Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[O:87]=[C:88]([NH:92][C:93]1[S:94][CH:95]=[CH:96][N:97]=1)[C:89](O)=[O:90]>>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][C:89](=[O:90])[C:88](=[O:87])[NH:92][C:93]1[S:94][CH:95]=[CH:96][N:97]=1)[CH2:19][CH2:18]2
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C(O)C(=O)Nc1nccs1
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)C(=O)Nc3nccs3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 23 %

Procedure:
The title compound was prepared in 23% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-oxo-2-(thiazol-2-ylamino)acetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 684.5 (M+H)+, 2.04 min (method 9). 1H NMR (500 MHz, 1:1 MeOD:CDCl3) δ=7.92 (d, J=8.5 Hz, 2H), 7.54 (d, J=3.7 Hz, 1H), 7.49 (s, 1H), 7.22-7.19 (m, 3H), 5.30 (dd, J=1.8, 6.1 Hz, 1H), 4.79 (d, J=1.2 Hz, 1H), 2.65-2.55 (m, 2H), 2.53-2.46 (m, 1H), 2.14 (dd, J=6.4, 17.1 Hz, 1H), 1.98-1.89 (m, 1H), 1.88-1.76 (m, 3H), 1.73 (s, 3H), 1.70 (s, 1H), 1.61-1.36 (m, 11H), 1.29-1.22 (m, 1H), 1.21-1.14 (m, 2H), 1.09 (s, 3H), 1.06 (s, 3H), 1.02 (s, 3H), 0.95-0.94 (m, 3H), 0.93 (s, 3H).
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Br:20])[CH:19]=1.CI.[NH4+].[Cl-]>CCCCCC.C1COCC1.CCOC(C)=O>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Br:20])[C:19]=1[CH3:1]
Reactant: Brc1cncc(Br)c1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(Br)cncc1Br
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyllithium in hexane (1.6 N, 16 ml) is added dropwise, under argon, to a solution of diisopropylamine (3.6 ml, 1.02 equiv.) in anhydrous THF (145 ml) maintained at −10° C. The reaction mixture is cooled to −78° C. and then a solution of 3,5-dibromopyridine (5.92 g, 25 mmol) in THF (200 ml), cooled to −78° C., is added dropwise. The reaction mixture is stirred for 30 min and then methyl iodide (2.17 ml, 1.4 equiv.) is added dropwise. The stirring is maintained for 2 h at −78° C. A saturated aqueous NH4Cl solution (120 ml) is added. After evaporation of the solvents, the reaction mixture is extracted with EtOAc. The organic phase is washed with brine, dried over MgSO4 and evaporated. The yellow solid obtained is taken up with EtOAc. The suspension is filtered. The filtrate is evaporated and the residue is chromatographed on silica gel, elution being carried out with a petroleum ether/EtOAc (97.5/2.5) mixture. 1.67 g of product are obtained in the form of a white solid.
Reaction SMILES: [F:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1N1C=CC(=O)NC1=O.[Cl:18][C:19]1[C:27]([Cl:28])=[CH:26][C:22]2[N:23]=[CH:24][NH:25][C:21]=2[CH:20]=1>C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O>[Cl:28][C:27]1[C:19]([Cl:18])=[CH:20][C:21]2[N:25]([C@@H:3]3[O:4][C@H:5]([CH2:8][OH:9])[C@@H:6]([OH:7])[C@H:2]3[F:1])[CH:24]=[N:23][C:22]=2[CH:26]=1
Reactant: Clc1cc2nc[nH]c2cc1Cl
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: OC[C@H]1O[C@@H](n2cnc3cc(Cl)c(Cl)cc32)[C@H](F)[C@@H]1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
2'-Deoxy-2'-fluorouridine, compound 13 (0.99 g, 4 mmol), which can be prepared by the method of Codington et al. (Codington et al., 1968), was dissolved in 800 mL of 50 mM pH 6.0 citrate buffer. 5,6-dichlorobenzimidazole, compound 14 (0.30g, 1.6 mmoles), which can be prepared by the method of Townsend et al. (Townsend et al., 1970), was added and the reaction was placed in a 50° C. water bath. N-deoxyribo-furanosyl transferase (60,000 units; see Cook et al., 1990) was added and the reaction mixture was gently shaken overnight. 5,6-dichlorobenzimidazole, compound 14 (0.30 g, 1.6 mmoles) was added and the reaction continued for 2 days. The enzyme was precipitated by heating to 80° C. followed by cooling to room temperature. Celite® (50-60 g) was added and the reaction mixture filtered. The product was extracted with ethyl acetate (3×). The ethyl acetate was removed in vacuo and the residue purified by chromatography on 75 g of basic alumina eluted with chloroform/methanol (95:5, v/v) followed by (9:1, v/v), then (2:1, v/v), and finally (1:1, v/v). The product containing fractions were combined and the solvents removed in vacuo to give 0.54 g (67%) of compound 15.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[N:15][N:16]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:17]=3[CH:18]=[CH:19][CH:20]=2)=[O:11])=[CH:4][CH:3]=1.[CH3:28][S:29]([O-:31])=[O:30].[Na+].CNCCNC>CCOC(C)=O.[O-]S(C(F)(F)F)(=O)=O.[Cu+2].[O-]S(C(F)(F)F)(=O)=O>[CH3:28][S:29]([C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[N:15][N:16]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:17]=3[CH:18]=[CH:19][CH:20]=2)=[O:11])=[CH:4][CH:3]=1)(=[O:31])=[O:30]
Reactant: CS(=O)[O-]
Reactant: O=C(NCc1ccc(Br)nc1)c1cccc2c1cnn2-c1ccc(F)cc1
Agent: [Cu+2]
Agent: CNCCNC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A microwave tube was charged with 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (6-bromo-pyridin-3-ylmethyl)-amide (650 mg, 1.5 mmol), copper(II) triflate (550 mg, 1.5 mmol) and sodium methanesulfinate (230 mg, 2.3 mmol). The flask was sealed, evacuated and purged (3 times) with nitrogen. The solids were taken up in DMSO (5 mL) and N,N′-dimethylethylene diamine (0.490 mL, 4.59 mmol) was added. The solution was stirred at 100° C. After 16 hours, the mixture was diluted with EtOAc (10 mL) and washed with saturated aqueous NH4Cl (5 mL), saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered through diatomaceous earth and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-80% ethyl acetate in hexanes. Fractions containing the product were pooled and further purified by silica gel chromatography eluting with a gradient of 0-60% ethyl acetate in hexanes. Desired fractions were pooled and concentrated, and the solid was triturated with hexanes (10 mL) to afford the title compound as a white solid.
Reaction SMILES: [C:1]([NH:8][C:9]1([CH:14]=O)[CH2:13][CH2:12][CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C:9]1([CH2:14][NH:21][C:20]2[CH:22]=[CH:23][C:17]([Br:16])=[CH:18][CH:19]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)NC1(C=O)CCCC1
Reactant: Nc1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1(CNc2ccc(Br)cc2)CCCC1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
To a solution of N-Boc-cycloleucinal (5.33 g, 25 mmol) and 4-bromoaniline (4.3 g, 25 mmol) in dichloroethane (160 mL) was added sodium triacetoxyborohydride (10.6 g, 50 mmol) portionwise. After the addition, the resulting mixture was stirred at rt for over night. The reaction mixture was quenched with saturated NaHCO3, and extracted with DCM (4×100 mL). The combined DCM was dried (Na2SO4) and concentrated. The residue was subjected to flash column (10-30% EtOAc in hexane) to give the desired product as a white solid (8.3 g, 90%). MS (MH+ 369 and 371).
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]3[N:14]4[CH2:18][CH2:19][CH:20]([CH2:21][C:22]([OH:24])=[O:23])[C:13]4=[CH:12][C:11]=3[CH:10]=2)=[CH:5][C:4]=1[C:27]([F:30])([F:29])[F:28])#[N:2].[Li+].[OH-:32].Cl>O1CCOCC1>[C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]3[N:14]4[CH2:18][CH2:19][CH:20]([CH2:21][C:22]([OH:24])=[O:23])[C:13]4=[CH:12][C:11]=3[CH:10]=2)=[CH:5][C:4]=1[C:27]([F:29])([F:30])[F:28])(=[O:32])[NH2:2]
Reactant: [OH-]
Reactant: N#Cc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)O)cc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Solvent: C1COCCO1
Product: NC(=O)c1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)O)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 48 h

Procedure:
To a solution of 2-(7-(4-cyano-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid (15.0 mg, 0.036 mmol) in dioxane (1 mL) was added 1 M LiOH (aq) (3.0 mL). The reaction was stirred at 50° C. for 48 h. 1 M HCl(aq) was added until pH=3. The mixture was extracted with EtOAc. The organic extract was dried over MgSO4 and purified by preparative HPLC/MS to give the title compound as a solid (3.1 mg). LCMS m/z=433.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.14-2.27 (m, 1H), 2.55 (dd, J=16.23, 8.02 Hz, 1H), 2.63-2.72 (m, 1H), 2.72-2.83 (m, 1H), 3.52-3.63 (m, 1H), 3.90-4.00 (m, 1H), 4.04-4.15 (m, 1H), 5.21 (s, 2H), 6.01 (s, 1H), 6.78 (dd, J=8.72, 2.40 Hz, 1H), 7.07 (d, J=2.27 Hz, 1H), 7.20 (d, J=8.72 Hz, 1H), 7.49-7.60 (m, 2H), 7.75 (d, J=7.83 Hz, 1H), 7.82 (s, 1H), 7.91 (s, 1H), 12.28 (bs, 1H).
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH3:12])[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][C:14]([CH3:27])([CH2:18][S:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:15]([OH:17])=[O:16].N1C=CC=CC=1.CCOCC>C1COCC1>[C:1]1([CH:7]([CH2:11][CH3:12])[C:8]([O:26][C:23]2[CH:24]=[CH:25][C:20]([S:19][CH2:18][C:14]([C:15]([OH:17])=[O:16])([CH3:27])[CH3:13])=[CH:21][CH:22]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(CSc1ccc(O)cc1)C(=O)O
Reactant: CCC(C(=O)Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(C(=O)Oc1ccc(SCC(C)(C)C(=O)O)cc1)c1ccccc1
Reaction time: 144 h
Yield: 87.7 %

Procedure:
A solution of 2-phenylbutyryl chloride (1.19 g, 6.5 mmol) in 5 mL of THF was added to a stirred solution of 2,2-dimethyl-3-(4'-hydroxyphenylthio)-propionic acid (1.36 g, 6.0 mmol) and pyridine (1.03 g, 13.0 mmol) in 10 mL of THF under N2. After 6 days, 30 mL of ether was added and the reaction mixture filtered into a separatory funnel. The organic layer was washed with 0.5N HCl (2×15 mL), saturated NaCl (15 mL), 1:9 saturated NaHCO3 /H2O (2×15 mL), saturated NaCl (15 mL) and dried over anhydrous MgSO4. Filtration and evaporation provided 1.96 g (88%) of the desired ester. 1H NMR (CDCl3) δ0.974 (t, 3H, J=7.2 Hz), 1.27 (s, 6H), 1.82-1.96 (m, 1H), 2.13-2.28 (m, 1H), 3.13 (s, 2H), 3.67 (t, 1H, J=7.5 Hz), 6.90 (d, 2H, J=8.7 Hz), 7.30-7.38 (ArH, 7H), 11.9 (br s, --OH); 13C NMR (CDCl3) δ11.84, 24.30, 26.45, 43.73, 44.95, 53.27, 122.06, 127.58, 128.01, 128.88, 131.66, 134.27, 138.58, 149.65, 172.75, 183.22.
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](Cl)=[N:16][OH:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O1CCCC1.[C:24]([C:26]1[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[Cl:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[CH:25]=[C:24]([C:26]4[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=4)[O:17][N:16]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(N)nc1
Reactant: ON=C(Cl)Cc1ccc(Cc2ccc(Cl)o2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(Cc4ccc(Cl)o4)cc3)no2)cn1
Temperature: 50 °C
Reaction time: 1 h
Yield: 6.4 %

Procedure:
To a mixture of (4-(5-chloro-furan-2-ylmethyl)-phenyl)-acetohydroximoyl chloride (25 mg, 0.088 mmol) described in Manufacturing Example 62-1-6 and tetrahydrofuran (1 mL) were added 5-ethynyl-pyridin-2-ylamine (8.0 mg, 0.068 mmol) described in Manufacturing Example 28-1-3 and triethylamine (19 μL, 0.14 mmol), which was stirred for 1 hour at 50° C. The reaction mixture was allowed to room temperature, and water was added to the system at the same temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue thus obtained was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (1.6 mg, 4.9%) as a trifluoroacetic acid salt.
Reaction SMILES: [C:1]1(=[O:15])[C:10]2[C:5]3=[C:6]([CH2:11][CH2:12][CH2:13][N:4]3[C:3](=[O:14])[NH:2]1)[CH:7]=[CH:8][CH:9]=2.CS(O[CH2:21][CH2:22][CH2:23][C@@H:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:31]=[CH:32][C:33]3[S:38][CH2:37][C:36](=[O:39])[NH:35][C:34]=3[CH:40]=2)[CH2:25]1)(=O)=O>>[O:29]=[C:27]1[N:26]([C:30]2[CH:31]=[CH:32][C:33]3[S:38][CH2:37][C:36](=[O:39])[NH:35][C:34]=3[CH:40]=2)[CH2:25][C@H:24]([CH2:23][CH2:22][CH2:21][N:2]2[C:1](=[O:15])[C:10]3[C:5]4=[C:6]([CH2:11][CH2:12][CH2:13][N:4]4[C:3]2=[O:14])[CH:7]=[CH:8][CH:9]=3)[O:28]1
Reactant: O=c1[nH]c(=O)n2c3c(cccc13)CCC2
Reactant: CS(=O)(=O)OCCC[C@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Product: O=C1CSc2ccc(N3C[C@H](CCCn4c(=O)c5cccc6c5n(c4=O)CCC6)OC3=O)cc2N1
Yield: 25 %

Procedure:
Starting from 6,7-dihydropyrido[3,2,1-ij]quinazoline-1,3(2H,5H)-dione (prepared according to WO 01/79206) and 6-[(5S)-5-[3-[(methylsulfonyl)oxy]propyl]-2-oxo-3-oxazolidinyl]-2H-1,4-benzothiazin-3(4H)-one (prepared according to WO 2010/041194) and using Procedure E, the title compound was obtained as a colourless solid (48 mg; 25% yield).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9](=[O:23])[N:10]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[N:11]=2)[CH:5]=[N:6][C:7]=1Cl.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:7]2[N:6]=[CH:5][N:4]3[C:9](=[O:23])[N:10]([CH2:12][C:13]4[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=4)[N:11]=[C:3]3[C:2]=2[C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=2)=[CH:27][CH:26]=1
Reactant: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(Br)c(Cl)ncn12
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ncn12
Temperature: 100 °C
Yield: 9.8 %

Procedure:
To a solution of 8-bromo-7-chloro-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (81.3 mg, 0.20 mmol) in toluene (3 mL) at room temperature under argon was added 4-chlorophenylboronic acid (46.8 mg, 0.30 mmol), tetrakis(triphenylphosphine)palladium (46 mg, 0.040 mmol), and aqueous Na2CO3 solution (2.0 M, 0.20 mL, 0.40 mmol). The resulting suspension was stirred and heated at 100° C. under argon for 22 h. Analysis by HPLC/MS indicated that starting material had been consumed. After the reaction mixture was cooled to room temperature, water (10 mL) and EtOAc (15 mL) were added. The layers were separated. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluted with ethyl acetate-hexanes to obtain the title compound (7.6 mg) as an off-white solid. HPLC/MS: retention time=4.10 min, [M+H]30 =516.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]2[C:17](O)=[O:18])=[CH:5][CH:4]=1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[F:32])[NH:28][N:27]=[CH:26]2.C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[F:32][C:31]1[CH:30]=[C:29]2[C:25]([CH:26]=[N:27][NH:28]2)=[CH:24][C:23]=1[NH:22][C:17]([C:10]1[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:21])([F:20])[F:1])=[CH:8][CH:7]=2)[CH2:14][C:13](=[O:15])[NH:12][C:11]=1[CH3:16])=[O:18]
Reactant: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2)CC(=O)N1
Reactant: Nc1cc2cn[nH]c2cc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC1=C(C(=O)Nc2cc3cn[nH]c3cc2F)C(c2ccc(C(F)(F)F)cc2)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.4 %

Procedure:
The product of Example 5, Step 2 (200 mg, 0.67 mmol, 1.00 equiv), 5-amino-6-fluoroindazole (101 mg, 0.67 mmol, 1.0 equiv), and EDC (153 mg, 0.80 mmol, 1.20 equiv) were suspended in 2.0 mL DMF. Et3N (0.112 mL, 0.80 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (20-100% EtOAc in Hexanes) to provide 65 mg (22%) of the title compound as an off white solid. MS (ES+) m/e 433 [M+H]+
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=O.C(O)(=O)C.[H][H]>C(OCC)(=O)C.CCCCCC.[OH-].[OH-].[Pd+2]>[CH3:14][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:12][C:13]=2[CH:1]=1
Reactant: O=Cc1ccc2c(c1)Cc1ccccc1-2
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc2c(c1)Cc1ccccc1-2
Yield: 69.1 %

Procedure:
A solution of 2-fluorenecarboxaldehyde (15 g, 77.1 mmol) in 250 mL of 10% solution of acetic acid in ethyl acetate was hydrogenated at 80 psi of hydrogen during 24 hours at room temperature over 20% palladium hydroxide on carbon (catalytic amount). The reaction was monitored by TLC (silica, 25% ethyl acetate in hexane). The catalyst was filtered off, evaporation of the solvents followed by recrystallization of the residual solid from ethanol:water 5:1 afforded 9.6 g (69.0%) of the product as colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=4)=[N:14][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:22])[CH2:3]1.C(O)(=O)C.CO[CH:30]1[CH2:34][CH2:33][CH:32](OC)O1>Cl.O>[CH3:1][C:2]1([CH3:23])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH:30]=[CH:34][CH:33]=[CH:32]5)=[CH:17][CH:16]=4)=[N:14][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:22])[CH2:3]1
Reactant: COC1CCC(OC)O1
Reactant: CC1(C)CC(=O)Nc2cc3nc(-c4ccc(N)cc4)[nH]c3cc21
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)CC(=O)Nc2cc3nc(-c4ccc(-n5cccc5)cc4)[nH]c3cc21
Reaction time: 20 h

Procedure:
3.06 g. 8,8-dimethyl-2-(4-aminophenyl)-5,6,7,8-tetrahydro-lH-imidazo[4,5-g]quinolin-6-one (see Example 38) were allowed to stand for 20 hours at 25° C. with 30 ml. glacial acetic acid, 5 ml. water, 2 drops of concentrated hydrochloric acid and 1.32 ml. 2,5-dimethoxytetrahydrofuran. The reaction mixture was then washed with 100 ml. water. After crystallisation from ethanol, there was obtained 0.8 g. of the title compound; m.p. 329 -350° C. (decomp.).
Reaction SMILES: N1C=CC=C(CCCN)C=1.C1(=O)CCCCC1.[BH3-]C#N.[Na+].[CH:22]1([NH:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[N:38]1[C:46]2[C:41]3[C:42](=[CH:47][CH:48]=[CH:49][C:40]=3[C:39]=1S)[CH:43]=[CH:44][CH:45]=2>CO.C(O)C>[CH:22]1([N:28]([CH2:29][CH2:30][CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[C:39]2[C:40]3[CH:49]=[CH:48][CH:47]=[C:42]4[C:41]=3[C:46](=[CH:45][CH:44]=[CH:43]4)[N:38]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: SC1=Nc2cccc3cccc1c23
Reactant: c1cncc(CCCNC2CCCCC2)c1
Agent: NCCCc1cccnc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O=C1CCCCC1
Solvent: CCO
Product: c1cncc(CCCN(C2=Nc3cccc4cccc2c34)C2CCCCC2)c1

Procedure:
The reaction of 3-(3-pyridinyl)propanamine and cyclohexanone in methanol in the presence of NaBH3CN leads to the preparation of N-cyclohexyl-3-(3-pyridinyl)propanamine. The latter compound, upon reaction with molar equivalents of benz(cd)indol-2-thiol and mercuric acetate in refluxing ethanol under the conditions of Example 55 leads to the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].S(=O)(=O)(O)O.[Cl:15][CH2:16][C:17](=O)[CH2:18][C:19](OCC)=[O:20]>>[Br:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[OH:9])[O:6][C:19](=[O:20])[CH:18]=[C:17]2[CH2:16][Cl:15]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Oc1ccc(Br)c(O)c1
Agent: O=S(=O)(O)O
Product: O=c1cc(CCl)c2cc(Br)c(O)cc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
A solution of 936.1 mg (4.953 mmol) 4-bromoresorcinol, concentrated sulfuric acid (5 mL) and ethyl 4-chloroacetoacetate (1 mL, 7.4 mmol) was stirred for 6 days at room temperature. The reaction mixture was poured into ice-water and stirred for 2 hours to give a fine precipitate. The precipitate was collected by filtration, washed with cold water and dried under vacuum over P2O5 to yield 847.6 mg (2.928 mmol, 59.1% yield) of compound 11 as a solid. 1H NMR (CD3OD) δ 7.96 (1H, s), 6.86 (1H, s), 6.43 (1H, s), 4.83 (2H, s).