Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[NH:24]/[C:23](=[N:25]\[C:26](=[O:34])[C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)/[N:22]([C@@H:35]4[CH2:40][CH2:39][C@H:38]([C:41](O)=[O:42])[CH2:37][CH2:36]4)[C:21]=3[CH:44]=2)[CH2:12][CH2:11]1)=O)(C)(C)C.S(Cl)(Cl)=O.[CH:49]([NH2:52])([CH3:51])[CH3:50].Cl>C1COCC1>[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[NH:24]/[C:23](=[N:25]\[C:26](=[O:34])[C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)/[N:22]([C@H:35]4[CH2:36][CH2:37][C@@H:38]([C:41](=[O:42])[NH:52][CH:49]([CH3:51])[CH3:50])[CH2:39][CH2:40]4)[C:21]=3[CH:44]=2)[CH2:12][CH2:11]1
Reactant: CC(C)N
Reactant: CC(C)(C)OC(=O)NCC1CCN(Cc2ccc3[nH]/c(=N\C(=O)c4ccc(F)cc4)n([C@H]4CC[C@@H](C(=O)O)CC4)c3c2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCC(CN)CC4)cc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
A suspension of cis-4-((E)-6-((4-((tert-butoxycarbonylamino)methyl)piperidin-1-yl)methyl)-2-(4-fluorobenzoylimino)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylic acid (0.57 g, 0.94 mmol) in thionyl chloride (6.85 mL, 94 mmol) under nitrogen atmosphere was stirred for 30 minutes at RT and then concentrated to dryness. The residue was suspended in THF (9.4 mL) and cooled in an ice bath under nitrogen atmosphere. To the resulting mixture was added isopropylamine (0.804 mL, 9.38 mmol) as a solution in THF (1 mL). The ice bath was removed and the mixture was stirred for 1 hour at RT. The resulting mixture was diluted with water (10 mL) and the aqueous layer extracted with DCM (30 mL). The organic layer was dried over sodium sulfate and concentrated to dryness under high vacuum to afford a tan solid. The solid was suspended in HCl (4.0M in dioxanes) (23.45 mL, 94 mmol) and stirred for 16 hours. The mixture was concentrated, suspended in DCM and washed with aqueous NaHCO3 solution. The organic portion was collected, dried over sodium sulfate, and concentrated to dryness under high vacuum to afford a tan solid. The solid was purified by silica gel chromatography (1-10% MeOH/DCM (1% NH4OH)) to afford (E)-N-(6-((4-(aminomethyl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide (0.3 g, 58.3% yield). MS m/z=549.2 [M+H]. Calc'd for C31H41FN6O2: 548.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:6]=2[CH:16]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[O:31][CH3:32].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=4[O:31][CH3:32])[CH2:14][CH2:15]3)[C:6]=2[CH:16]=1
Reactant: Fc1ccc2onc(C3CCNCC3)c2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3ccc(F)cc23)CC1
Yield: 93.8 %

Procedure:
A mixture of 5-fluoro-3-(-4-piperidinyl)-1,2benzisoxazole (2.2 g, 0.01 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (24g, 0.01 mole), K2CO3 (1.4 g), a few crystals of KI and acetonitrile (100 ml) was stirred and refluxed for 8hours. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate . The ethyl acetate extract was washed (brine), dried (MgSO4) and concentrated to afford 4.0 g of a white solid. The solid was chromatographed on a Waters Prep 500 HPLC utilizing silica gel columns and eluting with methylene chloride/methanol (5%). Concentration of the appropriate fractions afforded 2.0 g (47%) of 1-[4-[3-[4-(5-fluoro-1,2-benzisoxazol-[3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone as a white crystalline solid, m.p.=103°-105° C.
Reaction SMILES: [CH2:1]=[O:2].[CH:3]1([CH:9]=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[OH-].[Na+]>CO>[CH:9]([C:3]1([CH2:1][OH:2])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:10]
Reactant: C=O
Reactant: O=CC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=CC1(CO)CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
Methanol is added to a suspension of 37% formaldehyde solution (69 ml.) and cyclohexanecarboxaldehyde (100 g.; 0.89 mole) to afford a homogeneous solution. The mixture is cooled to 0° C. and a sodium hydroxide solution (1 N; 67 ml.) is added with stirring over the course of 15 minutes. The mixture is allowed to warm to room temperature and is stirred at 25° C. overnight. The solution is then concentrated, diluted with water and extracted with ether. The ether extract is dried, evaporated in vacuo and the residual colorless liquid is distilled to afford 51% of 1-formyl-1-hydroxymethylcyclohexane (65 g.), b.p. 120°-125° C./0.90 mm.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][N:12]3[C:16]([C:17]([O:19]CC)=[O:18])=[C:15]([CH2:22][CH2:23][CH3:24])[N:14]=[C:13]3[CH2:25][CH2:26][CH2:27][CH3:28])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[NH:39][N:38]=[N:37][N:36]=1.[OH-].[Na+]>CO.O>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][N:12]3[C:16]([C:17]([OH:19])=[O:18])=[C:15]([CH2:22][CH2:23][CH3:24])[N:14]=[C:13]3[CH2:25][CH2:26][CH2:27][CH3:28])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[NH:39][N:38]=[N:37][N:36]=1
Reactant: CCCCc1nc(CCC)c(C(=O)OCC)n1Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)c(Br)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCc1nc(CCC)c(C(=O)O)n1Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)c(Br)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product of Example 67 (220 mg) was dissolved in methanol (10 ml). 2N aqueous sodium hydroxide (10 ml) was added followed by methanol (~1 ml) to effect complete dissolution. The mixture was stirred at room temperature for 24 h, diluted with water (20 ml), washed with ether (3×20 ml) and then acidified to pH4 by the dropwise addition of 2N hydrochloric acid. The resultant precipitate was collected, washed with water on the filter pad, and dried in vacuo to give the title compound as a white amorphous solid (0.16 g).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8](O)=[O:9])[N:3]=1.C(Cl)(=O)C([Cl:17])=O.CN(C)C=O>O1CCCC1>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([Cl:17])=[O:9])[N:3]=1
Reactant: CO/N=C(\C(=O)O)c1nsc(N)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)Cl)c1nsc(N)n1
Temperature: 0 °C

Procedure:
In 30.0 ml of tetrahydrofuran (THF), 10.0 g of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetic acid were stirred at -20° C., followed by the dropwise addition of a chlorinating reagent, which had been prepared beforehand by gradually adding 6.97 g of oxalyl chloride at 5° C. to a mixture of 100 ml of THF and 4.0 g of N,N-dimethylformamide (DMF) and then reacting them for 30 minutes. After they were reacted for 5 minutes, the reaction mixture was poured into 250 ml of ice water to precipitate crystals. The crystals were collected by filtration and washed with 100 ml of ice water. The resulting crystals were thereafter suspended in water and the suspension was adjusted to pH 4.0 with a 1M aqueous solution of sodium acetate. The resulting solution was extracted with 250 ml of ethyl acetate. The organic layer was dried over magnesium sulfate, followed by filtration. The filtrate was concentrated and, under reduced pressure, was then dried, whereby the title compound was obtained. Yield: 7.5 g (68.7%). Purity: 98.7 %.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:13]2[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][CH2:15][C:14]2([CH3:22])[CH3:21])[N:3]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:20][C:18]1([CH3:19])[CH2:17][CH2:16][CH2:15][C:14]([CH3:21])([CH3:22])[N:13]1[C:4]1[N:3]=[C:2]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:7]=[C:6]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)[N:5]=1
Reactant: C1CNCCN1
Reactant: CC1(C)CCCC(C)(C)N1c1nc(Cl)cc(N2CCCC2)n1
Product: CC1(C)CCCC(C)(C)N1c1nc(N2CCCC2)cc(N2CCNCC2)n1
Yield: 80.2 %

Procedure:
4-Chloro-2-(2,2,6,6-tetramethyl-1-piperidinyl)-6-pyrrolidinopyrimidine is reacted with piperazine as described in Example 42 to give the title compound in a yield of 80.2%, m.p.: 134°-137° C.
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[CH2:17][CH3:18].C[O:20][B:21](OC)[O:22]C.Cl>C1COCC1>[CH2:17]([C:8]1[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=1[B:21]([OH:22])[OH:20])[CH3:18]
Reactant: CCc1ccc(C(F)(F)F)cc1I
Reactant: COB(OC)OC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCc1ccc(C(F)(F)F)cc1B(O)O
Reaction time: 0.5 h

Procedure:
i-Propylmagnesium chloride (2M sol. in THF, 5.81 mL, 11.6 mmol) was added drop wise to a cooled (−30° C.) solution of 2-iodo-1-ethyl-4-(trifluoromethyl)benzene (3.48 g, 11.6 mmol) in dry THF (30 mL) and the reaction mixture was stirred at the same temperature for 30 min, under argon. After this time, trimethylborate (2.6 mL, 23.2 mmol) was added drop wise and the reaction mixture was stirred at the same temperature for 1.5 h. HCl (1 M, 10 mL) was added and the reaction mixture extracted with EtOAc (3×40 mL). The combined organic layers were dried over sodium sulfate and the solvent was evaporated to obtain the title compound as a white solid, crystallized from hexane (2.46 g, 97%).
Reaction SMILES: [N:1]1C=CC=C(C(N)C)C=1.[CH3:10][N:11]1[C:19]2[C:14](=[C:15]([C:20](=O)[CH3:21])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1.N.CO.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:10][N:11]1[C:19]2[C:14](=[C:15]([CH:20]([NH2:1])[CH3:21])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1
Reactant: CC(=O)c1cccc2c1ccn2C
Reactant: CC(N)c1cccnc1
Agent: N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(N)c1cccc2c1ccn2C
Yield: 48 %

Procedure:
The title compound was prepared by the same procedure for preparing 1-pyridin-3-yl-ethylamine from 1-(1-methyl-1H-indol-4-yl)-ethanone (1.75 g, 10 mmol), 2 M ammonia solution in methyl alcohol (25 mL, 50 mmol, Aldrich), acetic acid (15 mL, J. T. Baker) and sodium cyanoborohydride (2.5 g, 40 mmol, Aldrich). The title compound was purified by column chromatography (silica gel, 2 M ammonia solution in methyl alcohol/ethyl acetate 1/10) in form as light yellow oil in 48% yield (0.83 g, 4.8 mmol).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:8]([O:7][C:5]([CH:4]1[CH2:3][CH2:2][N:1]([S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])[CH2:11][CH2:10]1)=[O:6])[CH3:9]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Product: CCOC(=O)C1CCN(S(=O)(=O)c2ccccc2)CC1
Yield: 78 %

Procedure:
In another preparation, 100 g (0.634 mole) of ethyl isonipecotate and 130.4 g (0.74 mole) of benzenesulfonyl chloride were reacted by the above procedure for 4.5 hr to give the title product in 78% yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][Cl:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]#[N:20].[Cl:21][C:22]1[CH:23]=[C:24]([NH2:35])[CH:25]=[CH:26][C:27]=1[S:28][C:29]1[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][C:27]=1[S:28][C:29]1[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=1)[NH:35][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][Cl:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]#[N:20]
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCCl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1OCCCCl

Procedure:
A 2.0 g (6.43 mmol) portion of 4-chloro-7-(3-chloropropoxy)-6-methoxy-3-quinolinecarbonitrile (Boschelli, Diane H.; Ye, Fei; Wang, Yanong D.; Dutia, Minu; Johnson, Steve L.; Wu, Biqi; Miller, Karen; Powell, Dennis W.; Yaczko, Deanna; Young, Mairead; Tischler, Mark; Arndt, Kim; Discafani, Carolyn; Etienne, Carlo; Gibbons, Jay; Grod, Janet; Lucas, Judy; Weber, Jennifer M.; Boschelli, Frank. J. Med. Chem. 2001, 44, 3965-3977) in 2-ethoxyethanol (20 mL) is heated to 60° C. To this is added 1.7 g (7.10 mmol) of 3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)phenylamine (U.S. Pat. No. 4,973,599) and 0.74 g (6.43 mmol) of pyridine hydrochloride, and the resulting mixture is refluxed for 2 hours. After cooling, the precipitated solid is filtered, washed with aqueous sodium bicarbonate and dried in vacuo to give 2.93 g of 4-{3-chloro-4-[(1-methyl-1H-imidazole-2-yl)sulfanyl]anilino}-7-(3-chloropropoxy)-6-methoxy-3-quinolinecarbonitrile as a tan solid, mp 271-276° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([O:12]C)=O)[C:5]([N+:14]([O-])=O)=[CH:4][C:3]=1[C:17]1[C:18](=[O:28])[N:19]([CH3:27])[C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1>C(O)(=O)C.[Fe]>[F:1][C:2]1[C:3]([C:17]2[C:18](=[O:28])[N:19]([CH3:27])[C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=2)=[CH:4][C:5]2[NH:14][C:10](=[O:12])[CH2:9][O:8][C:6]=2[CH:7]=1
Reactant: COC(=O)COc1cc(F)c(-c2ccc(C(F)(F)F)n(C)c2=O)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)ccc(-c2cc3c(cc2F)OCC(=O)N3)c1=O
Reaction time: 1 h
Yield: 75 %

Procedure:
1.5 g (3.7 mmol) of 3-(2-fluoro-4-methoxycarbonylmethoxy-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2-(1H)-pyridone was dissolved in 50 ml of acetic acid, and 0.64 g (11.5 mmol) of iron powder was added under heating and refluxing, followed by stirring for 1 hour. The reaction solution was subjected to filtration, and the filtrate was distilled off under reduced pressure. The obtained residue was poured into water and extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and then, the obtained residue was purified by silica gel column chromatography to obtain 0.95 g (yield: 80%) of the desired product. Melting point: 216-218° C.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[N:15]2[N:16]=[CH:17][CH:18]=[C:14]2[N:13]=[C:12]([CH3:19])[C:11]=1[CH2:20][CH2:21][Cl:22]>C(Cl)(Cl)Cl>[Cl:1][C:18]1[CH:17]=[N:16][N:15]2[C:10]([Cl:9])=[C:11]([CH2:20][CH2:21][Cl:22])[C:12]([CH3:19])=[N:13][C:14]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1nc2ccnn2c(Cl)c1CCCl
Solvent: ClC(Cl)Cl
Product: Cc1nc2c(Cl)cnn2c(Cl)c1CCCl
Reaction time: 1 h
Yield: 59 %

Procedure:
1.60 g (12 mmoles) of N-chlorosuccinimide were added to a solution of 2.30 g (10 mmoles) of 7-chloro-6-(2-chloroethyl)-5-methylpyrazolo[1.5-a]pyrimidine (prepared as described in Example 3) in 10 ml of chloroform, and the resulting mixture was heated under reflux, with stirring, for one hour. At the end of this time, the reaction mixture was washed with a 2N aqueous solution of potassium hydroxide and then with water, after which it was dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through alumina (eluted with chloroform) and recrystallized from diisopropyl ether to afford 1.56 g (yield 59%) of the title compound as light yellow needles, melting at 115°-117° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:41]=[CH:40][S:39][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:36]=[CH:37][CH:38]=3)[C:21]([NH:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[C:26]([O:34][CH3:35])[CH:25]=3)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:41]=[CH:40][S:39][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:36]=[CH:37][CH:38]=3)[C:21]([NH:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[C:26]([O:34][CH3:35])[CH:25]=3)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(NC(=O)c2cccc(-c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)c2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Nc2nc(-c3cccc(C(=O)Nc4ccc(C(=O)O)c(OC)c4)c3)nc3scnc23)cc1OC
Reaction time: 16 h
Yield: 30.7 %

Procedure:
To a stirred solution of methyl 4-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzamido)-2-methoxybenzoate (100 mg, 0.175 mmol) in 20 mL of THF and 5 mL of methanol was added a solution of 1N NaOH (2 mL) at room temperature. After the addition, the reaction was stirred at this temperature for 16 hours. The solvent was evaporated and the residue was diluted with water and adjusted to pH=2 by HCl (aq.). The mixture was concentrated by rotary evaporation. The residue was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 20% acetonitrile/80% water (0.1% TFA V/V) initially, and then proceed to 70% acetonitrile/30% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give 4-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzamido)-2-methoxybenzoic acid (30 mg, 31%). 1H NMR (300 MHz, DMSO): δ 10.70 (s, 1H), 10.21 (s, 1H), 9.41 (s, 1H), 8.96 (s, 1H), 8.62 (d, 1H, J=7.5 Hz), 8.09 (d, 1H, J=7.8 Hz), 7.84 (s, 1H), 7.77-7.70 (m, 3H), 7.54 (d, 1H, J=8.4 Hz), 6.99 (d, 1H, J=9.0 Hz), 3.84 (s, 3H), 3.81 (s, 3H), 3.74 (s, 3H). LC-MS: 558 [M+H]+, tR=1.54 min. HPLC: 100% at 214 nm, 100% at 254 nm, tR=6.02 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]1[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:5]2=1.[H-].[Na+].[CH3:22]OS(OC)(=O)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]1[N:13]([CH3:22])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:5]2=1
Reactant: COS(=O)(=O)OC
Reactant: Clc1ccc2nc(Cl)c3[nH]c4ccccc4c3c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c2ccccc2c2c3cc(Cl)ccc3nc(Cl)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 14.3 g. of 2,6-dichloro-7H-indolo[2,3-c]-quinoline in 500 ml. of tetrahydrofuran was added 2.5 g. of a 57 percent dispersion of sodium hydride in oil and 5.0 ml. of dimethylsulfate. The mixture was stirred at room temperature overnight. The initially clear solution soon deposited the product as a colorless amorphous precipitate. The solid was collected and washed with water and tetrahydrofuran. After recrystallizations from acetonitrile, 14.5 g. (98 percent) colorless fibrous needles of 2,6-dichloro-7-methylindolo[2,3-c]-quinoline were obtained, which had a melting point of 226°-227°.
Reaction SMILES: [C:1]([N:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)[CH3:5])(=[O:3])[CH3:2].C(C1(C2C=CC(OC)=C(C=2)[CH:27]=[O:28])CC1)#N>>[C:1]([N:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[C:13]([CH:14]=2)[CH:27]=[O:28])[CH2:7][CH2:8]1)[CH3:5])(=[O:3])[CH3:2]
Reactant: COc1ccc(C2(N(C)C(C)=O)CC2)cc1
Reactant: COc1ccc(C2(C#N)CC2)cc1C=O
Product: COc1ccc(C2(N(C)C(C)=O)CC2)cc1C=O

Procedure:
This compound was prepared from Compound 9 in the same manner of Compound 2.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH2:6])[CH3:5].[NH2:7][C:8]1[CH:15]=[C:14](F)[C:11]([C:12]#[N:13])=[CH:10][N:9]=1>CC(N(C)C)=O>[NH2:7][C:8]1[CH:15]=[C:14]([NH:6][C@@H:4]([CH3:5])[CH2:3][O:2][CH3:1])[C:11]([C:12]#[N:13])=[CH:10][N:9]=1
Reactant: COC[C@H](C)N
Reactant: N#Cc1cnc(N)cc1F
Solvent: CC(=O)N(C)C
Product: COC[C@H](C)Nc1cc(N)ncc1C#N
Temperature: 60 °C

Procedure:
A mixture of (S)-1-methoxy-2-propylamine (5.91 g, 65.6 mmol), 6-amino-4-fluoronicotinonitrile (intermediate 21, 3.0 g, 21.88 mmol) and diidopropylethylamine (11.52 ml, 65.6 mmol) in DMA (50 ml) was heated at 60° C. in a septum sealed reaction vessel for 48 h. The reaction mixture partitioned between DCM and aqueous NH4Cl, extracted with DCM (3×), the combined organic extracts were dried over Na2SO4 and evaporated to give the title compound as a pale yellow oil. (UPLC-MS 7) tR 0.40; ESI-MS 207.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23](O)=[O:24])=[C:16]2[N:15]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:50][CH2:51][C@H:52]([OH:55])[CH2:53][OH:54].C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([NH:50][CH2:51][C@H:52]([OH:55])[CH2:53][OH:54])=[O:24])=[C:16]2[N:15]=1
Reactant: NC[C@H](O)CO
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC[C@H](O)CO)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 42.3 %

Procedure:
A mixture of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation C, 400 mg, 1.16 mmol), HATU (486 mg, 1.28 mmol), and (S)-3-aminopropane-1,2-diol (318 mg, 3.49 mmol) in dry DMF (3.0 mL) was stirred for 1-2 minutes at ambient temperature. Diisopropylethylamine (DIEA) (0.62 mL, 3.49 mmol) was added and the reaction was flushed with N2, sealed and stirred at ambient temperature for 18 hours. The reaction mixture was added to H2O (15 mL), mixed and extracted with EtOAc. The combined EtOAc extracts were washed with H2O, saturated NaHCO3 and dried over MgSO4/activated carbon. The solution was eluted through a SiO2 column eluting first with EtOAc then 10% MeOH/EtOAc. The 10% MeOH/EtOAc pool was concentrated and the residual, colorless glass was dissolved in a minimal amount of CH2Cl2. Hexane was added and the resulting white suspension was sonicated and concentrated to give the title product as a white solid (205 mg, 42%). MS (apci) m/z=418.1 (M+H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]=[CH:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(=O)CCCCC
Reactant: c1ccc(CCCC2CCNCC2)cc1
Solvent: CCO
Product: CCCCCC(=O)CCN1CCC(CCCc2ccccc2)CC1

Procedure:
1 equivalent of 4-(3-phenylpropyl)piperidine was reacted with 1 equivalent of 1-octen-3-one in ethanol, at room temperature. The product was worked up and purified on a column of silica. The results of the NMR and mass spectrometry analyses were in accordance with the expected structure.