Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH3:13])[N:10]([CH:14]([CH2:16]O)[CH3:15])[C:9]2=[O:18])=[CH:4][CH:3]=1.O=S(Cl)[Cl:21]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH3:13])[N:10]([CH:14]([CH3:15])[CH2:16][Cl:21])[C:9]2=[O:18])=[CH:4][CH:3]=1
Reactant: CC(CO)N1C(=O)N(c2ccc(Cl)cc2)CC1C
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(CCl)N1C(=O)N(c2ccc(Cl)cc2)CC1C
Temperature: 0 °C
Yield: 94 %

Procedure:
To a solution of 16 g. of 1-(p-chlorophenyl)-3-(1-(hydroxymethyl)ethyl)-4-methyl-2-imidazolidinone in 400 ml. of anhydrous chloroform, 14.5 g. of SOCl2 is added dropwise with stirring while the temperature is maintained at 0° C. The mixture is then refluxed for 45 minutes, concentrated under vacuum and taken up with benzene, then evaporated to dryness again, yielding 15.1 grams (94%) of the title compound, m.p. 70°-72° C. (from diisopropyl ether). The corresponding m-chlorophenyl-substituted compound is prepared in the same way. Yield 97%, b.p. 200° C./0.5 mm Hg.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH:10]([OH:17])[CH2:11][NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=[C:4]([C:5]#[N:6])[C:3]=1[NH2:18].CCCCC.[OH2:24]>[OH-].[Na+].CCO>[NH2:18][C:3]1[C:2]([Br:1])=[CH:9][C:8]([CH:10]([OH:17])[CH2:11][NH:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:7][C:4]=1[C:5]([NH2:6])=[O:24]
Reactant: CC(C)(C)NCC(O)c1cc(Br)c(N)c(C#N)c1
Reactant: O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCCCC
Product: CC(C)(C)NCC(O)c1cc(Br)c(N)c(C(N)=O)c1

Procedure:
A mixture containing 1.02 g of 3-bromo-5-[2-(tert-butylamino)-1-hydroxyethyl]anthranilonitrile in 25 ml of H2O, 5 ml of 50% NaOH and 30 ml of EtOH is stirred and heated at 55°-65° C. under N2 atmosphere for 1.25 hours. The mixture is evaporated to remove EtOH and extracted with CHCl3. The CHCl3 extract is washed with 25 ml of 2% NaOH, dried (MgSO4) and evaporated to dryness to afford 0.74 g. This solid is stirred with pentane and filtered to afford 0.6 g, mp 135°-145° C., of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.O.O.[Sn](Cl)Cl.Cl>C(O)C>[NH2:12][C:10]1[CH:9]=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([Cl:1])[CH:11]=1
Reactant: O=[N+]([O-])c1cc(Cl)c2cccnc2c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)c2cccnc2c1
Temperature: 25 °C
Yield: 42 %

Procedure:
5-Chloro-7-nitroquinoline (D82) (50 mg, 0.24 mmol) was treated with tin dichloride dihydrate (216 mg, 0.96 mmol) and conc. hydrochloric acid (2 ml) in ethanol (5 ml) at 70° C. for 4 h. After cooling to room temperature and the ethanol removed in vacuo then the residue was dissolved in water and neutralised with potassium carbonate. This was then extracted with EtOAc which was dried over MgSO4 and concentrated in vacuo to give the title compound as a brown solid (18 mg). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.78 (d, 1H), 8.39 (d, 1H), 7.25 (dd, 1H), 7.18 (d, 1H), 7.11 (d, 1H).
Reaction SMILES: C(O[CH:5]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)(=O)C.C(N(CC)CC)C.[H][H]>CN(C)C=O.[OH-].[Pd+2].[OH-]>[C:33]([C:30]1[CH:31]=[CH:32][C:27]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[CH:8][CH:7]=2)=[CH:28][CH:29]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: COc1cc2nccc(Oc3ccc(C(OC(C)=O)c4ccc(C(C)(C)C)cc4)cc3)c2cc1OC
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(Cc4ccc(C(C)(C)C)cc4)cc3)c2cc1OC
Yield: 78.6 %

Procedure:
(4-Tert-butylphenyl)-[4-(6,7-dimethoxy-4-quinolyloxy)phenyl]-methyl acetate (Compound 31) (26 mg) was dissolved in N,N-dimethylformamide (3 ml) to prepare a solution. Triethylamine (0.5 ml) and 20% palladium hydroxide (200 mg) were then added to the solution, and the mixture was stirred in a hydrogen atmosphere at room temperature for 2 hr. The reaction solution was filtered, water and ethyl acetate were added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and was dried over sodium sulfate. The solvent was removed by evaporation under the reduced pressure to give the title compound (18 mg, yield 79%).
Reaction SMILES: [S:1]1[C:5]([C:6]([O:8]C)=O)=[CH:4][N:3]=[CH:2]1.[C:10](#[N:12])[CH3:11].[H-].[Na+:14].C(OC)(C)(C)C>C1COCC1>[C:10]([CH:11]=[C:6]([C:5]1[S:1][CH:2]=[N:3][CH:4]=1)[O-:8])#[N:12].[Na+:14]
Reactant: COC(=O)c1cncs1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: N#CC=C([O-])c1cncs1
Reaction time: 0.5 h

Procedure:
A solution of 1.5 g (10.5 mmol) of methyl 1,3-thiazole-5-carboxylate and 430 mg (10.8 mmol) of acetonitrile in 15 ml of THF was added dropwise to a suspension of 419 mg of sodium hydride (60% strength suspension in mineral oil) in 16 ml of THF which was heated under reflux. The reaction mixture was heated under reflux for 20 h. After cooling, 50 ml of methyl tert-butyl ether were added and the mixture was stirred for 30 minutes. The resulting precipitate was filtered off with suction through a frit and dried under oil pump vacuum. This gave 1.71 g (94% of theory) of the title compound which was combined with the product (3.48 g, 95% of theory) from a second batch starting with 3.0 g (21 mmol) of methyl 1,3-thiazole-5-carboxylate. This material was used without further characterization for the next step.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.[CH:20]1([C:25]2[NH:26][C:27]3[C:33]([C:34](OC)=[O:35])=[CH:32][CH:31]=[C:30]([O:38][CH3:39])[C:28]=3[N:29]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1>O1CCCC1>[CH:20]1([C:25]2[NH:26][C:27]3[C:33]([C:34](=[O:35])[CH2:19][C:16]4[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=4)=[CH:32][CH:31]=[C:30]([O:38][CH3:39])[C:28]=3[N:29]=2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: Cc1ccncc1
Reactant: COC(=O)c1ccc(OC)c2nc(C3CCCC3)[nH]c12
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2ccncc2)c2[nH]c(C3CCCC3)nc12
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of diisopropylamine (0.47 ml) in tetrahydrofuran (6 ml), cooled to −10° C., was treated dropwise, with a solution of butyl lithium in hexanes (1.2 ml, 2.5M). The resulting solution was stirred for 10 minutes, then cooled to −78° C. and then treated dropwise with a solution of 4-picoline (0.29 ml) in tetrahydrofuran (1 ml). This solution was stirred for 30 minutes then treated with a solution of methyl 2-cyclopentyl-7-methoxy-3H-benzimidazole-4-carboxylate [0.274 g, Reference Example 3(t)] in tetrahydrofuran (2 ml). The cold bath was removed and the reaction mixture stirred for 15 minutes at ambient temperature. The mixture was quenched with water, then diluted with ethyl acetate. The organic phase was separated then washed with brine, then dried over magnesium sulphate and then evaporated. The residue was subjected to flash chromatography on silica, eluting with a mixture of methanol and dichloromethane (8:92,v/v), to give the title compound (0.126 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([C:15]([OH:17])=O)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[NH2:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[OH:25]>>[OH:25][C@@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@H:19]1[NH:18][C:15]([C:5]1[CH:4]=[N:3][C:2]([Br:1])=[C:7]([C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[N:6]=1)=[O:17]
Reactant: O=C(O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1
Reactant: N[C@@H]1CCCC[C@H]1O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 19e, using 5-bromo-6-(4-chloro-phenyl)-pyrazine-2-carboxylic acid, and (1R,2R)-2-amino-cyclohexanol (commercially available) as starting materials to give the title compound as a light yellow solid, MS (ISP): 410.0, 412.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.C(OC([N:28]1[CH2:33][CH2:32][C:31]2([CH2:38][CH2:37][C:36]3[CH:39]=[C:40]([C:43](O)=O)[CH:41]=[CH:42][C:35]=3[O:34]2)[CH2:30][CH2:29]1)=O)(C)(C)C>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:43]([C:40]3[CH:39]=[C:36]4[C:35](=[CH:42][CH:41]=3)[O:34][C:31]3([CH2:30][CH2:29][NH:28][CH2:33][CH2:32]3)[CH2:38][CH2:37]4)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: CC(C)(C)OC(=O)N1CCC2(CCc3cc(C(=O)O)ccc3O2)CC1
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc5c(c4)CCC4(CCNCC4)O5)nc23)[C@H]2C=C[C@@H]1C2
Temperature: 50 °C

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50 mg, 0.148 mmol) and N-tert-butoxycarbonyl-6-carboxy-3,4-dihydrospiro[2H-1-benzopyran-2,4′-piperidine] (75.4 mg, 0.228 mmol) were reacted. The crude reaction was concentrated, then taken up into 4N HCl/dioxane and heated at 50° C. for 4 hours. The reaction mixture was then concentrated and chromatographed on Gilson HPLC 0-45% CH3CN/H2O. The desired fractions were neutralized with conc. bicarb. Attempted extraction into DCM and EtOAc failed but a solid formed in the sep funnel and was filtered. This solid was 7 mg (6%) of the title compound. mp: >250° C., 1H NMR (300 MHz, DMSO-d6): 13.12 (s, 1H), 7.92 (s, 2H), 7.88 (d, 1H), 7.76 (s, 1H), 7.24 (s, 1H), 7.15 (d, J=8 Hz, 1H), 6.98 (d, J=8 Hz, 1H), 6.38 (s, 2H), 5.15 (t, J=8 Hz, 1H), 3.23 (m, 2H), 3.14 (m, 2H), 2.88 (m, 3H), 2.78 (s, 1H), 2.62 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.96-1.85 (m, 4H), 1.39 (d, J=8 Hz, 1H). MS: 505 (M+H), HPLC: 1.96 min (G method).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH3:13][Si:14]([C:17]#[C:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([N:1]2[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:17]([Si:14]([CH3:16])([CH3:15])[CH3:13])[N:3]=[N:2]2)=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: [N-]=[N+]=Nc1ccc([N+](=O)[O-])cc1
Reactant: C[Si](C)(C)C#CN1CCOCC1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)c1nnn(-c2ccc([N+](=O)[O-])cc2)c1N1CCOCC1
Temperature: 60 °C

Procedure:
A mixture of 1-azido-4-nitrobenzene (0.5 g, 3.0 mmol), 4-((trimethylsilyl)ethynyl)morpholine (1.0 g, 9.0 mmol) and toluene (10 mL) was heated in a sealed tube to 60° C. for 24 h. The reaction mixture was concentrated in vacuo to give 4-(1-(4-nitrophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazol-5-yl)morpholine which was further reduced following procedure D to afford 4-(5-morpholino-4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)aniline.
Reaction SMILES: [Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C1([C:28]2[C:36]3[C:31](=[CH:32][C:33]([C:37]([O:39]C)=[O:38])=[CH:34][CH:35]=3)[NH:30][CH:29]=2)CCCCC1>C(Cl)(Cl)Cl.C1COCC1>[NH:30]1[C:31]2[C:36](=[CH:35][CH:34]=[C:33]([C:37]([OH:39])=[O:38])[CH:32]=2)[CH:28]=[CH:29]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Agent: [Br-]
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C(O)c1ccc2cc[nH]c2c1
Temperature: 2.5 °C
Reaction time: 2.5 h

Procedure:
Freshly recrystallized pyridinium tribromide (recrystallization from hot AcOH (5 mL per 1 g), rinsed with cold AcOH and dried under high vacuum over KOH) was added in portions (over 10 min.) to a stirring solution of methyl 3-cyclohexyl-1H-indole-6-carboxylate (60 g, 233 mmol) (prepared using procedures describe in WO2004/065367) in CHCl3/THF (1:1, 1.25 L) at 2° C. The reaction solution was stirred at 0-5° C. for 2.5 h, and washed with sat. aq. NaHSO3 (1 L), 1 N HCl (1 L) and brine (1 L). The organic layer was dried (MgSO4) and concentrated. The resulting red oil was diluted with Et2O and concentrated. The resulting pink solid was dissolved into Et2O (200 mL) treated with hexanes (300 mL) and partially concentrated. The solids were collected by filtration and rinsed with hexanes. The mother liquor was concentrated to dryness and the procedure repeated. The solids were combined to yield 1H-indole-6-carboxylic acid, 2-bromo-3-cyclohexyl-, methyl ester (64 g, 190 mmol, 82%) as a fluffy pink solid, which was used without further purification. 1HNMR (300 MHz, CDCl3) δ 8.47 (br s, 1H), 8.03 (d, J=1.4 Hz, 1H), 7.74 (dd, J=1.4, 8.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 3.92 (s, 3H), 2.82 (tt, J=3.7, 11.7 Hz, 1H), 1.98-1.72 (m, 7H), 1.50-1.27 (m, 3H). 13CNMR (75 MHz, CDCl3) δ 168.2, 135.6, 130.2, 123.1, 120.8, 120.3, 118.7, 112.8, 110.7, 52.1, 37.0, 32.2(2), 27.0(2), 26.1. LCMS: m/e 334 (M−H)−, ret time 3.34 min, column A, 4 minute gradient.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][CH:27]([CH3:32])[CH2:28][C:29](O)=[O:30]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:29](=[O:30])[CH2:28][CH:27]([CH3:32])[CH3:26])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: CC(C)CC(=O)O
Agent: Cl
Product: CC(C)CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, light yellow solid (9.1 mg, 31.4%), MS (ISP) m/z=415.5[(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.07 mmol) and 3-methylbutanoic acid
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:12]2[CH:18]=[CH:17][S:16][C:13]=2[NH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC([O-])(C)C.[K+]>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:12]2[CH:18]=[CH:17][S:16][C:13]=2[N:14]([S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])[CH:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCc1c[nH]c2sccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCc1cn(S(=O)(=O)c2ccccc2)c2sccc12
Reaction time: 8 h

Procedure:
A mixture of N-(t-butoxycarbonyl)-2-(6H-thieno[2,3-b]pyrrol-4-yl)ethylamine (54 mg, 0.2 mmol), phenylsulfonyl chloride (70 mg, 0.22 mmol) and KOt-Bu (0.22 mL 1 M solution in THF, 0.22 mmol) in THF is shaken at ambient temperatures for 8 h and concentrated in vacuo. The resultant residue is dissolved in THF, treated with 4N HCl in dioxane (2 mL) shaken at room temperature for 16 h and concentrated in vacuo. This residue is dissolved in a mixture of DMSO, methanol and water and purified by preparative HPLC1, to afford the title product, [M+H]307, retention time (RT) 1.53 min. 1 Gilson Preparative HPLC conditions: Gilson Preparative HPLC system; YMC Pro C18, 20 mm×50 mm ID, 5 uM column; 2 mL injection; Solvent A: 0.02% TFA/water; Solvent B: 0.02% TFA/acetonitrile; Gradient: Time 0: 95% A; 2 min: 95% A; 14 min: 10% A, 15 min: 10% A, 16 min: 95% A; Flow rate 22.5 mL/min; Detection: 254 nm DAD.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[CH3:5][O:6][C:7]1[C:11](=[O:12])[N:10]([CH3:13])[CH2:9][C:8]=1[C:14]([OH:16])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:5][O:6][C:7]1[C:11](=[O:12])[N:10]([CH3:13])[CH2:9][C:8]=1[C:14]([NH:4][CH2:1][C:2]#[CH:3])=[O:16]
Reactant: C#CCN
Reactant: COC1=C(C(=O)O)CN(C)C1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: C#CCNC(=O)C1=C(OC)C(=O)N(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a solution of prop-2-yn-1-amine (0.43 mL, 7.7 mmol), 4-methoxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (1.2 g, 7.0 mmol) and PyBOP® (4.01 g, 7.71 mmol) in DMF (25 mL) was added diisopropylethylene amine (3.67 mL, 21.0 mmol) and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated and purified by ISCO chromatography (ethyl acetate/hexane 1-100%, column 40 g cartridge) to afford Intermediate 21 (1.2 g, 82%) as a white paste. HPLC/MS (Method L) RT=0.99 min, [M+1]+ 209.2.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:4]([CH:7]=[C:8]([S:10][CH3:11])[CH:9]=1)[CH:5]=O.Cl.[NH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]1[NH:32][C:31]2[CH:33]=[CH:34][S:35][C:30]=2[C:29](=[O:36])[CH:28]=1>>[Br:1][C:2]1[C:3]([O:12][CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:4]([CH:7]=[C:8]([S:10][CH3:11])[CH:9]=1)[CH2:5][NH:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]1[NH:32][C:31]2[CH:33]=[CH:34][S:35][C:30]=2[C:29](=[O:36])[CH:28]=1
Reactant: NCCCNc1cc(=O)c2sccc2[nH]1
Reactant: CSc1cc(Br)c(OCCc2cccnc2)c(C=O)c1
Agent: Cl
Product: CSc1cc(Br)c(OCCc2cccnc2)c(CNCCCNc2cc(=O)c3sccc3[nH]2)c1

Procedure:
5-{3-[3-Bromo-5-methylsulfanyl-2-(2-pyridin-3-yl-ethoxy)-benzylamino]-propylamino}-4H-thieno[3,2-b]pyridin-7-one was prepared by reductive amination of the aldehyde prepared in Example 2 with amine XVIII following method C, Scheme 1.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:18][CH3:19])[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.[Cl:20]N1C(=O)CCC1=O>C1COCC1.CCOC(C)=O>[CH2:16]([O:15][C:13]([C:10]1[CH:11]=[C:12]2[C:7]([C:6]([Cl:20])=[CH:5][N:4]2[CH:1]2[CH2:2][CH2:3]2)=[C:8]([O:18][CH3:19])[CH:9]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)c1cc(OC)c2ccn(C3CC3)c2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(OC)c2c(Cl)cn(C3CC3)c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a stirred solution of 1.29 g of ethyl 1-cyclopropyl-4-methoxy-1H-indole-6-carboxylate in 13 ml of THF was added 801 mg of N-chlorosuccinimide and the mixture was stirred at 60° C. for 2 hrs. After diluted with EtOAc, the mixture was washed successively with water and saturated brine, dried over Na2SO4, and concentrated. The residue was purified on SiO2 column chromatography to afford 1.03 g of ethyl-3-chloro-1-cyclopropyl-4-(methoxy)-1H-indole-6-carboxylate as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[N:11]=1)[C:6]([OH:8])=O.CC1(C)[O:22][C@H:21]([CH2:23][O:24][C:25]2[C:34]([CH3:35])=[CH:33][C:28]([C:29]([NH:31]O)=[NH:30])=[CH:27][C:26]=2[CH2:36][CH3:37])[CH2:20][O:19]1>>[CH2:36]([C:26]1[CH:27]=[C:28]([C:29]2[N:31]=[C:6]([C:5]3[CH:9]=[C:10]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[N:11]=[C:3]([O:2][CH3:1])[CH:4]=3)[O:8][N:30]=2)[CH:33]=[C:34]([CH3:35])[C:25]=1[O:24][CH2:23][C@@H:21]([OH:22])[CH2:20][OH:19])[CH3:37]
Reactant: COc1cc(C(=O)O)cc(CCC(C)C)n1
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H]1COC(C)(C)O1
Product: CCc1cc(-c2noc(-c3cc(CCC(C)C)nc(OC)c3)n2)cc(C)c1OC[C@@H](O)CO

Procedure:
The title compound is prepared in analogy to Example 1 starting from 2-methoxy-6-(3-methyl-butyl)-isonicotinic acid and (R)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-ethyl-N-hydroxy-5-methyl-benzamidine; LC-MS: tR=1.14 min, [M+H]+=456.16; 1H NMR (CDCl3): δ 1.00 (d, J=6.3 Hz, 6H), 1.33 (t, J=7.5 Hz, 3H), 1.64-1.74 (m, 3H), 2.41 (s, 3H), 2.77 (q, J=7.5 Hz, 2H), 2.81-2.86 (m, 2H), 3.82-3.94 (m, 2H), 3.94-3.98 (m, 2H), 4.03 (s, 3H), 4.14-4.21 (m, 1H), 7.32 (d, J=0.8 Hz, 1H), 7.49 (d, J=0.8 Hz, 1H), 7.88 (s, 1H), 7.89 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[OH:13][S:14]([OH:17])(=[O:16])=[O:15].[CH3:18]O>>[S:14](=[O:15])(=[O:13])([OH:17])[OH:16].[CH3:18][O:11][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=1
Reactant: CO
Reactant: Nc1ccc(CCC(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1ccc(N)cc1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a mixture of 3-(4-amino-phenyl)-propionic acid (1.00 g, 6.05 mmol) in 10 mL of methyl alcohol (MeOH) was added 0.80 mL of conc H2SO4. The resulting mixture was refluxed for 2 h, concentrated down to ca. half volume by distillation and then cooled to 45° C. Methyl tert-butyl ether (MTBE, 15 mL) was added. The mixture was allowed to cool to 0° C. and stirred for 0.5 h. The solid was collected by filtration and washed with 1:4 MeOH/MTBE (2×10 mL), MTBE (3×10 mL) and dried under reduced pressure. The title compound (1.43 g, 85%) was obtained as a white solid. 1H-NMR (DMSO-d6; 400 MHz): δ 8.40-11.0 (br s, 4H), 7.34 (d, 2H, J=8.2 Hz), 7.23 (d, 2H, J=8.2 Hz), 3.57 (s, 3H), 2.86 (t, 2H, J=7.4 Hz), 2.64 (t, 2H, J=7.4 Hz).
Reaction SMILES: [N+:1]([O-])([OH:3])=[O:2].[CH2:5]([O:12][C:13]1[CH:18]=[C:17](/[CH:19]=[CH:20]/[N+:21]([O-:23])=[O:22])[CH:16]=[CH:15][C:14]=1[O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)(=O)C>[CH2:5]([O:12][C:13]1[CH:18]=[C:17](/[CH:19]=[CH:20]/[N+:21]([O-:23])=[O:22])[C:16]([N+:1]([O-:3])=[O:2])=[CH:15][C:14]=1[O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COCCCOc1ccc(/C=C/[N+](=O)[O-])cc1OCc1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COCCCOc1cc([N+](=O)[O-])c(/C=C/[N+](=O)[O-])cc1OCc1ccccc1
Reaction time: 6 h

Procedure:
69% Nitric acid (16 mL, 249 mmol) was added to a liquid mixture of (E)-2-(benzyloxy)-1-(3-methoxypropoxy)-4-(2-nitrovinyl)benzene described in Production Example 32-3 (22.6 g, 65.9 mmol) in acetic acid (150 mL) at room temperature. The liquid mixture was stirred at mom temperature for 6 hours. The reaction liquid was transferred into an ice bath, then the precipitate was collected by filteration and washed with water to quantitatively obtain the title compound.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:13]2[N:14]=[C:15]([CH2:22][O:23][CH2:24][CH3:25])[N:16]([CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])[C:12]=2[C:11]2[CH:10]=[CH:9][C:8]([O:26][CH2:27][CH2:28][NH2:29])=[CH:7][C:6]=2[N:5]=1.C(N(CC)CC)C.[CH:37]([N:40]=[C:41]=[O:42])([CH3:39])[CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:3][C:4]1[C:13]2[N:14]=[C:15]([CH2:22][O:23][CH2:24][CH3:25])[N:16]([CH2:17][C:18]([OH:20])([CH3:21])[CH3:19])[C:12]=2[C:11]2[CH:10]=[CH:9][C:8]([O:26][CH2:27][CH2:28][NH:29][C:41]([NH:40][CH:37]([CH3:39])[CH3:38])=[O:42])=[CH:7][C:6]=2[N:5]=1
Reactant: CC(C)N=C=O
Reactant: CCOCc1nc2c(N)nc3cc(OCCN)ccc3c2n1CC(C)(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3cc(OCCNC(=O)NC(C)C)ccc3c2n1CC(C)(C)O
Reaction time: 0.17 h

Procedure:
1-[4-Amino-7-(2-aminoethoxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol dihydrochloride (prepared as described in Part A of Example 654, 0.466 g, 1.00 mmol), dichloromethane (10 mL), and triethylamine (0.418 mL, 3.0 mmol) were combined. The mixture was stirred for 10 minutes. Isopropyl isocyanate (0.097 mL, 1.00 mmol) was added and the reaction was stirred for 16 hours. Saturated aqueous sodium carbonate (˜8 mL) was added and the layers were separated. The organic layer was concentrated and purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 2-25% CMA in chloroform). The fractions containing product were combined and concentrated. Trituration of the product in dichloromethane, followed by filtration provided 0.319 g of N-(2-{[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)-N′-isopropylurea as an off-white powder.