Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=[O:4])[CH:2]=[CH2:3].[CH3:34][N+:35]([O-:37])=[O:36].C(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[C:30]([O:29][C:27]([CH2:26][CH2:25][C:6]([NH:5][C:1](=[O:4])[CH:2]=[C:3]=[CH:34][N+:35]([O-:37])=[O:36])([CH2:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: C[N+](=O)[O-]
Reactant: C=CC(=O)NC(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)CCC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)CCC(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)NC(=O)C=C=C[N+](=O)[O-]
Temperature: 25 °C
Yield: 93 %

Procedure:
To a stirred solution of acryl amide 2 (2 g 4.2 mmol) in a MeNO2/CHCl3 mixture (1:1; 100 mL), TMG 200 μL) was added and maintained at 25° C. for 24 h. The mixture was then concentrated in vacuo to give a crude solid, which was dissolved in CHCl3 then sequentially washed with dilute aqueous HCl, water, and saturated brine. The organic solution was dried (Na2SO4), filtered, and concentrated in vacuo to give a crude oil, which was column chromatographed (SiO2) eluting with 25% ethyl acetate (EtOAc) in hexane to give (93%) amide 3, as a white solid: 2.1 g; mp 140-141° C.; 1H NMR δ 1.45 (s, 27H, CH3), 1.99 (t, 6H, J=7.5 Hz, CH2CH2CO), 2.24 (t, 6H, J=7.5 Hz, CH2CO), 2.26 (m, 4H, CH2CH2CO), 4.47 (t, 2H, J=6 Hz, O2NCH2), 6.19 (s, 1H, N); 13C NMR δ 22.8 (CH2CO), 27.7 (CH3), 29.6 (CH2CO), 29.8 (CH2CH2CO), 32.4 (O2NCH2CH2), 57.3 (NHC), 74.5 (O2NCH2), 80.2 (CMe3), 170.1 (CONH), 172.4 (CO2); IR 3300, 1710, 1670, 1552 cm−1; MS ESI; 553.3, Calculated 553.3 [M+Na+]. Analysis (C26H46N2O9) Found C, 57.94; H, 8.66; N, 5.20. Calculated C, 58.85; H, 8.74; N, 5.28.
Reaction SMILES: [CH2:1]([C@H:4]1[C:7](=[O:8])[N:6]([Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[C@@H:5]1[C:16]([OH:18])=[O:17])[CH:2]=[CH2:3].CCN=C=NCCCN(C)C.Cl.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]O)=[CH:35][CH:34]=1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][O:17][C:16]([C@@H:5]2[C@@H:4]([CH2:1][CH:2]=[CH2:3])[C:7](=[O:8])[N:6]2[Si:9]([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:10])[CH3:11])=[O:18])=[CH:35][CH:34]=1
Reactant: COc1ccc(CO)cc1
Reactant: C=CC[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=CC[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1C(=O)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
A mixture of 900 mg of crude compound 57 (3.34 mmol) above, EDC hydrochloride salt (1.34 g, 7.01 mmol), DMAP (83 mg, 0.67 mmol) and 4-methoxybenzyl alcohol (1.40 g, 10.1 mmol) in dichloromethane (9 mL) was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was dissolved with ethyl acetate, washed with 5% aqueous KHSO4, water (×2) and brine (×1). The organic layer was dried over Na2SO4, then concentrated to yield the crude 58 with LC purity: 60%. Purification by ISCO silica gel column using 0-20% AcOEt in Hexanes afforded 630 mg of compound 58 (49% yield, 81% purity): 1HNMR (300 MHz, CDCl3): 0.13 (s, 3H), 0.32 (s, 3H), 0.95 (s, 9H), 2.56 (m, 2H), 3.43 (m, 1H), 3.81 (d, J=2.60 Hz, 1H), 3.82 (s, 3H), 4.67 (s, 2H), 5.17 (m, 2H), 5.72 (m, 1H), 6.94 (d, 2H), 7.34 (d, 2H). Anal. C21H31NO4Si, Mol. Wt.: 389.56. Found: ESI-MS: 390.0 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:23])[CH2:19][C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>C(Cl)Cl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:23])[CH2:19][C:20]([O:22][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CN(CC(=O)O)C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(CC(=O)OCC(=O)OC(C)(C)C)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Yield: 86.8 %

Procedure:
A solution of 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)acetic acid (Fmoc-MeGly-OH) (1.94 g, 6.23 mmol) in methylene chloride (25 mL) was mixed with N-ethyldiisopropylamine (DIPEA) (3.26 mL, 18.7 mmol) and tert-butyl 2-bromoacetate (1.82 g, 9.34 mmol) with stirring at room temperature, and the reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was washed with 1 N hydrochloric acid, and the organic layer was extracted with methylene chloride. The resulting organic layer was washed with a saturated aqueous sodium chloride solution and then dried over sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford 2-(tert-butoxy)-2-oxoethyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)acetate (Fmoc-MeGly-HOGly-OtBu) (Compound SP637) (2.30 g, 5.41 mmol, 87%).
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([NH:27][CH2:16][CH2:15][C:2]2([OH:1])[CH2:3][CH2:4][C:5]3([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]3)[CH2:13][CH2:14]2)[CH3:26])=[CH:21][CH:20]=1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Reactant: C[C@H](N)c1ccc(Cl)cc1
Product: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(Cl)cc1
Yield: 63 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-(4-chloro-phenyl)-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 63% of theory; LC (method 1): tR=1.55 min; Mass spectrum (ESI+): m/z=382/384 (Cl) [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[C:10]([C:11]#[N:12])[C:5]2=[CH:4][CH:3]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1>>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[CH:9]=[C:10]([C:11]#[N:12])[C:5]2=[CH:4][CH:3]=1
Reactant: Fc1cccc(CBr)c1
Reactant: N#Cc1c[nH]c2nc(Br)ccc12
Product: N#Cc1cn(Cc2cccc(F)c2)c2nc(Br)ccc12

Procedure:
The title compound was prepared as described in Example 28A using 6-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile in place of 6-bromo-1H-pyrrolo[3,2-b]pyridine-3-carbonitrile and using 1-(bromomethyl)-3-fluorobenzene in place of 4-(bromomethyl)tetrahydro-2H-pyran.
Reaction SMILES: Cl[CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.[C:10]([O-:13])(=[S:12])[CH3:11].[K+].C(OCC)(=O)C>CN(C)C=O>[C:10](=[O:13])([S:12][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1)[CH3:11]
Reactant: CC([O-])=S
Reactant: CC1(CCl)COC(=O)N1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)SCC1(C)COC(=O)N1
Temperature: 90 °C
Yield: 45.7 %

Procedure:
To a solution of 4-(chloromethyl)-4-methyloxazolidin-2-one (10.22 g, 68.32 mmol) in N,N-dimethylformamide (100 ml) was added potassium thioacetate (9.07 g, 79.6 mmol). The suspension was heated to 90° C. for 18 hour, cooled to room temperature, and concentrated in vacuo. The residue was suspended in 400 ml ethyl acetate, washed three times with 100 ml saturated NaHCO3, 100 ml saturated NaCl, dried on MgSO4, and concentrated in vacuo. Flash chromatography (30% to 100% ethyl acetate in hexanes) afforded the title compound as a yellow oil (6.07 g, 31.2 mmol, 46%). 1H NMR (CDCl3, 400 MHz) δ 1.45 (s, 3H), 2.42 (s, 3H), 3.07 (d, J=14.0 Hz, 1H), 3.21 (d, J=14.0 Hz, 1H), 4.08 (d, J=8.8 Hz, 1H), 4.15 (d, J=8.8 Hz, 1H), 5.59 (br s, 1H); LRMS (ESI/APCI) m/z 190 [M+H]+.
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28](S(C)(=O)=O)[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH:37]([CH3:39])[CH3:38]>>[F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28]([CH:37]([CH3:39])[CH3:38])[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)Br
Reactant: C[C@@H]1CCCN1CCCOc1cnc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(OCCCN3CCC[C@H]3C)cnc21
Yield: 26 %

Procedure:
The title compound was synthesized in analogy to example 18 from (4,4-difluoro-piperidin-1-yl)-{1-methanesulfonyl-5-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-1H-pyrrolo[2,3-b]pyridin-2-yl}-methanone (example 20), sodium hydride and 2-bromopropane, to give the desired product as a colorless oil (26%).
Reaction SMILES: C[O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:7]=1[Cl:13].[C:15]12([CH2:25][CH2:26][C:27]3[NH:31][C:30]([CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[N:29][C:28]=3[C:38](O)=[O:39])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2>>[C:15]12([CH2:25][CH2:26][C:27]3[NH:31][C:30]([CH:32]4[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]4)=[N:29][C:28]=3[C:38]([NH:12][C:10]3[CH:9]=[CH:8][C:7]([Cl:13])=[C:6]([CH:5]=[CH:4][C:3]([OH:2])=[O:14])[CH:11]=3)=[O:39])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2
Reactant: O=C(O)c1nc(C2CCCCC2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)C=Cc1cc(N)ccc1Cl
Product: O=C(O)C=Cc1cc(NC(=O)c2nc(C3CCCCC3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)ccc1Cl

Procedure:
3-(5-Amino-2-chloro-phenyl)-acrylic acid methyl ester (prepared in two steps from 2-chloro-5-nitro-benzaldehyde) was reacted with 5-(2-adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) according to the procedure of Example 20, step d. The methyl ester was hydrolysed using the same procedure as in Example 36, step d to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 10.80 (1H, br s), 8.25 (1H, d), 7.96 (1H, d), 7.87 (1H, d), 7.55 (1H, d), 6.44 (1H, d), 2.94 (3H, m), 1.98-1.33 (27H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 55.45; H, 7.91; N, 6.97%. C38H55ClN4O8.5.0 mols H2O requires: C, 55.57; H, 7.98; N, 6.82%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])=[CH:18][CH:17]=1)#[N:2].[OH-:32].[Na+].Cl>CS(C)=O>[NH:25]([C:23]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([C:1]([NH2:2])=[O:32])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:24])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4)cc3)c2cc1C#N
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4)cc3)c2cc1C(N)=O
Reaction time: 2 h

Procedure:
The N-(4-(6-cyano-7-methoxy-4-quinolyl)oxyphenyl)-N′-phenylurea (100 mg) synthesized in Example 37 was dissolved in dimethylsulfoxide (3 ml) at 80° C., and then 5N aqueous sodium hydroxide was added and the mixture was heated and stirred for 2 hours. The reaction solution was neutralized with 1N hydrochloric acid, and the precipitated crystals were filtered out and washed with ethanol to obtain the title compound (60 mg).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:28]=[C:27]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36](=O)[CH3:37])=[CH:32][CH:31]=3)[C:26]([Cl:39])=[C:25]3[C:20]=2[CH2:21][CH2:22][CH2:23][O:24]3)[O:7][C@@H:6]1[CH2:40][O:41][C:42](=[O:44])[CH3:43])(=[O:3])[CH3:2]>C1(C)C=CC=CC=1>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:28]=[C:27]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([CH:36]=[CH2:37])=[CH:32][CH:31]=3)[C:26]([Cl:39])=[C:25]3[C:20]=2[CH2:21][CH2:22][CH2:23][O:24]3)[O:7][C@@H:6]1[CH2:40][O:41][C:42](=[O:44])[CH3:43])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cc(Cc3ccc(C(C)=O)cc3)c(Cl)c3c2CCCO3)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: Cc1ccccc1
Product: C=Cc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c3c(c2Cl)OCCC3)cc1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 57.8 %

Procedure:
To a solution of acetate 178 (480 mg, 0.76 mmol) in Toluene (10 mL) was added p-TsOH monohydrate. The mixture was stirred for 90 min at 120° C. The mixture was cooled to rt and evaporated in vacuo. The residue was purified by silica gel column chromatography to provide the product 179 (270 mg, 58%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[O:11][CH2:12][CH2:13][CH:14]=2)[C:3]=1[C:4]#[N:5].C([O-])=O.[NH4+].[S:19](Cl)(=[O:22])(=[O:21])[NH2:20]>CO.[Pd]>[S:19]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[CH2:14][CH2:13][CH2:12][O:11]2)[C:3]=1[C:4]#[N:5])(=[O:22])(=[O:21])[NH2:20]
Reactant: NS(=O)(=O)Cl
Reactant: N#Cc1c(N)cccc1C1=CCCO1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: N#Cc1c(NS(N)(=O)=O)cccc1C1CCCO1
Reaction time: 0.5 h
Yield: 17.4 %

Procedure:
2-Amino-6-(4,5-dihydrofuran-2-yl)benzonitrile (Example 186b) (0.24 g, 1.28 mmol), 10% Pd/C (0.24 g), and ammonium formate (2.40 g, 38.1 mmol) were refluxed in MeOH (25 mL) under nitrogen for 1.5 h. The insoluble solids were filtered out and discarded, and the solvent was removed under vacuum. The resultant residue was dissolved in EtOAc, washed with saturated Na2CO3 and brine, dried over MgSO4 and concentrated under vacuum. The residue was dissolved in anhydrous DMA (2.0 mL) and was treated with sulfamoyl chloride (0.11 g, 0.97 mmol). The reaction mixture was stirred under nitrogen for 30 minutes, quenched with water (5.0 mL) and extracted with EtOAc (3×50 mL). The combined extract was dried over MgSO4, filtered and concentrated under vacuum. The crude product was purified by silica gel prep-TLC using 65% EtOAc/hexanes to give 45.0 mg (13%) of the title compound as a white solid. 1H NMR (400 MHz, Acetone-d6) δ 1.71-1.78 (m, 1H), 2.02-2.07 (m, 2H), 2.45-2.52 (m, 1H), 3.90-3.95 (m, 1H), 4.10-4.15 (m, 1H), 5.08 (t, J=6.8 Hz, 1H), 6.6-6.8 (broad, 2H), 7.36-7.39 (m, 1H), 7.62-7.63 (m, 2H), 8.22 (broad s, 1H). MS 268 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].C(OC([NH:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][NH:31][CH2:30]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][N:31]([C:3]2[C:2]([Br:1])=[C:11]3[C:6]([C:7](=[O:18])[C:8]([C:15]([OH:17])=[O:16])=[CH:9][N:10]3[CH:12]3[CH2:14][CH2:13]3)=[CH:5][C:4]=2[F:19])[CH2:30]1
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Reactant: O=C(O)c1cn(C2CC2)c2c(Br)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Br)C[C@H]1N
Reaction time: 2.5 h
Yield: 25.6 %

Procedure:
A mixture of 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.19 g), cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.14 g), DBU (0.095 g) and anhydrous acetonitrile (5 ml) was refluxed for 2 hours and then concentrated. The resulting residue was dissolved in chloroform (70 ml), washed with 10% aqueous citric acid solution, water successively, dried over anhydrous sodium sulfate and then concentrated. To the resulting oily residue was added hot methanol to crystallize and cooled. The resulting precipitate was collected by filtration, added to the mixture of concentrated hydrochloric acid-methanol (1:1, 3 ml) and stirred for 2.5 hours under elevated temperature. The reaction mixture was neutralized with concentrated aqueous ammonia, the resulting precipitate was collected by filtration, washed with ice-water and recrystallized from dichloromethane-methanol-concentrated aqueous ammonia (10:10:1) to give the title compound (0.06 g) as yellow prisms, mp 225°-226.5° C. (decompd.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:26])=[O:25])[CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1CC=C(c2c[nH]c3ccc(Cl)cc23)CC1
Agent: Cl
Solvent: CCOCC
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3ccc(Cl)cc23)CC1
Yield: 76.2 %

Procedure:
from 5-chloro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4d, 25 mg, 0.10 mmol) and phenylsulfonyl chloride (26.4 mg, 0.15 mmol). The HCl salt (29.5 mg, 70%) was prepared from the crude product using 1M HCl in ether; m.p 245-8° C., HRMS-FAB+ for C20H19N2O2SCl.HCl, calculated MH+ (--HCl): 387.09341; found: 387.09262.
Reaction SMILES: [C:1](OC)(OC)(OC)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:12]([O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([NH:31][CH2:32][CH2:33][O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:25]([NH2:30])[CH:26]=[N:27]2)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:31]([CH2:32][CH2:33][O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:1]([CH2:2][CH2:3][CH2:4][CH3:5])=[N:30][C:25]=3[CH:26]=[N:27][C:28]=2[CH:29]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cnc2cc(OCc3ccccc3)ccc2c1NCCOc1ccccc1
Reactant: CCCCC(OC)(OC)OC
Product: CCCCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCOc1ccccc1
Temperature: 25 °C
Yield: 84 %

Procedure:
Under a nitrogen atmosphere, trimethyl orthovalerate (2.7 mL, 16 mmol) was added dropwise to a solution of 7-benzyloxy-N4-(2-phenoxyethyl)quinoline-3,4-diamine (3.0 g, 7.8 mmol), prepared as described in Parts A and B of Example 46, in xylenes (30 mL), and the reaction was heated at reflux for 24 hours. The reaction mixture was allowed to cool to ambient temperature; a precipitate formed, which was isolated by filtration, washed with hexanes, and dried for two hours in a vacuum oven to provide 2.96 g of 7-benzyloxy-2-butyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([Cl:28])=[CH:11][C:12]([F:27])=[C:13]([N:15]2[C:24](=[O:25])[N:18]3[CH2:19][CH2:20][CH:21](O)[CH2:22][N:17]3[C:16]2=[O:26])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)[Cl:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([Cl:28])=[CH:11][C:12]([F:27])=[C:13]([N:15]2[C:24](=[O:25])[N:18]3[CH2:19][CH2:20][CH:21]([Cl:30])[CH2:22][N:17]3[C:16]2=[O:26])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=c1n(-c2cc(OCc3ccccc3)c(Cl)cc2F)c(=O)n2n1CCC(O)C2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=c1n(-c2cc(OCc3ccccc3)c(Cl)cc2F)c(=O)n2n1CCC(Cl)C2
Yield: 90.1 %

Procedure:
A mixture of 212 mg (0.523 mmol) of 2-(5-benzyloxy-4-chloro-2-fluorophenyl)-5,6,7,8-tetrahydro-6-hydroxy-1H-[1,2,4]triazolo[1,2-α]pyridazine-1,3(2H)-dione (0.523 mmol), 76 μL of CCl4 (0.784 mmol), and 206 mg of triphenylphosphine (0.784 mmol) in 8 mL of dichloromethane was warmed under reflux for 2h. The mixture was then concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel, eluting with a 1: 1 v:v mixture of ethyl acetate and n-hexane to give 200 mg of the title product of Step C, a compound of the invention, as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 2.3 (m, 2H), 3.5 (m, 2H), 3.9 (m, 2H), 4.4 (m, 1H), 5.1 (s, 2H), 7.0 (d, 1H), 7.4 (m, 6H).
Reaction SMILES: [F:1][C:2]1[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=[CH:13][C:3]=1[C:4](OCCOCCBr)=[O:5].[BH4-].[Li+]>C1COCC1>[F:1][C:2]1[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][OH:5]
Reactant: O=C(OCCOCCBr)c1cccc(N2CCOCC2)c1F
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc(N2CCOCC2)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(2-bromoethoxy)ethyl 2-fluoro-3-morpholinobenzoate (450 mg, 1.2 mmol) in THF (5 mL) was added lithium borohydride (1.5 eq) and the reaction stirred at rt for 18 h. The reaction was quenched by addition of saturated NH4Cl (aq) and extracted with EtOAc. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was purified by column chromatography (petroleum ether: EtOAc) to give (2-fluoro-3-morpholinophenyl)methanol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[N:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[CH3:17][C:18]([S@:21]([NH:23][CH:14]([C:4]1[N:5]=[N:6][C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[C:2]([CH3:1])[CH:3]=1)[CH3:15])=[O:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cc(C)c(OCC(F)(F)F)nn1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)nnc1OCC(F)(F)F
Yield: 56 %

Procedure:
The title compound is prepared in 56% yield (402 mg, brown oil) from 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethanone (500 mg, 2.14 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (388 mg, 3.20 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][N:5]=[C:4]([N:16]=CN(C(C)C)C(C)C)[N:3]=1.[NH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31]>C(O)C>[NH2:16][C:4]1[N:3]=[C:2]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])[C:7]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][N:5]=1
Reactant: CC(C)N(C=Nc1ncc(C#Cc2ccccc2)c(Cl)n1)C(C)C
Reactant: NCCOCCO
Solvent: CCO
Product: Nc1ncc(C#Cc2ccccc2)c(NCCOCCO)n1
Yield: 37.3 %

Procedure:
A mixture of 1.5 g of 4-chloro-2-diisopropylaminomethyleneamino-5-phenylethynylpyrimidine, 20 mL of ethanol and 1.83 g of 2-(2-aminoethoxy)ethanol was refluxed for 18 hours. The tea colored solution was evaporated in vacuo and the residue partitioned between water and dichloromethane. The aqueous layer was washed twice more with dichloromethane and the combined organic extracts washed with water. The organic solution was dried over sodium sulfate, filtered and evaporated in vacuo. The yellow residue obtained was triturated with ether and filtered to give 0.49 g of a yellow solid, 2-amino-4-[2-(2-hydroxyethoxy)ethylamino]-5-phenylethynylpyrimidine. m.p. 128–129° C.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[Al](C)C.[C:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)#[N:18]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[NH:18])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: N#Cc1ccncc1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(NC(=N)c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline hydrochloride (10 g, 48.1 mmol) in toluene (250 ml) at 0° C., trimethylaluminum (2M solution in toluene, 36.1 ml, 72.2 mmol) was added over 10 minutes. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. A solution of 4-cyanopyridine (10 g, 96.2 mmol) in toluene (250 ml) was added over 10 minutes and the mixture was heated to 70° C. After 24 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol and later with methanol. The combined filtrates were concentrated and the resulting yellowish solid was stirred with ethyl acetate and filtered. The pale yellow solid (4.8 g, 36%) was used in the next reaction without further purification. Anal. Calc'd. for C13H14N3SClO2H2O: C, 47.34; H, 4.89; N, 12.74; S, 9.72. Found C, 47.69; H, 4.35; N, 12.77; S, 9.74.