH (0.483 g, 12.1 mmol) in water (6.4 mL). The reaction was stirred at ambient temperature for 1 hour. To the mixture was added 1 NHCl (22.8 mL), and the mixture stirred at ambient temperature overnight. The solids were collected by filtration, washed with water (2×4 mL) and dried in a vacuum oven at 45° C. overnights to give 3-{[(3-fluorophenyl)amino]sulfonyl}benzoic acid: 1H NMR (400 MHz, DMSO-d6) δ ppm 13.51 (bs, 1H), 10.68 (bs, 1H), 8.30 (t, J=1.8, 1H), 8.14 (dt, J=7.7, 1.4, 1H), 7.99 (ddd, J=7.8, 2.0, 1.1, 1H), 7.70 (t, J=7.8, 1H), 7.27 (m, 1H), 6.94-6.82 (m, 3H); MS (ESI) m/z 294 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[F:14][C:15]1[CH:21]=[C:20]([S:22][C:23]([F:28])([F:27])[CH:24]([F:26])[Cl:25])[CH:19]=[CH:18][C:16]=1[NH2:17]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([NH:6][C:7]([NH:17][C:16]1[CH:18]=[CH:19][C:20]([S:22][C:23]([F:28])([F:27])[CH:24]([F:26])[Cl:25])=[CH:21][C:15]=1[F:14])=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1ccc(SC(F)(F)C(F)Cl)cc1F
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(SC(F)(F)C(F)Cl)cc1F
Reaction time: 1 h

Procedure:
A 1.8 g quantity of 2,6-difluorobenzoyl isocyanate was added dropwise to a solution of 2.6 g of 2-fluoro-4-(1,1,2-trifluoro-2-chloroethylthio)aniline in 15 ml of toluene at room temperature (20°to 25° C.). After the reaction was allowed to proceed at the same temperature for 1 hour, the crystals which separated out were recovered by filtration and washed with toluene to give 3.6 g of N-(2,6-difluorobenzoyl)-N'-[2-fluoro-4-(1,1,2-trifluoro-2-chloroethylthio)phenyl]urea, m.p. of 172°-173° C.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]1[CH2:17][CH2:18][CH2:19][CH:20]([CH2:21][C:22]([O:24]CC)=[O:23])[C:12]1=[CH:11]2.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.O>[F:32][C:30]([F:31])([F:33])[C:28]1[CH:27]=[C:5]([CH:4]=[C:3]([C:2]([F:35])([F:34])[F:1])[CH:29]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]1[CH2:17][CH2:18][CH2:19][CH:20]([CH2:21][C:22]([OH:24])=[O:23])[C:12]1=[CH:11]2
Reactant: CCOC(=O)CC1CCCn2c1cc1cc(OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)ccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CC1CCCn2c1cc1cc(OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of ethyl 2-(2-(3,5-bis(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (145 mg, 0.29 mmol) in dioxane (1.5 mL) was added 1 M LiOH aqueous solution (1.16 mL, 1.161 mmol). The reaction was stirred at room temperature for 8 h, diluted with water, and acidified to pH 4 with 0.5 M aqueous citric acid. The solid precipitate was collected to give the title compound (125 mg). LCMS m/z=471.8 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.55-1.65 (m, 1H), 2.00-2.10 (m, 1H), 2.17-2.26 (m, 2H), 2.65 (dd, J=−16.1, 8.5 Hz, 1H), 3.00 (dd, J=16.1, 5.4 Hz, 1H), 3.45-3.54 (m, 1H), 3.85-3.94 (m, 1H), 4.14-4.22 (m, 1H), 5.19 (s, 2H), 6.23 (s, 1H), 6.91 (dd, J=8.8, 2.4 Hz, 1H), 7.09 (d, J=2.4 Hz, 1H), 7.19 (d, J=−8.7 Hz, 1H), 7.83 (s, 1H), 7.94 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[CH:8]=[CH:9][C:10]([C:16]([OH:18])=[O:17])=[CH:11][C:12]=3[CH2:13]2)=[CH:4][CH:3]=1.[CH3:19]O.S(=O)(=O)(O)O>O>[CH3:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[CH:8]=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:12]=3[CH2:13]2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: Cc1ccc2c(c1)Cc1cc(C(=O)O)ccc1O2
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc2c(c1)Cc1cc(C)ccc1O2
Temperature: 40 °C

Procedure:
Twenty-six grams of 7-methylxanthene-2-carboxylic acid is added to 400 ml. of absolute methanol. To the resultant solution are added 18 ml. of concentrated sulfuric acid and the mixture is then heated at reflux for about 2 hours. The mixture is then cooled to 40° C and sufficient water is added to bring the total volume to 1400 ml. The resultant mixture is then filtered to give methyl 7-methylxanthene-2-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH2:17]([NH2:22])[CH2:18][CH:19]([CH3:21])[CH3:20].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13][NH:22][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: CC(C)CCN
Reactant: O=Cc1ccc(Oc2ccc(Br)cn2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)CCNCc1ccc(Oc2ccc(Br)cn2)cc1
Reaction time: 8 h
Yield: 49.5 %

Procedure:
To a solution of 4-(5-Bromo-pyridin-2-yloxy)-benzaldehyde (RH3-A02640-038) (3.501 g, 12.6 mmol) in 1,2-dichloroethane (61 mL) is added isoamylamine (1.65 mL, 14.2 mmol), NaBH(OAc)3 (4.00 g, 18.9 mmol), and acetic acid (1.10 mL, 19.2 mmol). The reaction is stirred overnight. The reaction mixture is then washed with saturated NaHCO3 (2×100 mL), dried over MgSO4, filtered, and concentrated. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 25% of ethyl acetate to 100% of ethyl acetate to give [4-(5-Bromo-pyridin-2-yloxy)-benzyl]-(3-methyl-butyl)-amine (2.18 g, 50%) as a yellow oil. 1NMR (400 MHz, CDCl3) δ ppm: 8.21 (d, J=3.1 Hz, 1H), 7.75 (dd, J=2.6, 8.7 Hz, 1H), 7.37-7.34 (m, 2H), 7.09-7.05 (m, 2H), 6.82 (d, J=9.1 Hz, 1H), 2.49 (s, 2H), 2.66 (dd, J=7.6, 7.6 Hz, 2H), 1.67-1.61 (m, 1H), 1.44-1.38 (m, 2H), 1.15 (s br, 1H), 0.90 (d, J=6.6 Hz, 6H); MS (ES): [M+H]+ found 261.7.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:2]1.CO[C:16](=[O:35])[C:17]([C:19]1[C:29]2=[C:30]3[C:25](=[CH:26][CH:27]=[C:28]2[CH3:31])[CH:24]([CH3:32])[CH2:23][C:22]([CH3:34])([CH3:33])[N:21]3[CH:20]=1)=O>>[CH3:34][C:22]1([CH3:33])[CH2:23][CH:24]([CH3:32])[C:25]2[C:30]3=[C:29]([C:19]([C:17]4[C:16](=[O:35])[NH:13][C:11](=[O:12])[C:10]=4[C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][CH:2]=4)=[CH:20][N:21]13)[C:28]([CH3:31])=[CH:27][CH:26]=2
Reactant: COC(=O)C(=O)c1cn2c3c(ccc(C)c13)C(C)CC2(C)C
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Product: Cc1ccc2c3c1c(C1=C(c4c[nH]c5ccccc45)C(=O)NC1=O)cn3C(C)(C)CC2C

Procedure:
Beginning with (indol-3-yl)acetamide and (4,4,6,9-tetramethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:18]3[NH:22][C:21](=[O:23])[NH:20][N:19]=3)[N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:4][CH:3]=1.CC1C=CC=C(C)N=1.[C:32](Cl)(=[O:35])[CH:33]=[CH2:34]>C(Cl)Cl>[C:32]([N:15]1[CH2:16][CH2:17][C@H:13]([O:12][C:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=3)[CH:6]=[C:7]([C:18]3[NH:22][C:21](=[O:23])[NH:20][N:19]=3)[N:8]=2)[CH2:14]1)(=[O:35])[CH:33]=[CH2:34]
Reactant: C=CC(=O)Cl
Reactant: O=c1[nH]nc(-c2cc3ccc(Cl)cc3c(O[C@H]3CCNC3)n2)[nH]1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C=CC(=O)N1CC[C@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3ccc(Cl)cc23)C1
Temperature: 0 °C
Yield: 18.6 %

Procedure:
To a mixture of (S)-3-(7-chloro-1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one (180 mg, 0.489 mmol) in DCM (10 mL) was added 2,6-dimethylpyridine (157 mg, 1.467 mmol) at −20° C. followed by the dropwise addition of acryloyl chloride (88 mg, 0.978 mmol, 10 mg/mL in dry DCM). The reaction mixture was warmed to 0° C. over a 30 minute period. The reaction was quenched with MeOH (5 mL) and the mixture concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (35 mg, 18%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.06 (br, 1H), 11.84 (s, 1H), 8.16 (s, 1H), 8.09 (dd, J=1.8 Hz and 8.9 Hz, 1H), 8.03 (s, 1H), 7.83-7.86 (m, 1H), 6.55-6.72 (m, 1H), 6.12-6.19 (m, 2H), 5.63-5.72 (m, 1H), 4.65-4.12 (m, 4H), 2.25-2.42 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[O:22])[CH:16]=1.[Li+].CC([N-]C(C)C)C.O>C1COCC1.C(OCC)(=O)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:2]([Cl:1])[C:7]=1[CH:21]([C:17]1[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=1)[OH:22]
Reactant: O=Cc1cccnc1
Reactant: Clc1cc(Cl)c(-c2ccccc2)nn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: OC(c1cccnc1)c1c(Cl)nnc(-c2ccccc2)c1Cl
Temperature: -78 °C
Reaction time: 3 h
Yield: 123.4 %

Procedure:
To a solution of 4,6-dichloro-3-phenyl-pyridazine (2.27 g, 0.01 mol) in dry THF (30 mL) was added pyridine-3-carbaldehyde (1.3 g, 0.012 mol). The reaction mixture was cooled down to −78° C. and a solution of LDA (2 N, 22 mL) was added dropwise, keeping the internal temperature below −50° C. The reaction mixture was stirred for 3 h, then water and ethyl acetate were added. Phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (phase separator cartridge) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, isohexane/ethyl acetate 9:1 to 8:2) yielding the title compound as a solid (4.1 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13](#[N:15])[CH3:14].[F:16][C:17]1[CH:18]=[C:19]([CH:25]=[C:26]([F:28])[CH:27]=1)[C:20](OCC)=[O:21].C([N-]C(C)C)(C)C.[Li+]>C1COCC1>[F:16][C:17]1[CH:18]=[C:19]([C:20](=[O:21])[CH2:14][C:13]#[N:15])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: CC#N
Reactant: CCOC(=O)c1cc(F)cc(F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#CCC(=O)c1cc(F)cc(F)c1
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 43 %

Procedure:
Diisopropylamine (10.6 mL, 76 mmol) was dissolved in dry THF (10 mL) and the solution cooled to −20° C. A solution of n-butyllithium (2.5N in hexanes, 30.5 mL, 76 mmol) was added slowly at such a rate as to keep the internal temperature below 0° C. After stirring for 5 min, the solution was cooled to −20° C. and added to a solution of acetonitrile (2.37 mL, 45.3 mmol) and ethyl 3,5-difluorobenzoate (6.23 g, 36.2 mmol) in dry THF (18 mL) at such a rate as to keep the temperature below −40° C. A further 10 mL of dry THF was used to transfer the remaining lithium diisopropylamide to the reaction. The reaction was allowed to warm to ambient over 2 h before being quenched with saturated aqueous ammonium chloride solution. The reaction was extracted with ethyl acetate (×2) and the extracts discarded. The aqueous was acidified with 2N HCl and extracted with ethyl acetate. The organic extract was washed with 2N HCl and brine before being dried over MgSO4, filtered and evaporated. Purification using chromatography (silica gel, gradient 5 to 100% ethyl acetate/isohexane) gave 3-(3,5-difluorophenyl)-3-oxopropanenitrile as a yellow solid (2.82 g).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:26][C:27]1[N:31]=[CH:30][NH:29][N:28]=1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][S:26][C:27]3[N:31]=[CH:30][NH:29][N:28]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: Sc1nc[nH]n1
Product: O=C(CCCSc1nc[nH]n1)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 56 %

Procedure:
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 3-mercapto-1,2,4-triazole as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 87°-89° C., in a 56% yield.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[O:14][C@H:13]([N:15]2[CH:22]=[C:21]([F:23])[C:19]([NH2:20])=[N:18][C:16]2=[O:17])[C@H:12]([OH:24])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:25][S:26](Cl)(=[O:28])=[O:27].CO>N1C=CC=CC=1.C1(C)C=CC=CC=1>[S:26]([O:24][C@@H:12]1[CH2:11][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])[O:14][C@@H:13]1[N:15]1[CH:22]=[C:21]([F:23])[C:19]([NH2:20])=[N:18][C:16]1=[O:17])([CH3:25])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](O)[C@@H](n2cc(F)c(N)nc2=O)O1
Solvent: c1ccncc1
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](OS(C)(=O)=O)[C@@H](n2cc(F)c(N)nc2=O)O1
Temperature: 0 °C
Yield: 68.1 %

Procedure:
A suspension of 19 (1.70 g, 4.73 mmol) in dry pyridine (80 mL) was stirred under argon and cooled to 0° C. Methanesulfonyl chloride (MsCl, 1.21 mL, 15.6 mmol) was added dropwise and the reaction mixture stirred at 0° C. for 5 h. Then the mixture was poured onto ice/water (300 mL) and extracted with chloroform (3×300 mL). Combined extracts were washed with a 5% aqueous sodium hydrogen carbonate solution (300 mL), with water (2×300 mL) and then dried over sodium sulphate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: stepwise gradient of methanol (8-12%) in toluene] to give pure 20 (1.41 g, 68% yield) as a white solid: mp 75-76° C.; UV (ethanol): λmax 243 nm (ε 8100), 282 nm (ε 7300), λmin 225 nm (ε 6000), 265 nm (ε 6000); 1H NMR (DMSO-d6): δ 7.9-7.6 (br d, 2H, NH2), 7.85 (d, 1H, H-6, J6-F5=7.0 Hz), 6.08 (dd, 1H, H-1′, J1′-2′=5.2 Hz and J1′-F5=1.6 Hz), 5.4 (m, 1H, H-2′), 4.1 (m, 1H, H-4′), 3.9 (m, 1H, H-5′), 3.7 (m, 1H, H-5″), 3.11 (s, 3H, CH3SO2), 2.47 (m, 1H, H-3′), 2.0 (m, 1H, H-2″), 0.85 (s, 9H, (CH3)3C—Si), 0.05 (s, 6H, (CH3)2Si); MS (matrix GT): FAB>0 m/z 1312 (3M+H)+, 875 (2M+H)+, 438 (M+H)+, 309 (S)+, 130 (BH2)+; FAB<0 m/z 1310 (2M−H)−, 873 (2M−H)−, 436 (M−H)−, 128 (B)−, 95 (CH3SO3)−; [α]D20=−84 (c, 0.84 DMSO).
Reaction SMILES: C([N:8]1[CH2:11][CH:10]([C:12]#[N:13])[CH2:9]1)(OC(C)(C)C)=O.Cl.CCN(C(C)C)C(C)C.[CH3:24][N:25]1[CH:29]=[C:28]([S:30](Cl)(=[O:32])=[O:31])[N:27]=[CH:26]1>O1CCOCC1>[CH3:24][N:25]1[CH:29]=[C:28]([S:30]([N:8]2[CH2:9][CH:10]([C:12]#[N:13])[CH2:11]2)(=[O:32])=[O:31])[N:27]=[CH:26]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC(C#N)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cn1cnc(S(=O)(=O)N2CC(C#N)C2)c1
Reaction time: 2 h
Yield: 79.9 %

Procedure:
To a solution of 1-N-Boc-3-cyanoazetidine (5.0 g, 27.5 mmol) in 1,4-dioxane (50 mL) was added 4 N HCl (50 mL) and stirred for 2 h. The reaction was concentrated under vacuum. The residue was dissolved in CH2Cl2 (60 mL) and DIPEA (10.6 mL, 60.4 mmol) and added 1-methylimidazole-4-sulfonyl chloride (4.94 g, 27.5 mmol) and stirred at room temperature for 20 h. The reaction mixture was washed with 2 N NaOH (50 mL), dried over MgSO4 and concentrated under vacuum to afford 8 as a white crystalline solid (4.97 g, 80%); 1H-nmr (300 MHz, CDCl3) δ 7.06 (s, 1H), 7.56 (s, 1H), 4.27-4.19 (m, 4H), 3.82 (s, 3H), 3.43-3.31 (m, 1H); LC-MS (214) 99%, 0.93 min, m/z 227.1 (M+H).