Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[I:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[N:9][C:10]=2[NH2:12])[N:5]([CH:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[N:4]=1.[CH:18]1[C:30]2[CH:29]([CH2:31][O:32][C:33]([N:35]([CH3:42])[C:36]([CH3:41])([CH3:40])[C:37](O)=[O:38])=[O:34])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>ClCCl.O>[NH2:12][C:10]1[N:9]=[CH:8][N:7]=[C:6]2[N:5]([CH:13]3[CH2:17][CH2:16][N:15]([C:37](=[O:38])[C:36]([N:35]([CH3:42])[C:33](=[O:34])[O:32][CH2:31][CH:29]4[C:28]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[C:22]5[C:30]4=[CH:18][CH:19]=[CH:20][CH:21]=5)([CH3:41])[CH3:40])[CH2:14]3)[N:4]=[C:3]([I:2])[C:11]=12
Reactant: Nc1ncnc2c1c(I)nn2C1CCNC1
Reactant: CN(C(=O)OCC1c2ccccc2-c2ccccc21)C(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)OCC1c2ccccc2-c2ccccc21)C(C)(C)C(=O)N1CCC(n2nc(I)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 125.4 %

Procedure:
To a solution of rac-3-iodo-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine monohydrochloride (0.100 g, 0.273 mmol) in dichloromethane (5 mL) was added 2-[[(9H-9-fluorenylmethoxy)carbonyl](methyl)amino]-2-methylpropanoic acid (0.120 g, 0.354 mmol), 1-hydroxy-7-azabenzotriazole (0.041 g, 0.30 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.068 g, 0.35 mmol), and diisopropylethyl amine (0.18 g, 0.24 mL, 1.4 mmol). The reaction mixture was stirred at room temperature for 5 h and then poured into water (10 mL). The organic phase was separated and washed with brine (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to afford rac-9H-9-fluorenylmethyl N-{2-[3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydro-1H-1-pyrrolyl]-1,1-dimethyl-2-oxoethyl}-N-methylcarbamate as a yellow solid (0.223 g) which was used in subsequent reactions without further purification. RP-HPLC Rt 13.688 min, 63% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 652 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:18]=3)=[CH:15][C:14]([CH:43]([N:45]3[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][CH2:46]3)[CH3:44])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:15][C:14]([CH:43]([N:45]3[CH2:46][CH2:47][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:49][CH2:50]3)[CH3:44])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc(C(C)N3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 76 °C
Reaction time: 16 h
Yield: 62.4 %

Procedure:
4-(2-(5-Fluoro-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (456.7 mg, 0.6026 mmol) was dissolved in trifluoroacetic acid (9.5 mL) and the reaction flask was fitted with a reflux condenser and put in a preheated oil bath (75-77° C.) and stirred for 16 h. The reaction was cooled to room temperature and concentrated. The reaction was diluted with DCM (40 mL) and treated with saturated sodium bicarbonate and 5 N NaOH to raise the pH of the aqueous phase to about 8. Then, the layers were separated and the aqueous phase was extracted with DCM and 10:1 DCM/MeOH. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, treated with MeOH, and filtered. The solid was washed with MeOH. The solid was not >95% pure by HPLC, so the filtrate and solid were combined, concentrated, and purified on a silica gel column according to the procedure described by Still et al. (Journal of Organic Chemistry, 1978, 43, 2923-2925) using this eluent system: 30:1 DCM/2 N ammonia in MeOH to 20:1 DCM/2 N ammonia in MeOH to 15:1 DCM/2 N ammonia in MeOH to 5:1 DCM/2 N ammonia in MeOH. The fractions with product were collected, concentrated, treated with MeOH, and filtered. The solid was washed with MeOH, collected, and dried under high vacuum to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (194.7 mg, 62% yield) as a yellow powder. 1H NMR (CDCl3, 400 MHz) δ 11.93 (s, 1H), 8.71 (d, J=2.54 Hz, 1H), 8.31 (t, J=2.25 Hz, 1H), 8.27 (d, J=2.35 Hz, 1H), 8.05 (d, J=2.15 Hz, 1H), 5.42 (br s, 2H), 4.04 (s, 3H), 3.56 (quartet, J=6.65 Hz, 1H), 3.24 (t, J=4.69 Hz, 4H), 2.78 (s, 3H), 2.68-2.54 (m, 7H), 1.44 (t, J=6.85 Hz, 3H). m/z (ESI, pos. ion) 518 (M+H)+.
Reaction SMILES: ClC(OC(Cl)C)=O.C([N:15]1[CH2:24][CH2:23][C:22]2[C:21]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[N:20][C:19]([CH2:36][O:37][CH3:38])=[N:18][C:17]=2[CH2:16]1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C>ClCCCl>[F:35][C:32]([F:33])([F:34])[C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:21]2[C:22]3[CH2:23][CH2:24][NH:15][CH2:16][C:17]=3[N:18]=[C:19]([CH2:36][O:37][CH3:38])[N:20]=2)=[CH:27][CH:28]=1
Reactant: COCc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(Cc1ccccc1)C2
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COCc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCNC2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1-Chloroethyl chloroformate (543 mg, 3.8 mmol) was added dropwise to a mixture of 7-benzyl-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4-amine from Example 31 (820 mg, 1.9 mmol) and diisopropylethyl amine (490 mg, 3.8 mmol) in 1,2-dichloroethane (5 mL, anhydrous) at room temperature. After addition, the reaction mixture was stirred at 60° C. for 2 h under nitrogen. Solvent was removed in vacuo, residue was dissolved in methanol (10 mL) and was stirred at 60° C. for 1 hr. Solvent was removed in vacuo, residue was dissolved in ethyl acetate and was washed with saturated aqueous sodium bicarbonate, brine and dried over sodium sulfate. Solvent was removed in vacuo and light orange oily residue which was usd directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Br:25][C:26]1[CH:27]=[C:28]([CH2:32][S:33](Cl)(=[O:35])=[O:34])[CH:29]=[CH:30][CH:31]=1>>[Br:25][C:26]1[CH:27]=[C:28]([CH2:32][S:33]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)(=[O:35])=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=S(=O)(Cl)Cc1cccc(Br)c1
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)Cc3cccc(Br)c3)cc2)c2ccc3ccccc3c2N1
Yield: 92 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and (3-bromophenyl)methanesulfonyl chloride, the title compound (yield 92%) was obtained in the same manner as that of Example 145.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18]([C:20]2([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[O:31][CH3:32])[CH2:23][CH2:22][CH2:21]2)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]2[C:12]([CH2:15][CH2:16][N:17]=[C:18]2[C:20]2([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[O:31][CH3:32])[CH2:23][CH2:22][CH2:21]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(Cl)ccc1C1(C(=O)NCCc2ccc(OCc3ccccc3)cc2)CCC1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Cl)ccc1C1(C2=NCCc3ccc(OCc4ccccc4)cc32)CCC1

Procedure:
7-(Benzyloxy)-1-[1-(4-chloro-2-methoxyphenyl)cyclobutyl]-3,4-dihydroisoquinoline was prepared analogously to example 65 using N-{2-[4-(benzyloxy)phenyl]ethyl}-1-(4-chloro-2-methoxyphenyl)cyclobutanecarboxamide (1.1 g, 2.445 mmol) and phosphoric trichloride (3.75 g, 24.45 mmol). Yield: 65 mg (0.15 mmol, 6%).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[O:11]1[CH2:15][CH2:14][C:13]2[CH:16]=[C:17]([CH:20]=O)[CH:18]=[CH:19][C:12]1=2>>[O:11]1[C:12]2[CH:19]=[CH:18][C:17]([CH2:20][NH:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1]([OH:10])=[O:9])=[CH:16][C:13]=2[CH2:14][CH2:15]1
Reactant: O=Cc1ccc2c(c1)CCO2
Reactant: Nc1ccccc1C(=O)O
Product: O=C(O)c1ccccc1NCc1ccc2c(c1)CCO2

Procedure:
Prepared by a similar procedure as described for preparation 1A, starting from anthranilic acid and 2,3-dihydrobenzo[b]furan-5-carboxaldehyde (Matrix). 13C-NMR (DMSO-d6) δ 169.9, 158.7, 150.6, 134.3, 131.6, 130.9, 127.5, 126.8, 124.0, 114.3, 111.5, 110.1, 108.6, 70.8, 45.6, 29.0.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[N:14]([CH2:17]C)[CH:15]=[N:16][C:3]=12.[CH2:19]([O:21]C(C1C(Cl)=C2N=CN(C)C2=NC=1C)=O)[CH3:20]>>[CH3:17][N:14]1[C:4]2=[N:5][C:6]([CH3:13])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([O:21][CH2:19][CH3:20])=[C:3]2[N:16]=[CH:15]1
Reactant: CCOC(=O)c1c(C)nc2c(ncn2CC)c1Cl
Reactant: CCOC(=O)c1c(C)nc2c(ncn2C)c1Cl
Product: CCOC(=O)c1c(C)nc2c(ncn2C)c1OCC
Yield: 78 %

Procedure:
By replacing 7-chloro-3-ethyl-5-methyl-3H-imidazo-[4,5-b]pyridine-6-carboxylic acid, ethyl ester in Example 1 e with 7-chloro-3,5-dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid ethyl ester, 3,5-dimethyl-7-ethoxy-3H-imidazo-[4,5-b]pyridine-6-carboxylic acid, ethyl ester is obtained. Yield 78%, m.p. 85°-87° (ether).
Reaction SMILES: N1([CH:7]2[N:12](C(OCC)=O)[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[CH:9]=[C:8]2[C:28]([O:30][CH2:31][CH3:32])=[O:29])CCOCC1.O>CN(C=O)C>[CH2:31]([O:30][C:28]([C:8]1[CH:9]=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=2)[N:11]=[N:12][CH:7]=1)=[O:29])[CH3:32]
Reactant: CCOC(=O)C1=CC(c2cccc(C(F)(F)F)c2)=NN(C(=O)OCC)C1N1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnnc(-c2cccc(C(F)(F)F)c2)c1
Yield: 47 %

Procedure:
6-(4-morpholinyl)-3-[3-(trifluoromethyl)phenyl]-1,5(6H)-pyridazindicarboxylic acid, diethyl ester (10.73 g, 0.024 mole) was refluxed in DMF (150 mL) for 30 min. The mixture was poured into water and extracted 3×100 mL with ethyl acetate. The organic layer was dried (MgSO4), filtered through silica gel, and evaporated in vacuo to give a crude solid which was recrystallized from cyclohexane/ethyl acetate to give 6-[3-(trifluoromethyl)phenyl]-4-pyridazinecarboxylic acid ethyl ester (3.34 g, 47% yield, Compound No. 1) as a brown solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][C@H:2]1[CH2:7][O:8][C:9]1[CH:23]=[C:13]2[C:14]3[C:19]([CH2:20][CH2:21][N:12]2[C:11](=[O:24])[N:10]=1)=[CH:18][C:17]([OH:22])=[CH:16][CH:15]=3.C[C:26]([CH3:32])([CH3:31])[CH2:27][CH2:28][CH2:29]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1>[CH:26]1([CH2:27][CH2:28][CH2:29][O:22][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[C:13]2=[CH:23][C:9]([O:8][CH2:7][C@@H:2]4[CH2:3][O:4][CH2:5][CH2:6][O:1]4)=[N:10][C:11](=[O:24])[N:12]2[CH2:21][CH2:20]3)[CH2:31][CH2:32]1
Reactant: CC(C)(C)CCCO
Reactant: O=c1nc(OC[C@@H]2COCCO2)cc2n1CCc1cc(O)ccc1-2
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=c1nc(OC[C@@H]2COCCO2)cc2n1CCc1cc(OCCCC3CC3)ccc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Intermediate 6 (2.12 g, 2.42 mmol, 1 eq.), 4,4-dimethyl-pentan-1-ol (0.77 g, 7.71 mmol, 1.2 eq.) and PPh3 (2.02 g, 7.71 mmol, 1.2 eq.) were suspended in 1,4-dioxane (50 mL) and the mixture was degassed with N2. DIAD (1.56 mL, 7.71 mmol, 1.1 eq.) was added dropwise and the reaction was stirred at RT for 2 h. The reaction mixture was quenched with brine and extracted with EtOAc, the organic phase was dried over MgSO4 and evaporated to dryness. Compound 143 was obtained by purification by flash chromatography on silica gel, eluting from 60 to 100% EtOAc/H.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].F[B-](F)(F)F.[O:29]=[N+:30]=[O:31].C(=O)([O-])O.[Na+]>C(#N)C>[CH2:1]([N:7]1[CH2:8][CH:9]2[CH:11]([C:10]2([C:14]2[CH:19]=[CH:18][C:17]([N+:30]([O-:31])=[O:29])=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:15]=2)[CH3:13])[CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1)C2(C)c1cccc(NC(C)=O)c1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCN1CC2C(C1)C2(C)c1ccc([N+](=O)[O-])c(NC(C)=O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
To a solution of N-[3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]acetamide (Preparation 45, 1.5 g, 4.78 mmol) in acetonitrile (20 ml) at 0° C. was added nitronium tetrafluoroborate (1.0 g, 7.53 mmol) in several portions over 5 minutes. The mixture was stirred at 0° C. for 30 minutes and then saturated sodium hydrogen carbonate solution (30 ml) was added. The aqueous mixture was extracted with ethyl acetate (3×15 ml) and the combined extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica column chromatography eluting with ethyl acetate:hexane (50:50) to afford the title compound (534 mg, 32%) as pale yellow platelets.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]([O:23][C:24]([F:43])([F:42])[C:25]([F:41])([F:40])[O:26][C:27]([F:39])([F:38])[C:28]([F:37])([F:36])[C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])([F:22])[F:21])=[C:10]([F:44])[C:9]=2[F:45])=[N:6][CH:7]=1.I[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]>>[CH2:47]([O:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]([O:23][C:24]([F:43])([F:42])[C:25]([F:40])([F:41])[O:26][C:27]([F:38])([F:39])[C:28]([F:36])([F:37])[C:29]([F:34])([F:35])[C:30]([F:31])([F:32])[F:33])([F:21])[F:22])=[C:10]([F:44])[C:9]=2[F:45])=[N:4][CH:3]=1)[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCCCI
Reactant: Oc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c2F)nc1
Product: CCCCCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c2F)nc1

Procedure:
The title compound was prepared essentially as in Example 12 by combining 5-hydroxy-2-[4-(3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)propoxy)-2,3-difluorophenyl)pyrimidine (1.0 g, 1.4 mmol, prepared essentially as described in DE 4,220,065) with iodooctane (0.31 g, 1.5 mmol). The resulting crude product was isolated essentially as described in Example 3 and purified by chromatography on silica gel, eluting with toluene, followed by Kugelrohr distillation (200° C. at 0.15 torr) to provide a yield of 0.3 g.
Reaction SMILES: [N:1]([C:3]1[C:4]([O:11][CH2:12][CH3:13])=[N:5][C:6]([NH2:10])=[N:7][C:8]=1[NH2:9])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:10][C:6]1[N:5]=[C:4]([O:11][CH2:12][CH3:13])[C:3]([NH2:1])=[C:8]([NH2:9])[N:7]=1
Reactant: CCOc1nc(N)nc(N)c1N=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCOc1nc(N)nc(N)c1N
Temperature: 60 °C
Reaction time: 4 h
Yield: 61.1 %

Procedure:
To a suspension of the compound of example 56 (7.12 g, 38.9 mmoles) in water (150 ml) at 60° C. was added sodium dithionite (46.7 mmol, 8.12 g). Additional sodium dithionite was added till the pink colour completely disappeared and a yellow solution was formed. The solution was stirred at 60° C. for another 4 hours. Water was evaporated and the resulting residue was precipitated from a small amount of water, providing the title compound as a yellow powder (4.02 g, yield 61%). Spectral data are identical with literature data (W. Pfleiderer et al. cited supra).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH:9]([CH:13]2[CH2:15][CH2:14]2)[C:10]([NH2:12])=[O:11])[C:3]=1[O:16][CH3:17].Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]2[C:19](=[O:21])[NH:12][C:10](=[O:11])[C:9]([CH:13]3[CH2:14][CH2:15]3)=[C:4]2[C:3]=1[O:16][CH3:17]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1c(C(C(N)=O)C2CC2)ncc(F)c1Cl
Product: COc1c(Cl)c(F)cn2c(=O)[nH]c(=O)c(C3CC3)c12
Yield: 15.5 %

Procedure:
The title compound (0.15 g) was prepared from (4-chloro-5-fluoro-3-methoxypyridin-2-yl)cyclopropylacetamide (0.88 g, 3.40 mmol [Example 10]) and triphosgene (2.10 g, 7.20 mmol) using a similar procedure to that of Example 2. 1H NMR (400 MHz, CDCl3) δ 9.12 (bs, 1H), 8.13 (d, 1H), 3.82 (s, 3H), 1.33-1.24 (m, 1H), 1.05-0.98 (m, 2H), 0.71-0.60 (m, 2H). MSCI: m/z 285 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2([OH:9])[CH2:8][CH2:7]2)[N:3]=[CH:2]1.N1C=CN=C1.[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C=O)C>[Si:19]([O:9][C:6]1([C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)[CH2:8][CH2:7]1)([C:16]([CH3:18])([CH3:17])[CH3:15])([CH3:21])[CH3:20]
Reactant: OC1(c2c[nH]cn2)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1(c2c[nH]cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
A solution of 1-(1H-imidazol-4-yl)cyclopropanol (700 mg, 5.64 mmol) in DMF (1 mL) was treated with imidazole (768 mg, 11.28 mmol) and TBSCl (935 mg, 6.20 mmol) and the mixture was stirred at RT for 2 h. The mixture was then poured onto H2O, and extracted with AcOEt. The combined org. layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (850 mg) that was used as it is. UPLC-MS: MS 239.2 (M+H+); UPLC rt 0.82 min.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.C[O:18][C:19](=[O:24])[CH2:20][CH2:21][CH2:22]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[OH-].[Li+:34]>C(#N)C.O>[Li+:34].[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH2:22][CH2:21][CH2:20][C:19]([O-:24])=[O:18])[CH2:13][CH2:14]2)=[N:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C([O-])CCCN1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 100 °C
Yield: 116.4 %

Procedure:
A mixture of 1-(5-trifluoromethyl-pyridin-2-yl)-piperazine (370 mg; 1.60 mmol), 4-bromo-butyric acid methyl ester (312 g; 1.60 mmol), potassium carbonate (442 mg; 3.30 mmol) and potassium iodide (265 mg; 1.65 mmol) in acetonitrile (6 mL) is heated to 100° C. for 2 hours. The reaction mixture is allowed to attain room temperature, filtered and the filtrate is concentrated under high vacuum. The resulting residue is taken up in tetrahydrofuran (10 mL) and a solution of lithium hydroxide (115 mg; 4.80 mmol) in water (2 mL) is added. The resulting mixture is stirred at room temperature over night and is then diluted with acetonitrile (90 mL). The precipitate formed is then filtered and dried under high vacuum to afford the desired product (602 mg) which is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36]([CH:38]4[CH2:40][CH2:39]4)=[O:37])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Product: O=C(Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1)C1CC1

Procedure:
Example 120 was prepared from bis(4-fluorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopro panecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.64–7.55 (s, 1H), 7.55–7.47 (s, 1H), 7.47–7.37 (br, 1H), 7.36–7.17 (m, 6H), 7.05–6.95 (m, 4H), 6.95–6.87 (br, 1H), 4.81 (s, 1H), 3.47–3.35 (m, 2H), 3.07–2.94 (m, 2H), 2.58–2.41 (m, 3H), 2.15–1.99 (m, 2H), 1.90–1.79 (m, 2H), 1.79–1.60 (m, 4H), 1.59–1.44 (m, 1H), 1.13–0.99 (m, 2H), 0.90–0.75 (m, 2H); ESMS m/e: 532.2 (M+H)+.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:8](=[O:9])[O:7][CH2:6][C:5]=12.CN(C)C(=O)C.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[F:24])[NH2:20]>CCO>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][C:8]([C:4]2[C:5]([CH2:6][OH:7])=[N:1][O:2][N:3]=2)=[O:9])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: O=C1OCc2nonc21
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CO
Temperature: 80 °C
Yield: 74.1 %

Procedure:
4H,6H-Furo[3,4-c][1,2,5]oxadiazol-4-one (2.00 g, 0.0159 mol) was dissolved in EtOH (80 mL) and N,N-dimethylacetamide (10 mL) and then 3-chloro-4-fluoroaniline (2.5 g, 0.017 mol) was added as a solid. The reaction was heated at 80° C. overnight. The crude reaction mixture was concentrated in vacuo. The oil was extracted twice with EtOAc and washed with water. The organic was dried over Na2SO4 and concentrated. The crude residue was purified by flash column chromatography eluting with EtOAc:Hexane (1:1) to yield the desired product (3.2 g, 74%). 1H NMR (400 MHz, DMSO-d6) δ: 11.30 (s, 1H), 8.30 (dd, J=7.0, 2.7 Hz, 1H), 7.69 (ddd, J=9.1, 4.4, 2.6 Hz, 1H) 7.45 (dd, J=9.1, 9.1 Hz, 1H), 4.86 (d=5.8 Hz, 2H), 5.78 (t, 5.8 Hz, 1H); MF=C10H7ClFN3O3; LCMS calculated for C10H8ClFN3O3(M+H)+: m/z=272.024.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([NH:12][C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[N:9]=[CH:8][N:7]=1.C=O.[C:22](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([NH:12][C@@H:13]2[CH2:17][CH2:16][N:15]([CH3:22])[CH2:14]2)[N:9]=[CH:8][N:7]=1
Reactant: CC(=O)O
Reactant: CC(C)(C)CCNc1cc(N[C@@H]2CCNC2)ncn1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC[C@@H](Nc2cc(NCCC(C)(C)C)ncn2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35 %

Procedure:
A suspension of the compound of example 7 (38 mg, 0.144 mmol) in THF (1.5 mL) containing aqueous formaldehyde (11 μL, 0.144 mmol, 37% in water) and acetic acid (8.3 μL, 0.144 mmol) was treated with sodium triacetoxyborohydride (37 mg, 0.173 mmol) and stirred at ambient temperature for 10 min. The reaction mixture was applied directly to SCX resin, eluting non-basic compounds with MeOH and the basic compounds with 1 N ammonia in MeOH. The basic washings were concentrated in vacuo and purified by flash column chromatography on silica gel eluting with DCM:MeOH:0.880 ammonia (1:0:0 changing to 40:10:1, by volume) further purification on reverse phase silica eluting with water:acetonitrile (1:0 changing to 19:1 by volume) gave the title compound as a white solid (14 mg, 35%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.[BH4-].[Na+].[Na+].[Cl-]>O>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1cccnc1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Product: OCc1cccnc1Cl
Temperature: 25 °C
Yield: 90.1 %

Procedure:
A mixture of 2-chloronicotinic acid (5.0 g, 31.7 mmol) and thionyl chloride (20 mL) was heated at reflux for 1.5 h. The reaction mixture was concentrated in vacuo to remove an excess thionyl chloride. The resulting solid was added in portions to a solution of sodium borohydride (4.3 g, 114 mmol) in water at 10° C. The reaction was maintained at 10-15° C. during the addition to NaBH4. The reaction mixture was then warmed to room temperature. The mixture was saturated with NaCl and extracted with ether (30 mL×3). The combined organic layer was dried over MgSO4 and concentrated in vacuo to afford 4.1 g (90%) of (2-chloro-pyridin-3-yl)-methanol.