Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>C1C=CC=CC=1>[CH2:1]([NH:8][CH2:9][CH2:10][Cl:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCNCc1ccccc1
Solvent: c1ccccc1
Product: ClCCNCc1ccccc1
Temperature: 80 °C

Procedure:
N-Benzyl ethanolamine (15.1 g, 100 mmol) was stirred in benzene (160 ml) at room temperature. Thionyl chloride (30 ml) was added dropwise over ten minutes. A white precipitate began to form immediately and the reaction mixture was warmed to 80° C. for 30 minutes. After cooling to room temperature the white solid was filtered off, washed with ether and dried. This solid was neutralised with sodium hydroxide solution and extracted with ethylacetate, washed with brine, dried (MgSO4) and evaporated to a yellow oil which was chromatographed on silica gel. Elution with petrol/ethylacetate: 1/1 afforded the title amine as a colourless oil, yield 6.75 g (40%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N[CH2:34][CH2:35][CH2:36][OH:37].C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH2:34][CH2:35][CH2:36][OH:37])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Reactant: NCCCO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(=O)NCCCO)C1
Yield: 60 %

Procedure:
Following general method 6, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]amino}-piperidine-1-carboxylic acid tert-butyl ester and 3-amino-propan-1-ol, afforded the crude desired product. Column chromatography (silica, 12 g column, ISCO, 0-100% ethyl acetate in DCM) afforded the title compound as a glass (70 mg, 60%); LCMS (method B): RT=3.37 min, M+H+=504.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[Cl:11][C:12]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:13]=1[CH2:14][C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1>>[N:2]1([CH2:7][C:8]([N:18]2[CH2:19][C@H:15]([CH2:14][C:13]3[CH:37]=[CH:38][C:39]([F:41])=[CH:40][C:12]=3[Cl:11])[CH2:16][C@H:17]2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)=[O:21])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(O)Cn1cncn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2Cl)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2Cl)CN1C(=O)Cn1cncn1
Yield: 36 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(2-chloro-4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 9, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(2-chloro-4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (35.4 mg, 36%). Major isomer 1H-NMR (400 MHz, CDCl3): δ 9.08 (s, 1H), 8.27 (s, 1H), 7.98 (s, 1H), 7.37-7.33 (m, 2H), 7.23-7.19 (m, 1H), 7.16-7.12 (m, 1H), 7.02-6.82 (m, 7H), 5.07 (d, 1H), 5.00 (d, 1H), 4.73 (d, 1H), 3.75-3.69 (m, 1H), 3.31 (t, 1H), 3.08-2.98 (m, 1H), 2.88 (d, 2H), 2.46 (dd, 1H), 1.82-1.73 (m, 1H). MS (EI) for C28H24ClF2N5O3 found 552 (MH+).
Reaction SMILES: [NH2:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)([CH3:6])[C:3](O)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:1][C:2]([C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)([CH3:6])[CH2:3][OH:4]
Reactant: COc1ccc(C(C)(N)C(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)(N)CO)cc1

Procedure:
A solution of 15.0 mmol of 2-amino-2-(4-methoxyphenyl)propionic acid [74279-63-3] in 15 ml of tetrahydrofuran is added dropwise to a suspension of 30.0 mmol of lithium aluminium hydride in 5 ml of tetrahydrofuran. The reaction mixture is heated to reflux for 1 hour. It is quenched with a little water and 1M NaOH and stilted at room temperature. The suspension is filtered through Hyflo. The filtrate is evaporated. The title compound is obtained as a pale yellowish oil, which may crystallize, and is employed without further purification in the next stage. Rt=1.97 (gradient I).
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH:1]1([CH2:7][NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCC1CCCCC1
Solvent: C1CCOC1
Product: O=C(NCC1CCCCC1)c1ccccc1
Reaction time: 16 h

Procedure:
Cyclohexylmethylamine (4.37 mL, 33.6 mmol) was added to a solution of benzoyl chloride (2.47 mL, 21 mmol) in THF (20 mL) at 0° C., and stirring continued 16 h. The mixture was filtered, diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4), and concentrated in vacuo. The product crystallised (2.1 g, 45%) 1H-NMR (300 MHz, CDCl3) δH 7.76 (1H, m, Ar); 7.29 (8H, m, Ar); 1.04 (2H, m, CH2); 1.14 (2H, m, CH2); 1.61 (7H, m, 3×CH2); 3.23 (2H, t, J=6.78 Hz, N—CH2); 6.15 (1H, s, NH); 7.37 (3H, m, ArH), 7.70 (2H, m, ArH); LCMS (ESI+) 218 [M+H]+.
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]=1.[CH3:12][C:13]([C:15]1[CH2:19][CH2:18][CH2:17][CH:16]=1)=[O:14]>C(O)C>[CH2:16]1[CH:15]2[CH:19]([N:3]3[CH:2]([CH2:12][C:13]2=[O:14])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4]3)[CH2:18][CH2:17]1
Reactant: C1=NCCc2ccccc21
Reactant: CC(=O)C1=CCCC1
Agent: Cl
Solvent: CCO
Product: O=C1CC2c3ccccc3CCN2C2CCCC12

Procedure:
A mixture of 16.7 g (0.1 mole) of 3,4-dihydroisoquinoline hydrochloride and 27.0 g (0.02 mole) of 1-cyclopenten-1-yl methyl ketone in 22 ml of ethanol is refluxed overnight then evaporated to dryness. The remaining solid is dissolved in water and washed with ether. The aqueous layer is made basic with concentrated ammonium hydroxide solution with stirring. Upon the formation of an oil, ice is added to the mixture after which a solid is formed. The solid material is washed with water, dried overnight in a vacuum oven, and recrystallized from hexane to give 1,2,3,3a,5,6,10b,11,12,12 a-decahydrobenzo[a]cyclopenta[f]quinolizin-12-one, M.P. 101°-102.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].C1C(=O)N([I:17])C(=O)C1>CC(O)=O>[Cl:1][C:2]1[C:8]([F:9])=[CH:7][C:6]([I:17])=[C:4]([CH:3]=1)[NH2:5]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(F)cc1I
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-chloro-4-fluoroaniline (12.9 g, 88.9 mmol) and NIS (22.0 g, 97.8 mmol) in AcOH (90 mL) is stirred at RT for 1.5 h. After completion, the reaction mixture is quenched by H2O, DCM is added and the organic layer is washed with brine, dried over MgSO4 and evaporated in vacuo. Silica gel flash chromatography of the residue affords 5-chloro-4-fluoro-2-iodoaniline as a colorless powder; HPLC: AtRet=4.75 min; 1HNMR (CDCl3) 7.40 (d, 1H), 6.75 (d, 1H), 4.00 (bs, 2H).
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O1CCCC1>[CH2:4]([N:11]1[CH2:16][CH2:15][C:14]([CH3:1])([OH:17])[CH2:13][CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(O)CCN(Cc2ccccc2)CC1
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere, methylmagnesium bromide (3.0M solution in diethyl ether, 10.8 mL) was diluted with tetrahydrofuran (110 mL) with cooling on an ice bath. To the solution, was added dropwise a solution of 1-benzyl-4-piperidinone (5.6 g) in tetrahydrofuran (40 mL), and the mixture was stirred for 1 hr.
Reaction SMILES: [CH2:1]([C:3]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20]O)=[CH:15][CH:14]=2)[C:6]2=[N:7][C:8]([CH3:11])=[CH:9][CH:10]=[C:5]2[N:4]=1)[CH3:2].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P([N:67]=[N+:68]=[N-:69])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[CH2:1]([C:3]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:67]=[N+:68]=[N-:69])=[CH:15][CH:14]=2)[C:6]2=[N:7][C:8]([CH3:11])=[CH:9][CH:10]=[C:5]2[N:4]=1)[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCc1nc2ccc(C)nc2n1-c1ccc(CCO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1nc2ccc(C)nc2n1-c1ccc(CCN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 29.7 %

Procedure:
A mixture of 2-[4-(2-ethyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol (step 4, 217 mg, 0.77 mmol) in THF (20 mL) was added diethyl azodicarboxylate (DEAD) (0.3 mL, 1.5 mmol), triphenylphosphine (380 mg, 1.5 mmol) and diphenylphosphoryl azide (DPPA) (0.4 mL, 1.5 mmol). The mixture was stirred at room temperature for 4.5 h. After removal of solvent, the residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gladient elution from 1:1 to 1:2) to afford 70 mg (30%) of the title compound as a brown oil: 1H-NMR (CDCl3) δ 7.90 (1H, d, J=8.1 Hz), 7.34-7.44 (4H, m), 7.08 (1H, d, J=8.1 Hz), 3.60 (2H, t, J=7.1 Hz), 3.00 (2H, t, J=7.1 Hz), 2.80 (2H, q, J=7.5 Hz), 2.57 (3H, s), 1.35 (3H, t, J=7.5 Hz).
Reaction SMILES: C(O)(C(F)(F)F)=O.Cl[C:9]1[N:17]=[C:16]([N:18]2[C:22]3[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=3[N:20]=[CH:19]2)[N:15]=[C:14]2[C:10]=1[N:11]([CH3:36])[C:12](=[O:35])[N:13]2[C@H:28]1[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]1.[CH2:37]1[C@H:41]([F:42])[CH2:40][NH:39][CH2:38]1.Cl>>[F:27][C:24]1[CH:25]=[CH:26][C:21]2[N:20]=[CH:19][N:18]([C:16]3[N:15]=[C:14]4[C:10]([N:11]([CH3:36])[C:12](=[O:35])[N:13]4[C@H:28]4[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]4)=[C:9]([N:39]4[CH2:38][CH2:37][C@H:41]([F:42])[CH2:40]4)[N:17]=3)[C:22]=2[CH:23]=1
Reactant: Cn1c(=O)n([C@H]2CC[C@H](O)CC2)c2nc(-n3cnc4ccc(F)cc43)nc(Cl)c21
Reactant: F[C@H]1CCNC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)n([C@H]2CC[C@H](O)CC2)c2nc(-n3cnc4ccc(F)cc43)nc(N3CC[C@H](F)C3)c21

Procedure:
Light brown solid. TFA salt. Synthesized from 6-chloro-2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-9-(trans-4-hydroxycyclohexyl)-7-methyl-7H-purin-8(9H)-one and S-(+)-3-fluoropyrrolidine hydrochloride, following the general procedure for displacement reactions of 6-chloropurinones with aliphatic amines. 1H NMR (300 MHz, CDCl3+CD3OD) δ, ppm: 8.99 (s, 1H), 8.27 (dd, 1H), 7.74 (dd, 1H), 7.15 (td, 1H), 5.47 (d, J=52.4 Hz, 1H), 4.51-4.42 (m, 1H), 4.19-3.83 (overlap of 5H), 3.65 (s, 3H), 2.68-2.42 (overlap of 3H), 2.29-2.03 (overlap of 3H), 1.97-1.90 (m, 2H), 1.62-1.49 (m, 2H); MS (EI) m/z 470.3 (MH)+.
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15]4)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][C:26]=1[C:35]([O:37][CH3:38])=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[C:1]1([C:7]2[NH:11][C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[CH:18]=[C:17]([O:22][CH2:24][C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][C:26]=3[C:35]([O:37][CH3:38])=[O:36])[CH:16]=[CH:15]4)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc2cc(-c3ccc(-c4ccccc4)[nH]3)ccc2c1
Reactant: COC(=O)c1ccc(CBr)c(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(COc2ccc3cc(-c4ccc(-c5ccccc5)[nH]4)ccc3c2)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.3 %

Procedure:
A mixture of 6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthol (200 mg, 0.701 mmol), prepared in step 5 of Example 1, dimethyl 4-(bromomethyl)isophthalate (241 mg, 0.841 mmol) and cesium carbonate (1.14 g, 3.50 mmol) in 50 mL of acetone was stirred at room temperature for 1.5 h. The reaction was concentrated under reduced pressure to remove the acetone. The residue was partitioned between methylene chloride and water. The aqueous layer was separated and extracted two times with methylene chloride. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to give a yellow solid. Purification of the solid on a Biotage Horizon™ system with a KP-SIL Flash 40+M column using a gradient of 85% methylene chloride in hexane to 100% methylene chloride as the eluent gave dimethyl 4-({[6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)isophthalate (280 mg, 81%) as a yellow solid, mp 203–205° C. Elemental Analysis for C31H25NO5.0.10 CH2Cl2 Calc'd: C, 74.70; H, 5.08; N, 2.80. Found: C, 74.24; H, 4.80; N, 2.76.
Reaction SMILES: [H-].[Na+].[N:3]1[N:7]2[CH2:8][CH2:9][CH2:10][NH:11][C:6]2=[CH:5][CH:4]=1.CI.[C:14](OCC)(=O)C>CN(C)C=O>[CH3:14][N:11]1[CH2:10][CH2:9][CH2:8][N:7]2[N:3]=[CH:4][CH:5]=[C:6]12
Reactant: c1cc2n(n1)CCCN2
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCCn2nccc21
Reaction time: 1.5 h

Procedure:
To a suspension of 62% sodium hydride (1.41 g) in N,N-dimethylformamide (30 ml) was added 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (4.5 g) under ice-cooling. To this solution was added dropwise methyl iodide (2.27 ml) under ice-cooling, and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was poured into ethyl acetate (50 ml), and the resulting precipitate was filtered off. The filtrate was evaporated to give 4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (5.05 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@:9]([CH3:16])([CH:11]([O:14][CH3:15])[O:12][CH3:13])[C@@H:8]3[O:17][C@@H:7]3[C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH2:27][C:28]2[N:29]=[N:30][N:31]([CH3:33])[N:32]=2)=[CH:22][CH:21]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@:9]([CH3:16])([CH:11]([O:14][CH3:15])[O:12][CH3:13])[C@H:8]([OH:17])[C@@H:7]([N:26]([C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)[CH2:27][C:28]3[N:29]=[N:30][N:31]([CH3:33])[N:32]=3)[C:6]=2[CH:18]=1
Reactant: COC(OC)[C@]1(C)Oc2ccc(Br)cc2[C@H]2O[C@H]21
Reactant: Cn1nnc(CNc2ccc(Cl)cc2)n1
Product: COC(OC)[C@]1(C)Oc2ccc(Br)cc2[C@H](N(Cc2nnn(C)n2)c2ccc(Cl)cc2)[C@H]1O
Yield: 41.4 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using (2R,3R,4R)-6-bromo-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran (232 mg, 0.74 mmol) and N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (164 mg, 0.74 mmol). The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=3:1), to give desired compound (165 mg, yield: 41%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=1.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12]>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][C:11](=[O:12])[O:13][CH2:14][CH3:15])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Cl)nnc1N
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nnc(Cl)cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A 100 mL flask was charged with 6-chloro-4-methylpyridazin-3-amine (700 mg, 4.88 mmol) and pyridine (20 mL) then ethyl chloroformate (0.421 mL, 4.39 mmol) was added portionwise. The reaction mixture was stirred for 1 h at 0° C. The reaction mixture was then concentrated and partitioned between ammonium chloride and DCM. The aqueous layer was extracted with DCM (2×). The organic layers were combined and washed with brine (1×), eluted through a phase separator and concentrated to afford ethyl (6-chloro-4-methylpyridazin-3-yl)carbamate (549 mg, 49.6% yield).
Reaction SMILES: N[C:2]1[N:3]=[C:4]([O:11][CH3:12])[C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1.N([O-])=O.[Na+].C(Cl)(Cl)Cl.[FH:21].N1C=CC=CC=1>>[F:21][C:2]1[N:3]=[C:4]([O:11][CH3:12])[C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1
Reactant: COc1nc(N)cnc1C(N)=O
Reactant: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1nc(F)cnc1C(N)=O
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
In a nitrogen atmosphere, 0.5 g of 5-amino-3-methoxy-2-pyrazinecarboxamide is dissolved in 9 mL of 70% pyridine hydrofluoride under ice-cooling. Then, 0.23 g of sodium nitrite is added thereto at −70° C., and the resulting solution is heated to a temperature of −10° C. in 30 minutes. Further, the solution is stirred at ambient temperature for 30 minutes. A mixture of 30 mL of ice water and 100 mL of chloroform is added thereto and the resulting mixture is separated into layers. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue thus obtained is purified by column chromatography (eluent: chloroform:methanol =10:1) to obtain 0.37 q of 5-fluoro-3-methoxy-2-pyrazinecarboxamide.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:17])=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].[C:18](Cl)(Cl)=[S:19]>O1CCOCC1.O>[Cl:17][C:3]1[C:2]([N:1]=[C:18]=[S:19])=[C:15]([Cl:16])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: S=C(Cl)Cl
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N)c1Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reaction time: 8 h

Procedure:
A mixture of N-(3-amino-2,4-dichloro-benzyl)-2,2-dimethyl-propionamide (0.95 g, 3.4 mmol) in 4.0 mL dioxane is added to thiophosgene (0.45 mL, 5.8 mmol) in 2.5 mL water. The mixture is stirred overnight, extracted with DCM and the organic phase is washed with 5% aq NaHCO3 solution and water and dried with Na2SO4. After filtration and concentration, the crude product is diluted with DCM, filtered through a pad of silica gel and concentrated.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.N1C=CC=CC=1.Cl>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:19][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:1][CH2:2][C@@H:3]2[CH2:4][CH2:5][C:6](=[O:8])[O:7]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=C1CC[C@@H](CO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCC(=O)O2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.8 %

Procedure:
To a solution of (S)-5-(hydroxymethyl)dihydrofuran-2(3H)-one (25.97 g, 223.66 mmol) in THF (125 mL) were added p-toluenesulfonyl chloride (44.8 g, 234.84 mmol), pyridine (45.2 mL, 559.14 mmol) and DMAP (30.1 g, 246.02 mmol) at 0° C., and the mixture was stirred at room temperature for 4 hr. The reaction mixture was poured into ice water (400 mL), and the pH of the mixture was adjusted to 3 with 6N hydrochloric acid. Then, the mixture was extracted with ethyl acetate (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The crystals were collected by filtration, and washed with IPE/hexane to give (S)-(5-oxotetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate (51.81 g, 192 mmol, 86%) as a white powder.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([NH:30]C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl>CO.C(OCC)(=O)C>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([NH2:30])[CH2:28][CH2:29]2)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)N(CCCN2CCC(NC(=O)OC(C)(C)C)CC2)c2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(C(=O)N(CCCN2CCC(N)CC2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 121.8 %

Procedure:
The compound obtained in Example 193 (4.08 g, 7.34 mmol) was dissolved in methanol (20 mL). To the solution was added a solution of 4N-hydrogen chloride in ethyl acetate (40 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and to the concentrate was added diethyl ether. The resulting precipitates were collected by filtration, washed with diethyl ether, and dried under reduced pressure to give the titled compound (4.07 g) as white amorphous substance.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10]([S:13]([CH3:15])=O)[N:9]=[C:8]([NH2:16])[N:7]=1.SC[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10]([S:13][CH2:15][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:9]=[C:8]([NH2:16])[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Reactant: SCCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: Nc1nc(SCCc2ccccn2)c(I)c(-c2ccco2)n1

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, 2-mercaptoethylpyridine and DBU in dioxane. ES-MS m/e (%): 425 (M+H+, 100).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:18]=[C:19]([C:21]([O-])=[O:22])[S:20][C:13]=12.[Li+]>>[N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:21]([C:19]2[S:20][C:13]3[C:14](=[N:15][CH:16]=[CH:17][C:12]=3[Cl:11])[CH:18]=2)=[O:22])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: NCCCN1CCOCC1
Agent: [Li+]
Product: O=C(NCCCN1CCOCC1)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from 3-morpholin-4-ylpropylamine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 340/342 (MH+); HPLC Rf: 3.45 min.; HPLC purity: 89%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:26])=[C:4]([C:22]([F:25])=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:18]2[CH:17]=[N:16][C:15]([C:19]([OH:21])=O)=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.[CH2:27]([O:34][NH2:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][NH:35][C:19]([C:15]1[N:16]=[CH:17][C:18]2[N:6]([CH2:5][C:4]3[C:22]([F:25])=[CH:23][CH:24]=[C:2]([Cl:1])[C:3]=3[F:26])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:21])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)c1cc2c3ccccc3n(Cc3c(F)ccc(Cl)c3F)c2cn1
Product: O=C(NOCc1ccccc1)c1cc2c3ccccc3n(Cc3c(F)ccc(Cl)c3F)c2cn1

Procedure:
The title compound is prepared by coupling of 9-(3-chloro-2,6-difluorobenzyl)-9H-β-carboline-3-carboxylic acid and O-benzyl hydroxyamine under conditions similar to those provided in step (b) of example 7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].[NH2:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16](Cl)[N:15]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[NH2:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]([O:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]=2[Cl:1])[N:15]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1nc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 76.5 %

Procedure:
12.5 g of 2-chloro-4-trifluoromethylphenol, 10.0 g of 2-amino-3-nitro-6-chloropyridine, 10.5 g of potassium carbonate, and 200 ml of dimethyl sulfoxide were charged in a flask, and the mixture was allowed to react at 30° C. for twenty-four hours while stirring. After completion of the reaction, the reaction product was poured into water, followed by extracting with methylene chloride. The extracted phase was washed with water and dried, and the methylene chloride was distilled off under reduced pressure to obtain 14.7 g of a titled compound having a melting point of 80° to 84° C.