Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]3[CH2:14][C@H:15]([NH:18][C:19](=[O:39])[C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29](CC6C=CC=CC=6)[CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH2:16][O:17][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[C:13]3[CH2:14][C@H:15]([NH:18][C:19](=[O:39])[C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[CH:24][CH:25]=4)[CH2:16][O:17][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCN(Cc5ccccc5)CC4)cc2)CO3)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCNCC4)cc2)CO3)CC1
Temperature: 50 °C
Reaction time: 19 h
Yield: 93.3 %

Procedure:
(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4 dihydro-2H-1-benzopyran-3-yl]-4-(4-benzylpiperazin-1-yl)benzamide (1.7 g, 3.2 mmol) was dissolved in methanol (100 mL). Palladium (10%) on activated carbon (510 mg) and ammonium formate (1.6 g, 26 mmol) were added and the reaction mixture was stirred at 50° C. for 19 h. The catalyst was filtered off and the solvent was evaporated in vacuo to give 1.3 g (92% yield) of the title compound as a pale yellow solid: mp>102° C. sinters; EIMS (70 eV) m/z (relative intensity) 435 (8, M+); [α]22D −102° (c 0.15, chloroform).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]2)[O:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].[F:25][C:26]([F:30])([F:29])[CH2:27][OH:28]>O>[C:8]1([C:7]2[O:6][C:5]([CH:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]3)=[N:4][C:3]=2[CH2:2][O:28][CH2:27][C:26]([F:30])([F:29])[F:25])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)N1CCC(c2nc(CCl)c(-c3ccccc3)o2)CC1
Reactant: OCC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N1CCC(c2nc(COCC(F)(F)F)c(-c3ccccc3)o2)CC1
Temperature: 72 °C

Procedure:
A solution of 1-[4-(4-chloromethyl-5-phenyl-oxazol-2-yl)-piperidin-1-yl]ethanone (30 g, 94.1 mmol), prepared as in Intermediate 3B, in 2,2,2-trifluoroethanol (450 ml) is treated with a solution of NaOH (56 g, 1412 mmol) in water (150 ml). After heating at 72° C. for 15 hours, the reaction mixture is concentrated. The residue is partitioned between EtOAc and water. The aqueous phase is reextracted once with EtOAc, and the combined organic phases are washed with saturated brine, dried (Na2SO4) and concentrated to afford 1-{4-[5-phenyl-4-(2,2,2-trifluoroethoxymethyl)-oxazol-2-yl]-piperidin-1-yl}-ethanone.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[F:10][C:11]1([F:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>CN(C)C=O>[F:10][C:11]1([F:17])[CH2:16][CH2:15][N:14]([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1
Reactant: BrCc1ccc(Br)cc1
Reactant: FC1(F)CCNCC1
Solvent: CN(C)C=O
Product: FC1(F)CCN(Cc2ccc(Br)cc2)CC1
Yield: 87.3 %

Procedure:
4-Bromobenzyl bromide (1.55 g) and 4,4-difluoropiperidine (1.50 g) were stirred in dimethylformamide (30 ml) for 18 h. The mixture was partitioned between diethyl ether (40 ml) and water (40 ml). The aqueous phase was extracted further with ether (40 ml) and the combined organic phases were washed with water (50 ml), dried (MgSO4) and concentrated in vacuo to give the product as a white crystalline solid (1.57 g).
Reaction SMILES: Br[CH2:2][C:3]1[C:15]([Cl:16])=[CH:14][C:6]([C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8])=[C:5]([F:17])[CH:4]=1.[CH:18]1[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=[CH:20][C:19]=1[OH:28].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:16][C:15]1[C:3]([CH2:2][O:28][C:19]2[CH:20]=[CH:21][C:22]3[CH2:23][CH2:24][CH2:25][CH2:26][C:27]=3[CH:18]=2)=[CH:4][C:5]([F:17])=[C:6]([CH:14]=1)[C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8]
Reactant: Oc1ccc2c(c1)CCCC2
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(COc2ccc3c(c2)CCCC3)cc1F
Temperature: 50 °C
Reaction time: 4 h
Yield: 15.6 %

Procedure:
A mixture of 4-(bromomethyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide (40 mg, 0.12 mmol), 5,6,7,8-tetrahydronaphthalen-2-ol (40 mg, 0.24 mmol) and K2CO3 (60 mg, 0.24 mmol) in acetone (10 mL) was stirred at 50° C. for 4 h. The reaction was filtered and purified by reverse phase Combiflash (20%-50% MeCN in 0.1% formic acid) to give target compound (7.7 mg, 16%) as a white solid. LCMS (ESI) Method A: RT=4.12 min, m/z: 412.1 [M+H]+. 1H-NMR (400 MHz, MeOD-d4) δ 7.80 (d, J=6.0 Hz, 1H), 7.37 (d, J=5.6 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.74-6.68 (m, 2H), 5.11 (s, 2H), 3.20 (s, 3H), 2.74-2.70 (m, 4H), 1.80-1.77 (m, 4H).
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][C:14]=1[O:23][CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O.O>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][C:14]=2[O:23][CH3:24])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: COc1cc(CC(=O)O)ccc1O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(CC(=O)O)ccc1Oc1ccc(N)cc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
A mixture of 4-fluoro-3-nitroaniline (3.45 g, 22.1 mmol), 4-hydroxy-3-methoxyphenylacetic acid (4.03 g, 22.1 mmol) and cesium carbonate (18.0 g, 55.3 mmol) in methylsulfoxide (40 mL) was heated to 120° C. (external temperature, oil bath) overnight. After 16 h the reaction was poured into water and the pH adjusted to <4 by addition of citric acid. The aqueous mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water then brine. The organic separation was stirred over magnesium sulfate, filtered and the filtrate concentrated in vacuo on a rotary evaporator to afford a dark brown oil. The product was isolated by chromatography on silica gel, eluting with an ethyl acetate/hexane gradient, to afford an orange foamy solid. LC-MS ESI (neg.) m/z: 317.0 (M−H). 1H NMR (400 MHz) (CDCl3) δ 7.27 (d, J=8.4 Hz, 1H); 6.93 (s, 1H); 6.84-6.79 (m, 4H); 5.90 (br s, 2H); 3.85 (s, 31H); 3.63 (s, 2H) ppm.
Reaction SMILES: [N:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])[N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22]CC4C=CC=CC=4)=[CH:18][CH:17]=3)[C:14]=2[CH3:15])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.O>C(Cl)Cl>[N:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])[N:13]([C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)[C:14]=2[CH3:15])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(OCc2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
1-(4-Benzyloxyphenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide, from Ex. 1, Step 4 (2.78 g, 5.2 mmol) was dissolved in 80 ml CH2Cl2 and cooled to 0° C. Boron tribromide solution (1 M in CH2Cl2, 10.4 ml, 10.4 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 1 hour. Water (200 ml) was added and the solution extracted with EtOAc (3×200 ml). The combined organic phases were dried (Na2SO4), filtered and concentrated. Flash chromatography (silica, hexane:EtOAc 1:3, EtOAc) afforded 1.34 g (58%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:41]([NH2:43])=[O:42])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36]COC)[CH:31]=[CH:30][C:29]=4[F:40])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH3:44][O:45][CH2:46][CH2:47]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:41]([NH2:43])=[O:42])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][CH2:47][CH2:46][O:45][CH3:44])[CH:31]=[CH:30][C:29]=4[F:40])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CNCCOC)ccc4F)cc23)CC1
Reactant: COCCN
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CNCCCOC)ccc4F)cc23)CC1
Yield: 64.5 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-fluoro-5-({[2-(methyloxy)ethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 3-(methyloxy)-1-propanamine (53 μL, 0.524 mmol) for 2-(methyloxy)ethanamine to afford 15 mg of the title compound (64.5%)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[N+:11]([C:5]1[N:1]=[C:2]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[NH:3][CH:4]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ncc[nH]1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1nc([N+](=O)[O-])c[nH]1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
16.08 g (114.7 mmol) of ethyl imidazole-2-carboxylate are dissolved in 71.7 ml of concentrated sulphuric acid while cooling in ice. Then 71.7 ml of 100% strength fuming nitric acid are added dropwise. The reaction solution is stirred at 50 to 60° C. for 3 h and, after cooling, poured into 800 ml of ice/water mixture. The crystals which separate out are filtered off with suction and washed with 1500 ml of ice-water.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[CH2:14][O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])[CH2:20][CH2:19]1)=[O:17])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[N:21]1[CH2:20][CH2:19][N:18]([C:16]([O:15][CH2:14][CH:9]2[CH2:10][O:11][CH2:12][CH2:13][NH:8]2)=[O:17])[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCOCC1COC(=O)N1CCN(c2ccc(F)cc2F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCC1COCCN1)N1CCN(c2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To 3-[4-(2,4-difluoro-phenyl)-piperazine-1-carbonyloxymethyl]-morpholine-4-carboxylic acid tert-butyl ester (170 mg, 0.39 mmol) in DCM (5 mL) at 0° C. was added TFA (1 mL in 5 mL DCM). The reaction mixture was allowed to warm to room temperature and stirred overnight. The solvent was removed in vacuo and the residue suspended between sat aq NaHCO3 (10 mL) and DCM (10 mL). The aqueous phase was extracted with DCM (2×10 mL). The combined organic layers were dried (MgSO4) and the solvent removed in vacuo to give morpholin-3-ylmethyl 4-(2,4-difluorophenyl)piperazine-1-carboxylate (104 mg, 79%) as a colourless oil.
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[C:14]1[CH:29]=[CH:28][C:17]2[C@:18]3([CH3:27])[C@@H:23]([CH2:24][CH2:25][C:16]=2[CH:15]=1)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]3.[CH2:30](O)CCC.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:30][N:22]1[C@H:23]2[C@@:18]([CH3:27])([C:17]3[CH:28]=[CH:29][C:14]([C:2]4[CH:3]=[CH:4][C:5]5[C:6]6[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=6)[CH2:12][C:13]=5[CH:1]=4)=[CH:15][C:16]=3[CH2:25][CH2:24]2)[CH2:19][CH2:20][C:21]1=[O:26]
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3ccc4c(c3)Cc3ccccc3-4)ccc12
Reactant: CCCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc5c(c4)Cc4ccccc4-5)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(2-fluorenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (31 mg, 0.08 mmol), 0.2 mL of butanol, and potassium t-butoxide (27 mg, 0.24 mmol). Methyl iodide (0.015 mL, 0.24 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 26 mg (82%) of the title compound as an off-white solid. mp 175° (decomp). FDMS: m/e=393.
Reaction SMILES: [C:1]([CH:4]([C:10]([O:12]CC)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].Cl.[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][NH2:25])[CH:20]=[CH:21][C:22]=1[Cl:23].C([O-])(=O)C.[Na+].C(O)C>O>[Cl:16][C:17]1[CH:18]=[C:19]([N:24]2[C:10](=[O:12])[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:1]([CH3:2])=[N:25]2)[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: NNc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C(C(C)=O)C(=O)OCC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1C(=O)N(c2ccc(Cl)c(Cl)c2)N=C1C

Procedure:
The starting material is prepared as follows: The mixture of 1.3 g of diethyl α-acetyl-malonate, 1.3 g of 3,4-dichlorophenylhydrazine hydrochloride, 0.5 g of sodium acetate, 30 ml of ethanol and 10 ml of water is warmed on the steam cone for 10 minutes. It is diluted with water, extracted with diethyl ether, the extract washed with water, dried and evaporated. The residue is taken up in 50 ml of xylene, the solution distilled for 10 minutes and refluxed for 85 minutes. It is evaporated and the residue triturated with diethyl ether to yield the 1-(3,4-dichlorophenyl)-3-methyl-4-carbethoxy-2-pyrazolin-5-one, melting at 147°-148°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:11][CH3:12])[O:9][CH3:10])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.CN(C)[CH:20]=[O:21].O>O1CCCC1>[CH3:10][O:9][CH:8]([O:11][CH3:12])[C:5]1[CH:6]=[CH:7][C:2]([CH:20]=[O:21])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: COC(OC)c1ccc(Br)nc1
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(OC)c1ccc(C=O)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.4 %

Procedure:
To a solution of 2-bromo-5-dimethoxymethylpyridine (1.19 g, 5.13 mmol) in tetrahydrofuran (8 mL) was added isopropylmagnesium chloride (2 mol/L in tetrahydrofuran; 4.2 mL, 8.4 mmol) under nitrogen atmosphere, and the mixture was stirred at room temperature for 3 h. Dimethylformamide (0.774 mL, 10.3 mmol) was added, and the mixture was stirred for additional 10 min. Water was added, and the mixture was extracted with ethyl acetate twice. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (5:1 to 3:1 hexane/ethyl acetate) to afford 5-dimethoxymethyl-2-pyridinecarboxaldehyde (413 mg, 44%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:31]=[O:32])[C:26]([O:29][CH3:30])=[N:27][CH:28]=1>>[Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH:31]([C:25]4[C:26]([O:29][CH3:30])=[N:27][CH:28]=[C:23]([F:22])[CH:24]=4)[OH:32])=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1
Reactant: COc1ncc(F)cc1C=O
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Product: COC(=O)c1nc2n(c1C(O)c1cc(F)cnc1OC)C1CC(C1)c1cc(F)c(Br)cc1-2
Yield: 68 %

Procedure:
Methyl 10-bromo-9-fluoro-3-((5-fluoro-2-methoxypyridin-3-yl)(hydroxy)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was prepared similarly according to the procedure in Example 9. Methyl 10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with 5-fluoro-2-methoxy-pyridine-3-carbaldehyde to afford 196 mg (68% yield) of the title compound.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[CH3:5][CH:6]1[CH2:12][C:11]2[CH:13]=[C:14]3[O:19][CH2:18][O:17][C:15]3=[CH:16][C:10]=2[C:9]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[N:8][NH:7]1>C(O)(=O)C>[CH3:5][CH:6]1[CH2:12][C:11]2[CH:13]=[C:14]3[O:19][CH2:18][O:17][C:15]3=[CH:16][C:10]=2[C:9]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[N:8][N:7]1[C:2](=[S:1])[NH2:3]
Reactant: N#C[S-]
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1)OCO3
Agent: [K+]
Solvent: CC(=O)O
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(N)=S)OCO3
Temperature: 105 °C
Reaction time: 6 h
Yield: 76.1 %

Procedure:
A mixture of 0.90 g (9.26 mmol) of potassium thiocyanate, 2.00 g (6.15 mmol) of (±)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine and 40 ml of acetic acid was stirred at 100-110° C. for 6 h. After cooling, the precipitated crystals were filtered off, washed with water and dried to yield 1.80 g (76%) of the title compound. Mp.: 242-243° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[C:12]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[CH:11][C:10]([Cl:27])=[CH:9][N:8]=2)[CH:6]=1.[C:28](Cl)(=[O:30])[CH3:29].C(N(CC)CC)C>>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([S:14]([NH:13][C:12]2[C:7]([N:5]3[CH:6]=[C:2]([NH:1][C:28](=[O:30])[CH3:29])[CH:3]=[N:4]3)=[N:8][CH:9]=[C:10]([Cl:27])[CH:11]=2)(=[O:15])=[O:16])=[CH:18][CH:19]=1)([CH3:24])([CH3:26])[CH3:25]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2-n2cc(N)cn2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cnn(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-[2-(4-amino-pyrazol-1-yl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide (20 mg, 0.049 mmol), acetyl chloride (3.5 μL, 0.049 mmol), and triethylamine (14 μL, 0.099 mmol) were stirred at room temperature for 1 hour. The reaction was concentrated in vacuo, followed by the addition of dicholoromethane (1 mL) and tetrabutylammonium fluoride (0.4 mL, 1.0 M in THF). The reaction was stirred for 2 hours at room temperature and then the crude mixture was partitioned with saturated sodium bicarbonate. The aqueous phase was subsequently extracted with dichloromethane and the combined organic layers dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% ethyl acetate in hexanes) to afford N-{1-[3-(4-tert-butyl-benzenesulfonylamino)-5-chloro-pyridin-2-yl]-1H-pyrazol-4-yl}-acetamide: MS (ES) M+H expected 448.1, found 448.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([CH2:7][O:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[CH2:6])[CH3:2].C([O-])(O)=O.[Na+].[CH2:21]([SH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C.O>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:7][O:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[CH2:6][S:28][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:2]
Reactant: SCc1ccccc1
Reactant: C=C(COC1CCOCC1)C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(COC1CCOCC1)CSCc1ccccc1
Yield: 36.8 %

Procedure:
A suspension of 2-(tetrahydro-pyran-4-yloxymethyl)-acrylic acid ethyl ester (2.2 g, 10.2 mmol) in ethanol (100 ml) was treated with a solution of NaHCO3 (0.86 g, 10.2 mmol) in water ml (10 ml) and benzyl mercaptan (1.21 ml, 10.2 mmol) at room temperature overnight. Ethanol evaporated off under reduced pressure, crude partitioned between ethyl acetate and water, organic layer separated and purified by mplc eluting with 1:9 to 2:8 v/v ethyl acetate-heptane mixture to give the title compound as pale yellow oil (1.27 g). MS: 339 (MH+); LCMS (Protocol B) retention time 4.3 minutes.
Reaction SMILES: [CH:1]([NH:3][CH:4]=[O:5])=[CH2:2].CC([O-])(C)C.[K+].Br[CH2:13][CH2:14][CH2:15][CH3:16]>C1COCC1>[CH2:13]([N:3]([CH:1]=[CH2:2])[CH:4]=[O:5])[CH2:14][CH2:15][CH3:16]
Reactant: C=CNC=O
Reactant: CCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CN(C=O)CCCC
Temperature: 15 °C
Reaction time: 0.75 h

Procedure:
Into a dry 500 mL three-necked round-bottomed flask equipped with magnetic stirring bar and dropping funnel were placed 11.67 g (0.164 mol) of N-vinylformamide and 200 mL of anhydrous THF. The mixture was cooled to 15° C. in an ice bath under nitrogen and a total of 18.8 g (0.167 mol) of t-BuOK was added in three portions with constant stirring over 45 minutes. 1-Bromobutane, 24.5 g (0.179 mol) was then added to the reaction mixture dropwise over 30 minutes. When addition was complete, the reaction was allowed to warm to ambient temperature and stirred overnight. After potassium bromide salt was removed, the reaction mixture was concentrated under reduced pressure and diluted with 200 mL of water. The organic layer was extracted three times with diethyl ether. The combined organic layers were washed twice with water and dried over anhydrous magnesium sulfate. The resulting product was recovered after concentration in vacuum and purification by chromatography on silica (diethyl ether/petroleum ether (v/v=3:7). yield: 11.7 g (56%). IR (NaCl, v: cm−1): 1693 (—NHC(═O)H); 1630 (C═C). 1H-NMR (CDCl3, δ: ppm): 8.31, 8.14 (2s, 1H, —C(═O)H); 7.25–7.16, 6.61–6.52 (m, 1H, H2C═CH—); 4.62–4.45 (m, 1H, HaHbC═CH—); 4.43–(s, 1H, HaHbC═CH—); 3.60–3.45 (t, 2H, —NCH2CH2—); 1.61–1.54 (m, 2H, —CH2CH2CH2—); 1.40–1.32 (m, 2H, —CH2CH2CH3); 0.99–0.94 (t, 3H, —NCH2CH2CH2CH3).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)(Cl)(Cl)[Cl:7].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][N:14]=1>>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([Cl:7])=[O:18])=[CH:15][N:14]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Cl)c1ccc(Cl)nc1

Procedure:
75 Ml. of phosphorous oxychloride and 144 g. of phosphorous pentachloride were added to 100 g. of 6-chloronicotinic acid and intimately mixed. The reaction mixture was slowly heated in an oil bath to 80° over 25 minutes with stirring. The bath temperature was raised to 125° and the solution was stirred and refluxed for 1 hour. After concentration under reduced pressure, anhydrous toluene was added and the solution was concentrated again, finally on the oil pump, to yield 6-chloronicotinoyl chloride as a colorless solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:21][C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=3)=[C:18]([OH:20])[CH:19]=2)=[N:3][CH:2]=1.I[CH:33]([CH3:35])[CH3:34].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH:33]([O:20][C:18]1[CH:19]=[C:14]([CH2:13][CH2:12][NH:11][C:4]2[C:5]3[C:10](=[N:9][CH:8]=[CH:7][N:6]=3)[N:1]=[CH:2][N:3]=2)[CH:15]=[CH:16][C:17]=1[O:21][C:22]1[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][N:23]=1)([CH3:35])[CH3:34]
Reactant: Oc1cc(CCNc2ncnc3nccnc23)ccc1Oc1cc(C(F)(F)F)ccn1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)Oc1cc(CCNc2ncnc3nccnc23)ccc1Oc1cc(C(F)(F)F)ccn1
Temperature: 50 °C
Yield: 81.4 %

Procedure:
To a solution of 5-[2-(pteridin-4-ylamino)-ethyl]-2-(4-trifluoromethylpyridin-2-yloxy)-phenol (200 mg, 0.47 mmol) in 2 mL of DMSO was added 2-iodopropane (62 mg, 0.5 mmol), and K2CO3 (97 mg, 0.7 mmol). The solution was heated 2 h at 50° C., after which TLC analysis indicated absence of starting material. The mixture was poured onto ice. The product precipitated and was collected by suction filtration, washed with H2O, and air dried, yielding {2-[3-(isopropoxy)-4-(4-trifluoromethylpyridin-2-yloxy)-phenyl]-ethyl}-pteridin-4-ylamine (180 mg; 81% yield) as a light brown solid: ESIMS m/z: 471 ([M+H]+).