Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([NH:7][CH2:8][C:9]2C(C(N(C(C)C)C(C)C)=O)=[C:13]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[N:12]=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[CH3:38][CH2:39][OH:40]>Cl>[C:1]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:2]=[CH:3][C:4]([N:7]2[CH2:8][C:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)[C:38]=3[C:39]2=[O:40])=[CH:5][CH:6]=1
Reactant: CCO
Reactant: CC(C)N(C(=O)c1c(CNc2ccc(-c3ccccc3)cc2)ccnc1NCc1ccncc1)C(C)C
Agent: Cl
Product: O=C1c2c(ccnc2NCc2ccncc2)CN1c1ccc(-c2ccccc2)cc1

Procedure:
A solution of 4-(biphenyl-4-ylaminomethyl)-N,N-diisopropyl-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide (13 mg, 0.026 mmol, Step C) in absolute EtOH (3 mL) and HCl (12 N, 1 mL) was heated to reflux for 2 days, then concentrated in vacuo. The crude material was dissolved in 1:1 DMSO to MeOH (2 mL) and purified by reverse phase HPLC (10-95% CH3CN in H2O). MS (ES+): 393.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:26])=[CH:4][N:3]=1.CCO.[O:30]1[C:35]2[CH:36]=[CH:37][C:38]([CH:40]=O)=[CH:39][C:34]=2[O:33][CH2:32][CH2:31]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Cl:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:40]([C:38]3[CH:37]=[CH:36][C:35]4[O:30][CH2:31][CH2:32][O:33][C:34]=4[CH:39]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: O=C(CN1CCN(c2c(Cl)cnc3[nH]c(-c4ccc5c(c4)OCCO5)nc23)CC1)Nc1nccs1
Temperature: 80 °C
Reaction time: 22 h

Procedure:
To a mixture of 2-[4-(2-amino-5-chloro-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (0.024 g, 0.06 mmol) and EtOH (3.0 ml) was added 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde (0.017 g, 0.10 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.35 ml, 0.35 mmol). The reaction mixture was stirred at 80° C. for 22 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with 2% methanol in ethyl acetate/dichloromethane (v:v; 1:1) afforded a pale yellow solid. The title compound was obtained as a white solid after trituration with diethyl ether (0.007 g, 23%); 1H-NMR (500 MHz, DMSO-d6) 2.77 (br s, 4H, piperazine N(CH2)2), 3.40 (s, 2H, NCH2CON), 3.73 (br s, 4H, piperazine N(CH2)2), 4.31 (s, 4H, OCH2CH2O), 7.01 (d, J=8.2 Hz, 2H, PhH), 7.24 (d, J=3.5 Hz, 1H, thiazole H), 7.48 (d, J=3.5 Hz, 1H, thiazole H), 7.69 (m, 3H, PhH)), 8.08 (s, 1H, imidazo[4,5-b]pyridine 5-H), 11.87 (s, 1H, CONH), 13.30 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [N+]([C:4]1[NH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[N:8]=1)([O-])=O.[O:12]1[CH2:14][CH:13]1[CH2:15][NH:16][C:17](=[O:25])[O:18][C:19]1C=CC=C[CH:20]=1.C([O-])(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)C.C(Cl)Cl>[N+:9]([C:7]1[N:8]=[C:4]2[N:5]([CH:6]=1)[CH2:14][CH:13]([CH2:15][NH:16][C:17](=[O:25])[O:18][CH2:19][CH3:20])[O:12]2)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1c[nH]c([N+](=O)[O-])n1
Reactant: O=C(NCC1CO1)Oc1ccccc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)NCC1Cn2cc([N+](=O)[O-])nc2O1
Yield: 11.5 %

Procedure:
2,4-Dinitro-1H-imidazole (0.678 g, 3.92 mmol) and phenyl oxiran-2-ylmethylcarbamate (1.04 g, 5.87 mmol) were dissolved in ethanol (20 ml). To the solution, sodium acetate (0.386 g, 4.70 mmol) was added followed by stirring under reflux overnight. To the reaction mixture, a saturated sodium hydrogencarbonate solution and methylene chloride were added, and the solution was extracted with methylene chloride. The organic phase was dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) and treated with diisopropyl ether to afford ethyl (6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)carbamate (0.116 g, yield 11.6%) as a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][S:12](O)(=[O:14])=[O:13].[Cl-].[Na+]>>[Cl:11][S:12]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[F:1])[C:6]([OH:8])=[O:7])(=[O:14])=[O:13]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: O=S(=O)(O)Cl
Agent: [Cl-]
Agent: [Na+]
Product: O=C(O)c1ccc(F)c(S(=O)(=O)Cl)c1
Temperature: 160 °C
Yield: 51.5 %

Procedure:
4-Fluoro-benzoic acid (8 g, 57 mmol) is added carefully to chlorosulfonic acid (58 g, 498 mmol) then sodium chloride (10 g, 169 mmol) is added in small portions. After complete addition, the reaction is heated at 160° C. for 5 h. The reaction mixture is cooled down and poured into ice-water. A white solid precipitate is collected and redissolved in ethyl acetate. The organic layer is washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and the solvent is removed in vacuo. The residue is triturated with hexane to give 7 g (51% yield) of the title compound as a white solid. 1H NMR (CDCl3): δ 8.78 (m, 1H), 8.52 (m, 1H), 7.5 (t, 1H). MS (m/z): 308 (M−1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[OH-:12].[K+].Cl>O>[Cl:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: [OH-]
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=c1[nH]c(Cl)nc2[nH]ccc12

Procedure:
A solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (400 mg, 2.13 mmol) in a 2M aqueous potassium hydroxide solution (12 mL) was heated to 100° C. for 4 h. At this time, the resulting mixture was poured onto iced water and then acidified to pH 6.5 with a 6M aqueous hydrochloric acid solution. The acidic solution was extracted with ethyl acetate. The combined organics were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was triturated with acetonitrile and ether to afford 2-chloro-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one. 1HNMR (400 MHz, DMSO-d6) δ ppm 6.40-6.48 (m, 1H) 7.01-7.10 (m, 1H) 12.0 (s, 1H) 12.8 (s, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:23]([CH2:24][OH:25])=[C:22]([CH:26]([CH3:28])[CH3:27])[N:21]=[C:20]([CH:29]([CH3:31])[CH3:30])[C:19]=2[CH2:32][OH:33])=[CH:14][CH:13]=1>CS(C)=O.ClCCl>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([CH:32]=[O:33])=[C:20]([CH:29]([CH3:31])[CH3:30])[N:21]=[C:22]([CH:26]([CH3:28])[CH3:27])[C:23]=2[CH:24]=[O:25])=[CH:14][CH:13]=1
Reactant: CC(C)c1nc(C(C)C)c(CO)c(-c2ccc(F)cc2)c1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)c1nc(C(C)C)c(C=O)c(-c2ccc(F)cc2)c1C=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To solution of 16 ml (0.18 mol) oxalyl chloride in 150 ml dry diohloromethans was added, et -78° C., 40 ml dimethyl sulfoxide over a period of 5 minutes. After 10 minutes, 26 g (0,082 mol) of the product of step 3 in 200 ml of 1:3 solution dimethyl sulfoxide/dichloromethane was added dropwise. This reaction mixture was stirred at -78° C. for 20 minutes, before it was quenched with 80 ml triethylamime. The cooling bath was removed and the reaction was allowed to warm to room temperature. The reaction was partitioned between ethyl acetate (500 ml) and 1N hydrochloric acid (200 ml). The organic layer was washed With water (4×100 ml) and brine and dried over magnesium sulfate and filtered. Evaporation of the filtrate in vaouo gave 24.5 g of the Step 4 title product as a viscous oil which was used without further purification.
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10](=[O:32])[NH:11][C@@H:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:13]([OH:24])[CH2:14][NH:15][CH2:16][C:17]([CH3:23])([CH3:22])[CH2:18][CH2:19][C:20]#[N:21])[CH2:2]1.C(N(C(C)C)CC)(C)C.[C:42]([NH:45][C:46]1[CH:47]=[C:48]([S:52](Cl)(=[O:54])=[O:53])[CH:49]=[CH:50][CH:51]=1)(=[O:44])[CH3:43]>C(Cl)Cl>[O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10](=[O:32])[NH:11][C@@H:12]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@H:13]([OH:24])[CH2:14][N:15]([S:52]([C:48]2[CH:49]=[CH:50][CH:51]=[C:46]([NH:45][C:42](=[O:44])[CH3:43])[CH:47]=2)(=[O:54])=[O:53])[CH2:16][C:17]([CH3:22])([CH3:23])[CH2:18][CH2:19][C:20]#[N:21])[CH2:2]1
Reactant: CC(=O)Nc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(CCC#N)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCC#N)c1
Yield: 59.1 %

Procedure:
[(1S,2R)-1-Benzyl-3-(4-cyano-2,2-dimethylbutylamino)-2-hydroxy-propyl]-carbamic acid (3R,3aS,6aR)hexahydro-furo[2,3-b]furan-3-yl ester (0.020 g, 0.05 mmol) was dissolved in CH2Cl2 and treated with diisopropylethylamine (0.025 ml, 0.13 mmol) and 3-acetamidobenzenesulfonyl chloride (0.012 g, 0.05 mmol) at ambient temperature under argon with stirring. After 15 h the reaction mixture was concentrated in vacuo, taken up in EtOAc, washed with sat. aq. NaHCO3, and brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuo. Purification by preparative thin layer chromatography (3% MeOH in CH2Cl2) gave 0.019 g of a white solid. MS (ES): 643 (M+1).
Reaction SMILES: [F:1][CH:2]([F:17])[CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]1[CH2:15]O.[CH:18]1([N:21]2[C:29]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[NH:23][C:22]2=[O:30])[CH2:20][CH2:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1COCC1>[CH:18]1([N:21]2[C:29]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[N:23]([CH2:15][C:7]3[N:6]([CH2:5][CH2:4][CH2:3][CH:2]([F:17])[F:1])[C:14]4[C:9]([N:8]=3)=[N:10][CH:11]=[CH:12][CH:13]=4)[C:22]2=[O:30])[CH2:20][CH2:19]1
Reactant: OCc1nc2ncccc2n1CCCC(F)F
Reactant: O=c1[nH]c2cnccc2n1C1CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1n(Cc2nc3ncccc3n2CCCC(F)F)c2cnccc2n1C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.4 %

Procedure:
To a suspension of (1-(4,4-difluorobutyl)-1H-imidazo[4,5-b]pyridin-2-yl)methanol 43-5 (470 mg, 1.9 mmol), 1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one 10-d (431 mg, 2.3 mmol) and triphenylphosphine (613 mg, 2 3 mmol) in 14 ml dry THF was added (E)-diisopropyl diazene-1,2-dicarboxylate (0.6 ml, 2.9 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The precipitate was filtered off and washed with some diethyl ether to obtain the title product as a white powder (450 mg, 58%). m/z=399 (M+H)+.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:30]12[CH2:38][CH2:37][CH:34]([CH2:35][CH2:36]1)[NH:33][CH2:32][CH2:31]2>>[CH3:28][N:26]([CH3:27])[C:25]([C:7]1[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:33]4[CH:34]5[CH2:37][CH2:38][N:30]([CH2:36][CH2:35]5)[CH2:31][CH2:32]4)=[O:21])=[CH:18][N:17]=3)[N:13]=[CH:14][C:9]=2[CH:8]=1)=[O:29]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Reactant: C1CN2CCC(CC2)N1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CCN5CCC4CC5)cn3)nc2n1C1CCCC1
Yield: 25.1 %

Procedure:
Following general amide formation method 1, 6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (120 mg, 0.198 mmol, 1.0 eq) was combined with 1,4-Diaza-bicyclo[3.2.2]nonane (43.3 mg, 0.218 mmol, 1.1 eq) which gave 7-cyclopentyl-2-[5-(1,4-diaza-bicyclo[3.2.2]nonane-4-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (25 mg) in 23% yield. 1H NMR (400 MHz, CDCl3-d) δ ppm 1.64-1.81 (m, 2H) 1.86 (br. s., 2H) 2.00-2.22 (m, 6H) 2.51-2.70 (m, 2H) 3.03-3.16 (m, 5H) 3.18 (s, 7H) 3.79 (br. s., 2H) 4.83 (quin, J=8.84 Hz, 1H) 6.50 (s, 1H) 7.81 (dd, J=8.84, 2.27 Hz, 1H) 8.35-8.44 (m, 2H) 8.58 (d, J=8.59 Hz, 1H) 8.79 (s, 1H). HRMS m/z, (M+H)+: 503.2891
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Cl[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[O:20][N:19]=1>>[F:15][C:2]([F:14])([F:1])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=2)[O:20][N:19]=1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 23 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole: MS (ES) m/z 437 (M+1).
Reaction SMILES: Cl.C([O:4][C:5](=[O:29])[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[C:15]([Cl:18])[C:16]=1[Cl:17])[C:13](=[O:19])[C:12]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1)([CH3:20])[CH2:11]2)C.C(=O)(O)[O-].[Na+:34].C(O)C.Cl>O>[Na+:34].[O:19]=[C:13]1[C:14]2[C:10](=[CH:9][C:8]([O:7][CH2:6][C:5]([O-:29])=[O:4])=[C:16]([Cl:17])[C:15]=2[Cl:18])[CH2:11][C:12]1([C:21]1[CH:22]=[CH:23][C:24]([CH2:27][NH2:28])=[CH:25][CH:26]=1)[CH3:20]
Reactant: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccc(CN)cc1)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1(c2ccc(CN)cc2)Cc2cc(OCC(=O)[O-])c(Cl)c(Cl)c2C1=O

Procedure:
Ethyl[1-oxo-2-(4-aminomethylphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetate hydrochloride (1.57 g., 0.0034 mole), sodium bicarbonate (1.15 g., 0.0136 mole), absolute ethanol (50 ml.) and water (50 ml.) are combined and heated at reflux for 1.5 hours leaving a solution which is filtered, then neutralized with 1 N hydrochloric acid (10.26 ml., 0.01026 mole) to precipitate 900 mg. of [1-oxo-2-(4-aminomethylphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid sodium salt which melts at 270°-271° C. after drying.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:13][CH3:14])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][C:10]1[CH:11]=[CH:12][C:5]([O:4][CH2:3][C@@H:2]([CH3:1])[CH2:13][CH3:14])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CC[C@H](C)COc1ccccc1C#N
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CC[C@H](C)COc1ccc(Br)cc1C#N
Reaction time: 24 h

Procedure:
A mixture of compound 39 (4.25 g, 0.022 mol), bromine (12.31 g, 0.077 mol) and chloroform (50 ml) was heated under reflux overnight. A further portion of bromine (12.31 g, 0.077 mol) was then added and heating continued for another 24 h. The resultant solution was washed with a saturated solution of sodium thiosulphate and finally with water. The dichloromethane solution was dried (MgSO4) and evaporated in vacuo and the crude oil was purified by column chromatography (10% petrol/dichloromethane) to yield a fawn oil.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][C:14]([OH:16])=O.O>FC(F)(F)S(O)(=O)=O>[Br:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:12][CH2:13][C:14]2=[O:16]
Reactant: O=C(O)CCc1cccc(C(F)(F)F)c1Br
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Product: O=C1CCc2c1ccc(C(F)(F)F)c2Br
Temperature: 25 °C

Procedure:
3-(2-Bromo-3-trifluoromethyl-phenyl)-propionic acid (3.25 g) in trifluoromethane-sulfonic acid (30 ml) is stirred at 75° C. for 2.5 h. After cooling to room temperature, the mixture is poured into water and the resulting mixture is extracted with ethyl acetate. The combined organic extract is washed with aqueous NaHCO3 solution, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→80:20) to afford the title compound. LC (method 5): tR=0.90 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH3:13])[CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[N:20]2[N:21]=[C:22](F)[CH:23]=[CH:24][C:19]2=[N:18][CH:17]=1.C(N(CC)CC)C>C(O)(C)C>[C:1]([O:5][C:6](=[O:14])[N:7]([CH:8]1[CH2:12][CH2:11][N:10]([C:22]2[CH:23]=[CH:24][C:19]3[N:20]([C:16]([Br:15])=[CH:17][N:18]=3)[N:21]=2)[CH2:9]1)[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc2ncc(Br)n2n1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc3ncc(Br)n3n2)C1
Temperature: 140 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
A mixture of methyl-pyrrolidin-3-yl-carbamic acid tert-butyl ester (1.2 g, 6 mmol), 3-bromo-6-fluoro-imidazo[1,2-b]pyridazine (648 mg, 3 mmol), and triethylamine (1.67 ml, 12 mmol) in isopropyl alcohol (3 ml) was heated in a microwave at 140° C. for 20 min. The reaction mixture was allowed to stand for overnight and the white solid was collected by filtration and washed with MeOH to give the titled compound (750 mg). The filtrate was concentrated and the residue was subjected to ISCO (40 g column), to give further titled compound (360 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45-1.52 (m, 9H) 2.03-2.27 (m, 2H) 2.83 (s, 3H) 3.39-3.54 (m, 2H) 3.69-3.77 (m, 2H) 6.58 (d, J=9.92 Hz, 1H) 7.49 (s, 1H) 7.65 (d, J=9.70 Hz, 1H). LRMS (ESI) m/z 396.1 and 398 [(M+H)]+, calc'd for C16H22BrN6O2: 396.29.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:29]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]([CH2:39][CH2:40]O)[CH2:31][CH2:30]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[S:29]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]([CH2:39][CH2:40][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:31][CH2:30]1
Reactant: O=Cc1ccc(O)cc1
Reactant: OCCN1CCSc2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(OCCN2CCSc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.4 %

Procedure:
To a mixture of 4-hydroxy benzaldehyde (1.8 g, 14.8 mmol) and triphenyl phosphine (4.85 g, 18.5 mmol) in tetrahydrofuran (15 ml) was added 2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethanol (2.39 g, 12.3 mmol) and diisopropyl azodicarboxylate (3.74 g, 18.5 mmol) in THF (20 ml) at 25° C. The reaction mixture was stirred for 12 h at 25° C. Water (100 ml) was added and the mixture was extracted with ethyl acetate (2×100 ml). The organic extracts were dried (Na2SO4) and solvent was evaporated under reduced pressure. The crude product was chromatographed over silica gel using a mixture of methanol and chloroform (5:95) as an eluent to afford the title compound (1.6 g, 44%) as an oil.
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]2[C:15]3=[C:16]([CH2:18][CH2:19][CH2:20][N:14]3[CH2:13][C@@H:12]3[CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][C@H:11]23)[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:2]1([NH:1][C:8]2[CH:9]=[C:10]3[C:15]4=[C:16]([CH2:18][CH2:19][CH2:20][N:14]4[CH2:13][C@@H:12]4[CH2:21][NH:22][CH2:23][C@H:11]34)[CH:17]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN3CCCc4cc(Nc5ccccc5)cc(c43)[C@H]2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(Nc2cc3c4c(c2)[C@H]2CNC[C@H]2CN4CCC3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.6 %

Procedure:
To a solution of (±)-cis-tert-butyl 2-anilino-5,6,8a,9,11,11a-hexahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline-10(8H)-carboxylate (80 mg, 0.20 mmol) in 5 ml of CH2Cl2 was added 1 ml of trifluoroacetic acid and the reaction was stirred at room temperature for 3 h. The volatiles were removed under reduced pressure and the residue was purified by prep HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA). Product-containing fractions were combined, concentrated and partitioned between chloroform and saturated aqueous sodium carbonate. The organics were washed with brine, dried (K2CO3) and concentrated in vacuo to afford 15 mg (23%) of the title compound of EXAMPLE 17. 1H NMR (CDCl3): δ 7.18 (app t, 2H, J=7.8 Hz), 6.84 (app d, 2H, J=8.0 Hz), 6.78-6.72 (m, 1H), 6.67 (s, 1H), 6.65 (s, 1H), 5.46 (s, 1H), 3.45-3.30 (m, 2H), 3.24-3.17 (m, 1H), 3.08-3.00 (m, 2H), 2.97-2.85 (m, 1H), 2.78-2.55 (broad m, 6H), 2.05-1.93 (m, 2H). LRMS (ES)+: 306.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.[CH3:12][O:13]C(Cl)Cl.[Sn](Cl)(Cl)(Cl)Cl.Cl>ClCCCl>[CH3:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)OCCO2
Reactant: COC(Cl)Cl
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: Cc1cc2c(cc1C=O)OCCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
A mixture of 6-methyl-2,3-dihydrobenzo[b][1,4]dioxine (6.4 g, 42.8 mmol) and 1,2-dichloroethane (250 mL) was cooled to 0° C. and then stirred for 1 h. After this time, dichloromethyl methyl ether (11.5 mL, 128.5 mmol) was then added and the reaction stirred for 1 h then, tin (IV) chloride (7.52 mL, 64.3 mmol) was added portion wise to the reaction over 3 h, and the reaction then allowed to warm to room temperature overnight. After this time, the reaction was poured into 3 N hydrochloric acid (150 mL) and the organic layer extracted three times with dichloromethane (100 mL). The combined organic extracts were then dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 7-methyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde (4.8 g, 79%) as an off-white solid; 1H NMR(500 MHz, CDCl3) δ 10.07 (s, 1H), 7.33 (s, 1H), 6.72 (s, 1H), 4.28 (m, 4H), 2.55 (s, 3H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].[O:20]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21]1>C(O)CCC>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:25][CH:22]1[CH2:23][CH2:24][O:20][CH2:21]1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NC1CCOC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccccc1NC1CCOC1
Temperature: 180 °C
Reaction time: 0.33 h

Procedure:
N,N-Diisopropylethylamine (3.2 mL, 18.4 mmol) was added to a solution of 1-fluoro-2-nitrobenzene (0.484 mL, 4.6 mmol) and (±)-tetrahydrofuran-3-amine (400 mg, 4.6 mmol) in n-butanol (10 mL) and the mixture heated to 180° C. in a microwave reactor. After 20 min, the reaction was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, gave the title compound. MS: m/z=209 (M+1).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=2)O1>>[NH2:32][C:29]1[N:30]=[CH:31][C:26]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)=[CH:27][CH:28]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(N)nc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, light grey solid (64 mg, 82%), MS (ISP) m/z=311.5 [(M+H)+], mp 254° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (71.5 mg, 0.325 mmol).