Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([OH:18])=[O:17])[C:10](=[O:19])[C:9]2=[O:20])(=[O:4])=[O:3].[Cl:21][C:22]1[CH:23]=[N+:24]([O-:47])[CH:25]=[C:26]([Cl:46])[C:27]=1[CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]([F:40])[F:39])=[C:33]([O:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)[CH:32]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[N+:24]([O-:47])[CH:25]=[C:26]([Cl:46])[C:27]=1[CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]([F:40])[F:39])=[C:33]([O:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)[CH:32]=1)[O:17][C:16](=[O:18])[CH2:15][N:11]1[C:12]2[C:8](=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][CH:13]=2)[C:9](=[O:20])[C:10]1=[O:19]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(=O)C(=O)N2CC(=O)O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)C(=O)N2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.3 %

Procedure:
A mixture of 2-(5-(methylsulfonamido)-2,3-dioxoindolin-1-yl)acetic acid (141 mg, 0.473 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (166 mg, 0.394 mmol), EDC (227 mg, 1.182 mmol) and DMAP (24.06 mg, 0.197 mmol) in DCM (25 ml) was stirred at room temperature overnight. The solvent was evaporated, DMF (10 ml) was added, and the resulting solution was stirred at 80° C. for 6 hours. DMAP (48.1 mg, 0.394 mmol) was added, and stirring at 80° C. was continued for 2 days. The solvent was evaporated, DCM was added, and the mixture was washed with NaHCO3 5% and 1N HCl; the organic layer was dried over Na2SO4, filtered and evaporated affording a crude that was purified by flash chromatography on silica gel (DCM:Ethyl acetate from 50:50 to 30:70; then 100% DCM and then DCM:MeOH from 99:1 to 97:3). The product was further purified by Preparative HPLC (Method 3) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(2-(5-(methylsulfonamido)-2,3-dioxoindolin-1-yl)acetoxy)ethyl)pyridine 1-oxide (0.012 g, 0.017 mmol, 4% yield). MS/ESI+ 700.16 [MH]+; [αD]=+63.50, c=0.12 in DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 9.75 (br. s., 1H), 8.43 (s, 2H), 7.45 (dd, 1H), 7.41 (d, 1H), 7.18 (d, 1H), 7.07 (d, 1H), 7.05 (d, 1H), 6.95 (dd, 1H), 7.07 (t, 1H), 6.03 (dd, 1H), 4.64 (d, 1H), 4.56 (d, 1H), 3.91 (d, 2H), 3.40 (dd, 1H), 3.22 (dd, 1H), 3.02 (s, 3H), 1.12-1.31 (m, 1H), 0.54-0.63 (m, 2H), 0.31-0.44 (m, 2H).
Reaction SMILES: [Br-].[C:2]([NH:10][C:11]1[CH:16]=[CH:15][N+:14]([CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[CH:13][CH:12]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+]>C(O)(C)C.O>[C:2]([NH:10][CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:16]1)(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cc[n+](CCc2c[nH]c3ccccc23)cc1)c1ccccc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: O=C(NC1CCN(CCc2c[nH]c3ccccc23)CC1)c1ccccc1

Procedure:
A suspension of 4-benzamido-1-[2-(3-indolyl)ethyl]-pyridinium bromide (7.3 kg.) and sodium borohydride (2.5 kg.) in isopropanol (57 kg.) was stirred and refluxed for 6 hours. The reaction mixture was cooled to 25° and diluted with water. The product was separated by filtration and washed with aqueous methanol then with water and finally with methanol, and dried to give 4.45 kg. of the crude title compound. This was purified by dissolving in dimethylformamide (21 kg.) at 50°-60° and slowly adding water (22 kg.). After cooling, the product was separated by filtration, washed with water then with methanol, and dried to give 3.9 kg. of the title compound (65% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](O)([CH3:13])[O:11][C:10](=O)[C:9]=2[C:16]2[N:17]=[C:18]([CH3:22])[S:19][C:20]=2[CH3:21])=[CH:4][CH:3]=1.O.[NH2:24][NH2:25]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[N:25][NH:24][C:10](=[O:11])[C:9]=2[C:16]2[N:17]=[C:18]([CH3:22])[S:19][C:20]=2[CH3:21])=[CH:4][CH:3]=1
Reactant: Cc1nc(C2=C(c3ccc(Cl)cc3)C(C)(O)OC2=O)c(C)s1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: Cc1nc(-c2c(-c3ccc(Cl)cc3)c(C)n[nH]c2=O)c(C)s1
Temperature: 0 °C
Yield: 63.5 %

Procedure:
A mixture of 0.86 g of 4-(4-chlorophenyl)-3-(2,5-dimethyl-4-thiazolyl)-5-hydroxy-5-methyl-2(5H)-furanone, 0.18 g of hydrazine monohydrate and 8 ml of 1-butanol was heated under reflux for 5 hours. The reaction mixture was cooled to 0° C. The deposited solid was collected by filtration. The solid was washed with a mixed solvent of hexane and t-butyl methyl ether, and dried under reduced pressure to obtain 0.54 g of 5-(4-chlorophenyl)-4-(2,5-dimethyl-4-thiazolyl)-6-methyl-2H-pyridazin-3-one.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:23][C:21]3[C:22]4[C:13](=[N:14][NH:15][C:16](=[O:24])[C:17]=4[CH:18]=[CH:19][CH:20]=3)[CH:12]2[C:25]2[CH:35]=[CH:34][C:28]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[CH:27][CH:26]=2)=[CH:7][CH:6]=1)C.FC(F)(F)C(O)=O>C(#N)C>[CH:4]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[NH:23][C:21]3[C:22]4[C:13](=[N:14][NH:15][C:16](=[O:24])[C:17]=4[CH:18]=[CH:19][CH:20]=3)[CH:12]2[C:25]2[CH:26]=[CH:27][C:28]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[CH:34][CH:35]=2)=[CH:9][CH:10]=1)=[O:3]
Reactant: CCOC(OCC)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C(=O)N(C)C)cc2)cc1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)c1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccc(C=O)cc2)cc1
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
To a solution of 4-(8-(4-(diethoxymethyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)-N,N-dimethylbenzamide (180 mg, 0.35 mmol) in acetonitrile (10 mL) was added trifluoroacetic acid (5 mL), stirred for 30 min, Then the mixture was evaporated under reduced pressure to get the title compound (140 mg, yield 91%). LC-MS (ESI) m/z: 439(M+1)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[N:9]=1)[C:5]#[N:6].CN1C(=O)CCC1.[F:18][C:19]1[CH:20]=[C:21]([CH2:25][NH2:26])[CH:22]=[CH:23][CH:24]=1>CCOC(C)=O>[Cl:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([NH:26][CH2:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([F:18])[CH:20]=2)[N:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Cl)nc(Cl)c1
Reactant: NCc1cccc(F)c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1cc(Cl)nc(NCc2cccc(F)c2)c1
Temperature: 110 °C
Yield: 99.2 %

Procedure:
To a scintillation vial containing 2,6-dichloroisonicotinonitrile (500 mg, 2.89 mmol) was added NMP (6 ml) and (3-fluorophenyl)methanamine (868 mg, 6.94 mmol). The homogenous reaction mixture was capped and heated to 110° C. in a oil bath for 1 hr. The reaction mixture was diluted with EtOAc and washed with sat NaHCO3, H2O and sat NaCl. The organic layer was dried Na2SO4, filtered and concentrated. The crude residue was purified by column chromatography on silica gel (0-20% EtOAc/Hexane) to give 2-chloro-6-(3-fluorobenzylamino)isonicotinonitrile (750 mg, 95%). LCMS (m/z): 262.0 (MH+), retention time=1.03 min.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=2)[CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[F:24])[NH2:20]>C(O)CCC>[NH2:15][C:11]1[N:10]=[C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:20][C:19]3[CH:21]=[CH:22][C:23]([F:24])=[C:17]([Cl:16])[CH:18]=3)[N:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Nc1cccc(Nc2cc(Cl)ncn2)n1
Solvent: CCCCO
Product: Nc1cccc(Nc2cc(Nc3ccc(F)c(Cl)c3)ncn2)n1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 232.9 %

Procedure:
A mixture of N-(6-chloro-pyrimidin-4-yl)-pyridine-2,6-diamine (1.000 g, 4.512 mmol) and 3-chloro-4-fluoroaniline (1.380 mmol) in 10 mL of n-butanol in a sealed vial was heated at 120° C. for 24 h. The sample was cooled, was concentrated to remove most of the n-butanol, and was then diluted with EtOAc and sat. NaHCO3 solution. The sample was stirred at room temperature for 30 min and was filtered. The solid was washed with fresh EtOAc and water and vacuum dried to give 1.063 g of N-(6-amino-pyridin-2-yl)-N′-(3-chloro-4-fluorophenyl)-pyrimidine-4,6-diamine (Int-E) as tan solid. MS (ES) (m/z) 331/333 (M+1, 100/65%). TLC (SiO2, 10% MeOH in CHCl3): Rf 0.25.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[CH2:3][O:4][C:5]1[C:6]([O:31]CC2C=CC=CC=2)=[CH:7][C:8]2[CH2:9][CH2:10][C@@H:11]3[C@@H:20]([C:21]=2[CH:22]=1)[CH2:19][CH2:18][C@@:16]1([CH3:17])[C@H:12]3[CH2:13][CH2:14][C@@H:15]1[O:23]CC1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:1][C:2]([F:39])([F:40])[CH2:3][O:4][C:5]1[C:6]([OH:31])=[CH:7][C:8]2[CH2:9][CH2:10][C@@H:11]3[C@@H:20]([C:21]=2[CH:22]=1)[CH2:19][CH2:18][C@@:16]1([CH3:17])[C@H:12]3[CH2:13][CH2:14][C@@H:15]1[OH:23]
Reactant: C[C@]12CC[C@@H]3c4cc(OCC(F)(F)F)c(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CC[C@@H]2OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@]12CC[C@@H]3c4cc(OCC(F)(F)F)c(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reaction time: 24 h
Yield: 75 %

Procedure:
Pd(OH)2 --C(20%, 1.0 g) was added carefully under argon atmosphere to a solution of estradiol (7) (1.0 g, 1.8 mmol) in anhydrous THF (50 mL). The resulting mixture was hydrogenated at 45-50 psi on a Parr apparatus for 24 h. The catalyst was removed by filtration using a celite pad under argon atmosphere, and the pad was washed with dichloromethane (200 mL). Evaporation of the filtrate under reduced pressure, followed by purification on a silica gel column, gave compound (9) (0.5 g, 75%): mp 167-168° C.; IR (KBr) 3550, 2960-2840, 1590, 1510, 870 cm-1 ; 1H NMR (CDCl)3 δ 0.80 (s, 3H), 1.10-2.40 (m, 13H), 2.70-2.85 (m, 2H), 3.75 (m, 1H), 4.40 (q, J=8.5 Hz, 2H), 5.35 (s, 1H, OH), 5.5 (s, 1H), 6.70 (s, 1H), 6.80 (s, 1H); MS m/z (relative intensity) 370 (100), 311 (9), 270 (8), 244 (8), 205(6). Anal. (C20H25O3 0.7 H2O) C, H.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].N1C=CC=CC=1.[CH2:16]([N:23]1[CH2:28][CH2:27][CH:26]([C:29](Cl)=[O:30])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[CH2:16]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]([NH:1][C:2]2[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=2[OH:9])=[O:30])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)C1CCN(Cc2ccccc2)CC1
Reactant: Nc1cc(Br)ccc1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cc(Br)ccc1O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
1-Benzylpiperidine-4-carboxylic acid (29 g, 0.13 mol) dissolved in DCM (300 ml), cooled to 0° C. and added oxalyl chloride (17.3 ml, 0.2 mol). Catalytic amount of DMF was added to this mixture and stirred at rt for 2 h. After 2 h, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 1-benzylpiperidine-4-carbonyl chloride quantitatively. 2-Amino-4-bromophenol (23 g, 0.12 mol) dissolved in DCM and added pyridine (11.5 g, 0.15 mol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 1-benzylpiperidine-4-carbonyl chloride (29 g, 0.12 mol) in DCM (100 ml). After continuing stirring at rt for 2 h, DCM was removed on the rotavapour to obtain the titled compound (47.6 g), which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[NH:13][C:14]2[CH:15]=[C:16]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=[CH:18][C:19]=2[CH3:20])[CH:3]=1.[CH:30]1([NH2:33])[CH2:32][CH2:31]1>CC(O)C>[CH:30]1([NH:33][C:2]2[N:7]=[CH:6][N:5]=[C:4]([N:8]3[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][C:14]3[CH:15]=[C:16]([NH:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])[CH:3]=2)[CH2:32][CH2:31]1
Reactant: NC1CC1
Reactant: Cc1ccc(NC(=O)c2ccccc2)cc1Nc1nccn1-c1cc(Cl)ncn1
Solvent: CC(C)O
Product: Cc1ccc(NC(=O)c2ccccc2)cc1Nc1nccn1-c1cc(NC2CC2)ncn1
Temperature: 65 °C

Procedure:
A mixture of N-{3-[1-(6-chloro-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-benzamide (2.65 g, 6.55 mmol), cyclopropylamine (8.8 mL, 124.43 mmol) in 2-propanol (30 mL) was heated at 65° C. for 16 h. The reaction mixture was then cooled down to room temperature and concentrated. The residue yellow solid was washed with water, dried under vacuum to afford the title compound. The obtained crude title compound was directly used for the next step reaction without any further purification. 1H NMR 600 MHz (DMSO-d6) δ 11.13 (bs, 1H), 10.24 (s, 1H), 8.77 (s, 1H), 8.48 (bs, 1H), 8.10 (bs, 1H), 7.98 (d, 2H, J=6.0 Hz), 7.71 (bs, 1H), 7.57 (s, 1H), 7.52 (s, 2H), 7.34 (d, 1H, J=6.6 Hz), 7.15 (d, 1H, J=6.6 Hz), 6.88 (s, 1H), 6.74 (bs, 1H), 2.61 (bs, 1H), 2.33 (s, 3H), 0.82 (s, 2H), 0.53 (s, 2H); MS m/z 426.5 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Br:6][C:7]1[CH:8]=[N:9][N:10]([CH2:12][CH2:13]Cl)[CH:11]=1>CS(C)=O.CCOC(C)=O>[Br:6][C:7]1[CH:8]=[N:9][N:10]([CH2:12][CH2:13][NH:5][CH2:4][CH2:3][O:2][CH3:1])[CH:11]=1
Reactant: COCCN
Reactant: ClCCn1cc(Br)cn1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COCCNCCn1cc(Br)cn1
Temperature: 25 °C

Procedure:
A solution of 2-methoxyethanamine (8.9 mL, 102.06 mmol) and chloride 75 (7.13 g, 34.02 mmol) in DMSO (20 mL) was heated at 60° C. 5 h. The mixture was then cooled to room temperature, diluted with EtOAc, washed with aqueous sodium bicarbonate, water and brine.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:49][C:50]([NH2:52])=[O:51]>CN(C)C=O.C(OCC)(=O)C>[NH2:52][C:50](=[O:51])[CH2:49][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]2[C@H:35]3[C@H:31]([O:32][CH2:33][CH2:34]3)[O:30][CH2:29]2)[C@H:15]([OH:37])[CH2:14][N:13]([S:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)(=[O:12])=[O:11])[CH2:38][CH:39]([CH3:41])[CH3:40])=[CH:19][CH:20]=1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCC(N)=O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl) (isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate (47 mg, 0.08 mmol) in anhydrous dimethylformamide (2 mL) was added cesium carbonate (78 mg, 0.24 mmol) and 2-bromoacetamide (22 mg, 0.16 mmol). After 1 h at ambient temperature, the mixture was diluted with ethyl acetate, washed with water (3×), brine, dried (sodium sulfate), and evaporated. The residue was purified by chromatography (silica gel, dichloromethane/methanol, 97:3) to afford the title product as a white solid (45 mg) 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.82 (3H, d), 1.2 (1H, dd), 1.4 (1H, quintuplet), 1.9-2.0 (1H, m), 2.35 (1H, t), 2.6-2.8 (3H, m), 2.9 (1H, d), 2.95 (1H, dd), 3.25-3.30 (1H, m), 3.45 (1H, br s), 3.5-3.6 (3H, m), 3.7 (1H, t), 3.8 (1H, dd), 4.3 (2H, s), 4.8 (1H, dt), 5.0 (1H, d), 5.5 (1H, d), 6.18 (2H, s), 6.8 (2H, d), 7.0-7.15 (3H, m), 7.22 (1H, s), 7.24 (1H, d), 7.26 (1H, d), 7.32 (1H, s), 7.42 (1H, s); MS: 650 (MH+)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[CH:15]=[CH:14][O:13][CH:12]=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]1[CH:15]=[CH:14][O:13][CH:12]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1-c1ccoc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: Cc1ccc(N)cc1-c1ccoc1
Temperature: 25 °C
Yield: 95.6 %

Procedure:
A suspension of 4-methyl-3-(3-furyl) nitrobenzene 1 (91 mg, 0.45 mmol) and Lindlar's catalyst (0.2 mmol) in methanol was placed under an H2 atmosphere and the resulting reaction was maintained overnight at rt. The reaction mixture was filtered through Celite and the remaining solids were washed with EtOAc. The combined organic portions were concentrated to provide 74 mg (0.43 mmol, 96%) of an amber residue as 2: 1H NMR (300 MHz, CD3OD) δ 7.56 (app t, J=1.1 Hz, 1H), 7.52 (dd, J=1.7, 1.9 Hz, 1 H), 6.97 (d, J=8.0 Hz, 1H), 6.75 (d, J=2.5 Hz, 1H), 6.60 (m, 2H), 2.23 (s, 3H).
Reaction SMILES: [C:1]1(=O)[O:5][CH2:4][CH2:3][O:2]1.[F:7][C:8]([F:32])([F:31])[C:9]1[N:13]2[N:14]=[C:15]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28]C(O)=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:32][C:8]([F:7])([F:31])[C:9]1[N:13]2[N:14]=[C:15]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]4[CH:29]=[CH:28][C:1]([O:2][CH2:3][CH2:4][OH:5])=[CH:26][CH:25]=4)[CH2:22][CH2:23]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1
Reactant: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 71.6 %

Procedure:
A solution of ethylene carbonate (18.18 g, 206.42 mmol) in DMF (30 mL) was added dropwise to a stirred suspension of 4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol (obtained as described in Example 4.2, preparation of starting materials) (15 g, 41.28 mmol) and potassium carbonate (11.41 g, 82.57 mmol) in DMF (30 mL) at 80° C. over a period of 10 minutes under nitrogen. The resulting mixture was stirred at 80° C. for 20 hours. The reaction mixture was cooled to room temperature then concentrated and diluted with DCM (500 mL), and washed sequentially with water (500 mL) and saturated brine (250 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 70 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to give 2-(4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethanol (12.04 g, 71.6%) as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:30][CH2:29][C:5]2[N:6]([CH2:14][C:15]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:16][C:17](OCC)=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:31][NH2:32]>O>[CH3:1][N:2]1[CH2:30][CH2:29][C:5]2[N:6](/[CH:14]=[C:15](/[C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)\[CH2:16][C:17]([NH:32][CH3:31])=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CN
Reactant: CCOC(=O)C=C(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1
Solvent: O
Product: CNC(=O)C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
Ethyl 4-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-fluorophenyl)but-2-enoate (50 mg, 0.123 mmol; prepared according to General Method 5) in 40% aqueous methyl amine (1 mL) was heated overnight at 100° C. The reaction mixture was cooled to RT and diluted with water (5 mL). A white solid precipitated out which was filtered and dried under vacuum. 1H NMR (CD3OD, HCl salt) δ (ppm): 7.60 (m, 2H), 7.30 (d, 1H), 7.20 (m, 3H), 7.10 (m, 1H), 7.0 (d, 1H), 4.70 (m, 1H), 4.35 (m, 1H), 3.80 (m, 2H), 3.60 (m, 2H), 3.30 (m, 3H), 3.15 (s, 3H), 2.55 (s, 3H), 2.40 (s, 2H).
Reaction SMILES: CO.[H-].[Na+].[F:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[CH3:14][CH:15]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:16]([O:18]C)=[O:17]>C1(C)C=CC=CC=1>[CH3:24][O:23][C:21](=[O:22])[C:20](=[CH:10][C:9]1[CH:12]=[CH:13][C:6]([F:5])=[CH:7][CH:8]=1)[CH:15]([CH3:14])[C:16]([OH:18])=[O:17]
Reactant: COC(=O)CC(C)C(=O)OC
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C(=Cc1ccc(F)cc1)C(C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.7 %

Procedure:
After the careful addition of absolute methanol (0.1 mL) to a suspension of sodium hydride (20 g, 0.5 mol, 60% in mineral oil) in anhydrous toluene (200 mL), a solution of 4-fluoro-benzaldehyde (31 g, 0.25 mol) and dimethyl 2-methyl-succinate (60 g, 0.38 mol) in anhydrous toluene (100 mL) was added at room temperature under a stream of nitrogen. The resulting mixture was stirred at room temperature for 30 minutes and then quenched by the slow addition of water (20 mL). The mixture was acidified to pH 3 by the addition of concentrated hydrochloric acid, and extracted with ethyl acetate (200 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (elution with 30% ethyl acetate in petroleum ether) to afford 2-(4-fluoro-benzylidene)-3-methyl-succinic acid 1-methyl ester (20 g, 33%) as a white solid. 1H NMR (400 MHz, acetone-d6) δ ppm 7.77 (s, 1H), 7.54 (d, J=8.8 Hz, 2H), 7.25 (d, J=8.8 Hz, 2H), 3.82 (q, 7.2 Hz, 1H), 1.40 (d, J=6.8 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:13]=[CH:14][C:15](Cl)=[N:16][CH:17]=2)=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.[CH3:19][OH:20].C[O-].[Na+]>O1CCOCC1>[NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:13]=[CH:14][C:15]([O:20][CH3:19])=[N:16][CH:17]=2)=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: CO
Reactant: Nc1nc(-c2ccco2)c(-c2ccc(Cl)nc2)s1
Agent: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(-c2sc(N)nc2-c2ccco2)cn1
Temperature: 95 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
2-Amino-5-(2-chloropyridin-5-yl)-4-(2-furyl)thiazole (2.22 g, 80.0 mmol) obtained in Step 1 and a methanol solution of 28% sodium methoxide (4.63 g, 24.0 mmol) were suspended in 1,4-dioxane (8 mL), followed by stirring at 95° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (chloroform:methanol=9:1) to afford 2-amino-4-(2-furyl)-5-(2-methoxypyridin-5-yl)thiazole (1.32 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[NH:14][C:13]3[CH2:15][S:16][CH2:17][C:12]=3[C:11](=O)[N:10]=2)=[C:4]([F:19])[CH:3]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:11]1[C:12]2[CH2:17][S:16][CH2:15][C:13]=2[N:14]=[C:9]([C:5]2[CH:6]=[C:7]([F:8])[C:2]([Cl:1])=[CH:3][C:4]=2[F:19])[N:10]=1
Reactant: O=c1nc(-c2cc(F)c(Cl)cc2F)[nH]c2c1CSC2
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1cc(-c2nc(Cl)c3c(n2)CSC3)c(F)cc1Cl
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A mixture of 2-(4-chloro-2,5-difluorophenyl)-5,7-dihydrothieno[3,4-d]pyrimidin-4(1H)-one and phosphorous oxychloride was stirred at 90° C. for 4 hours to yield 4-chloro-2-(4-chloro-2,5-difluorophenyl)-5,7-dihydrothieno[3,4-d]pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5](N(OC)C)=[O:6].[CH2:14]([Mg]Br)[CH2:15][CH3:16]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH2:14][CH2:15][CH3:16])[CH:11]=[CH:12][CH:13]=1
Reactant: CCC[Mg]Br
Reactant: CON(C)C(=O)c1cccc(Br)c1
Solvent: C1CCOC1
Product: CCCC(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
A cold (0° C.) solution of 3-bromo-N-methoxy-N-methylbenzamide (3 g, 12.3 mmol) in THF was treated with propylmagnesium bromide (6.15 mL, 12.3 mmol), stirred at room temperature for 1 hour, quenched with aqueous NH4Cl, acidified with HCl (2N) and extracted with ethyl ether. The organic extracts were combined, dried over MgSO4 and concentrated under vacuum. Purification of the resultant residue on silica gel (Biotage) using hexanes/EtOAc (20/1) as the eluting solvents gave 1-(3-bromophenyl)butan-1-one as a tan solid (2.1 g, 75% yield).