Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:7][CH:6]=[CH:5][N:4]=1.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:26](Cl)=[O:27]>CCCCCCC.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:16][C:17]([F:18])([F:20])[F:19])[C:26](=[O:27])[C:25]2[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=[C:23]([C:22]([F:21])([F:36])[F:37])[CH:24]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1-c1ccncc1NCC(F)(F)F
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1ncccc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from (2-methoxy-[3,4]bipyridinyl-3′-yl)-(2,2,2-trifluoro-ethyl)-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Light yellow foam (21%). MS (ESI): m/z=524.100 [M+H]+.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[C:29]([CH2:30][CH3:31])=[C:28]([CH3:32])[C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:6]([CH3:33])[C:5]=1[CH2:34][CH3:35].[CH2:36]([O:38][C:39](=[O:50])[CH:40]=[C:41]([CH3:49])[CH:42]=[CH:43][CH:44]=[C:45]([CH:47]=O)[CH3:46])[CH3:37]>>[CH2:36]([O:38][C:39](=[O:50])[CH:40]=[C:41]([CH3:49])[CH:42]=[CH:43][CH:44]=[C:45]([CH3:47])[CH:46]=[CH:8][C:7]1[C:6]([CH3:33])=[C:5]([CH2:34][CH3:35])[C:4]([O:3][CH3:2])=[C:29]([CH2:30][CH3:31])[C:28]=1[CH3:32])[CH3:37]
Reactant: CCc1c(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c(CC)c1OC
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Agent: [Cl-]
Product: CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)c(CC)c(OC)c(CC)c1C

Procedure:
4-methoxy-3,5-diethyl-2,6-dimethyl-benzyl-triphenylphosphonium chloride is condensed with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester to produce the 9-(4-methoxy-3,5-diethyl-2,6-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid ethyl ester which is converted by the procedure of Example 7 to 9-(4-methoxy-3,5-diethyl-2,6-dimethyl-phenyl)-acid, m.p: 153°-154° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[Br-].[CH3:14][C:15]1[C:16]([Zn+])=[N:17][CH:18]=[CH:19][CH:20]=1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][C:15]1[C:16]([C:2]2[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([C:8]#[N:9])=[N:6][CH:7]=2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cccnc1[Zn+]
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1cccnc1-c1cnc(C#N)c([N+](=O)[O-])c1
Yield: 87.8 %

Procedure:
Heat a solution of 5-bromo-3-nitropyridine-2-carbonitrile (228 mg, 1.0 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg), 3-methyl-2-pyridylzinc bromide (0.5 M in THF, 3 mL, 1.5 mmol) in THF (5 mL) to 60° C. for 2 hours. Cool the solution and partition between ethyl acetate (10 mL) and saturated aqueous NaHCO3 (10 mL), Extract the aqueous solution with ethyl acetate (2×15 mL), wash with water (10 mL), brine (10 mL), dry (MgSO4) and evaporate to obtain the title compound as a pale yellow solid (211 mg, 88%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[C:4]([Br:10])[CH:3]=1.[CH3:11][O:12][C:13](=[O:24])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[CH3:23]>>[CH3:11][O:12][C:13](=[O:24])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[C:4]([Br:10])[CH:3]=2)=[CH:18][C:17]=1[CH3:23]
Reactant: COC(=O)CCc1ccc(O)cc1C
Reactant: CCc1cc(Br)cc(Br)c1
Product: CCc1cc(Br)cc(Oc2ccc(CCC(=O)OC)c(C)c2)c1
Yield: 56 %

Procedure:
Compound of 1,3-dibromo-5-ethyl-benzene is reacted with 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester as in Example 18 to afford 0.898 g (56%) of the title compound. Rf=0.32 (4/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C19H21O3Br 376, found 377 and 379 (M+1 and M+3, 100%).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH2:11]([N:16]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:13][CH2:14][CH3:15]>O>[CH2:11]([N:16]1[C:17]2[CH:18]=[CH:19][C:20]([CH:3]=[O:4])=[CH:21][C:22]=2[C:23]2[C:28]1=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CN(C)C=O
Reactant: CCCCCn1c2ccccc2c2ccccc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCCCCn1c2ccccc2c2cc(C=O)ccc21
Reaction time: 1.5 h

Procedure:
Dimethylformamide (100 mL) is stirred and cooled in an ice bath while phosphorus oxychloride (35 mL, 58 g, 0.38 mol) is gradually added. 9-Pentylcarbazole (52 g, 0.22 mol) is introduced and the resulting mixture is heated on a steam bath with stirring for 1.5 hours. The entire mixture is cooled and added to water (200 mL) and the crude product is filtered off at the pump, washed with water (200 mL). The crude product is recrystallized to form 9-pentyl-3-carbazolecarboxaldehyde.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:14]([O:12][C:11]1[C:10]([CH3:13])=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[CH3:1])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(C)c(O)c(C)c1
Solvent: c1ccncc1
Product: COC(=O)c1cc(C)c(OC(C)=O)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 3,5-dimethyl-4-hydroxybenzoate (2.146 g) in pyridine (20 mL) was cooled in an ice-bath under a nitrogen atmosphere. Acetic anhydride (5 mL) was added drop wise and after 30 minutes at 0° C., the reaction was warmed to room temperature and stirred for 2-3 hours. The solvent was then removed under reduced pressure and the crude product was dissolved in ethyl acetate (50 mL). This solution was washed with 1 N HCl, water and brine. It was then dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. Yield=2.4 g, white powder.
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:6][N:5](C(OC(C)(C)C)=O)[C@@H:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH2:3]1.Cl.[OH-].[Na+]>>[F:21][C:2]1([F:1])[CH2:6][NH:5][C@@H:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@@H]1c1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Fc1cccc([C@H]2CC(F)(F)CN2)c1
Temperature: 60 °C

Procedure:
To (R)-tert-butyl 4,4-difluoro-2-(3-fluorophenyl)pyrrolidine-1-carboxylate (180 mg, 0.6 mmol) in a pressure reaction tube was added a solution of HCl (2 mL, 4 N dioxane, 8 mmol), then the reaction was sealed and heated at 60° C. for 4 hours. For workup, the reaction was poured into a mixture of ice and 1 M NaOH, and extracted with several portions of EtOAc. The combined organic extracts were filtered through a Phase Separator filter paper and concentrated, yielding the final product as clear oil, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[N:18]=[CH:17]2)([C:5]1[CH:6]=[N:7][C:8]([O:12]C)=[C:9]([CH3:11])[CH:10]=1)[OH:4].Cl.[NH+]1C=CC=CC=1>CCOCC.O>[CH3:11][C:9]1[C:8](=[O:12])[NH:7][CH:6]=[C:5]([C:3]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[N:18]=[CH:17]3)([OH:4])[C:2]([F:1])([F:30])[F:31])[CH:10]=1
Reactant: COc1ncc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cc1C
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCOCC
Product: Cc1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c[nH]c1=O
Temperature: 125 °C

Procedure:
A mixture of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-(5-methyl-6-methoxypyridin-3-yl)ethanol (0.679 mmol) and pyridinium hydrochloride (6.79 mmol) was warmed at 125° C. in a sealed tube for 20 minutes, cooled to room temperature and diluted with ether and water. The organic layer was washed with brine and dried over magnesium sulfate. The volatiles were removed in vacuo and the residue triturated with petroleum ether to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]2=[O:19].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:20][CH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]2=[O:19]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)CCN1C(=O)c2ccc(C)cc2C1=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)CCN1C(=O)c2ccc(CBr)cc2C1=O
Yield: 104.1 %

Procedure:
The material from step 1 (27.3 g, 0.10 mol) was dissolved in carbon tetrachloride (50 mL), and N-bromosuccinimide (19.5 g, 0.11 mol) and AIBN (200 mg) was added. The mixture was refluxed for 5 hours, filtered by suction, and the filtrate was concentrated to give 35.4 g yellow oil.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:3])[NH2:2].[OH:18]O.O>S(=O)(=O)(O)O>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][OH:18])=[O:16])(=[O:3])[NH2:2]
Reactant: NC(=O)NCCCCCCCCCCC(=O)O
Reactant: OO
Agent: O=S(=O)(O)O
Solvent: O
Product: NC(=O)NCCCCCCCCCCC(=O)OO
Temperature: 15 °C

Procedure:
61.6 g (0.25 mol) of N-carbamoyl-11-aminoundecanoic acid are dissolved in 74.4 g of sulfuric acid (96% strength by weight) and the solution is cooled to 15° C. 23.8 g (0.6 mol) of hydrogen peroxide (85% strength by weight) are added dropwise with cooling at such a rate that the internal temperature can be maintained between 15 and 20° C. The reaction mixture is subsequently stirred with occasional cooling at 20° C. internal temperature for 1 h and then cooled down to 10° C., 200 ml of water are added dropwise, and the precipitated peroxycarboxylic acid is filtered off with suction. The filter cake is washed with water until free of mineral acid and is dried at 40° C. under an aspirator vacuum.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[N:11]=[C:10]([CH3:12])[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][CH:15]=2)=[C:8]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:7]=1>C(Cl)Cl>[Cl:3][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:9]2[C:8]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[N:7][C:6]([NH2:5])=[N:11][C:10]=2[CH3:12])=[CH:15][CH:16]=1
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (1 ml) was added to a mixture of the product from step (v) (1.2 g) in DCM (20 ml) and stirred at rt for 2 h. The solvent was evaporated under reduced pressure and the residue used crude in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5](N)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[I-:21].[K+]>O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]([I:21])=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: Nc1ccc(Cl)nc1-c1ncccc1F
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Fc1cccnc1-c1nc(Cl)ccc1I
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 161.6 %

Procedure:
A 500 mL 3 neck RBF equipped with mechanical stirrer, reflux condenser, and addition funnel was charged with 6-chloro-3′-fluoro-[2,2′-bipyridin]-3-amine (6.63 g, 29.6 mmol). It was treated with 2M sulfuric acid (111 mL, 222 mmol) creating a yellow/orange solution. The reaction was cooled to −5° C. and treated dropwise with a solution of sodium nitrile (2.66 g, 38.5 mmol) in 49 mL water at −5° C. The yellow/orange suspension was stirred at 0° C. for 30 minutes, then treated dropwise with a solution of potassium iodide (14.76 g, 89 mmol) in 63 mL of water. The reaction was stirred at room temperature for 30 minutes, then heated to 80° C. for 1 hour. After cooling, the reaction was extracted with EtOAc, washed with water, 2M Na2CO3, NaHSO3, and brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography using 20% EtOAc/hexanes to give 6-chloro-3′-fluoro-3-iodo-2,2′-bipyridine (16 g, 81% yield).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(OCC)=O)C.[OH:19][C:20]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:21]=1[CH:22]=O.C(O)(=O)C>O1CCCC1>[OH:19][C:20]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:21]=1/[CH:22]=[CH:11]/[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/c1cc([N+](=O)[O-])ccc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.5 %

Procedure:
Sodium hydride (content: 62%, 3.3g) was suspended in tetrahydrofuran (30 ml). The suspension was ice-cooled in an atmosphere of argon gas. A solution of t-butyl diethylphosphonoacetate (20.9 g) in tetrahydrofuran (20 ml) was added to the suspension. The mixture was stirred for 15 min. at room temperature. A solution of 2-hydroxy-5-nitrobenzaldehyde (6.6 g) in tetrahydrofuran (20 ml) was gradually added to the mixture often with ice-cooling. The mixture was stirred for 10 min. at room temperature. Acetic acid was gradually added to the mixture until pH of the mixture was down to 5.0. The reaction mixture was gel-filtered with using YMC gel. Moreover the gel was washed with ethyl acetate. A mixture of the filtrate and washings was evaporated. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1→3:2) to give the title compound (10.0 g) having the following physical data.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>O.CCOC(C)=O>[CH3:8][C:6]1[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]2=[C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:7]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(N2CCNCC2)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 25 °C
Yield: 29.1 %

Procedure:
This compound was prepared according to the method described in Example 26 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (0.10 g, 0.41 mmol), piperazine (Aldrich Chemical Company) (0.382 g, 4.43 mmol) and K2CO3 (0.34 g, 2.50 mmol) in H2O (2.5 mL) to give crude pink solids. These solids were taken up in hot EtOAc, cooled to room temperature, and the impurities were removed by filtration. The filtrate was concentrated to give 0.035 g (29%) of the title compound as an off-white solid. Mp: 236° C. 1H NMR (DMSO-d6; 500 MHz): δ 2.42 (s, 3), 2.85 (t, 4, J=5.2), 3.62 (t, 4, J=5.2), 6.77 (s, 1), 7.36 (m, 1), 7.45 (t, 2, J=7.8), 7.95 (d, 2, J=7.6), 10.96 (s, 1); MS m/z: 294 (M+1). Anal. Calcd for C17H19N5O.0.5 H2O: C 67.53, H 6.67, N 23.16. Found: C 67.35, H 6.59, N 23.01.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH3:9])=[CH:4][C:3]=1[C:16]1[CH:21]=[C:20]([S:22][CH3:23])[N:19]=[C:18]([CH3:24])[N:17]=1.[NH2:25][C:26]1[CH:27]=[C:28]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:29]([Cl:32])=[N:30][CH:31]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:32][C:29]1[C:28]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:27][C:26]([NH:25][C:2]2[C:3]([C:16]3[CH:21]=[C:20]([S:22][CH3:23])[N:19]=[C:18]([CH3:24])[N:17]=3)=[CH:4][C:5]([CH:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH3:9])=[CH:6][N:7]=2)=[CH:31][N:30]=1
Reactant: CSc1cc(-c2cc(C(C)N3CCOCC3)cnc2F)nc(C)n1
Reactant: CS(=O)(=O)Nc1cc(N)cnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1cc(-c2cc(C(C)N3CCOCC3)cnc2Nc2cnc(Cl)c(NS(C)(=O)=O)c2)nc(C)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69.3 %

Procedure:
To a flame dry 15 mL round-bottom flask was added 4-(1-(6-fluoro-5-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyridin-3-yl)ethyl)morpholine (0.160 g, 0.459 mmol), N-(5-amino-2-chloropyridin-3-yl)methanesulfonamide (0.122 g, 0.551 mmol), and THF (4.0 mL). The mixture was cooled to 0° C. under N2. Sodium bis(trimethylsilyl)amide, 1.0 m in THF (Aldrich) (1.837 mL, 1.837 mmol) was then added to the solution in one portion. The now dark burgundy color mixture was stirred at 0° C. for 10 min then warmed up to rt and stirred for 1 h. The reaction mixture was quenched with sat. NH4Cl. The reaction mixture was partitioned between water and CHCl3. The aqueous layer was extracted with CHCl3 (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40 g, DCM:EtOAc:MeOH=65%:32%:3%) to afford the product as a yellow solid (175 mg). MS (ESI pos. ion) m/z: 550.0. 1H NMR (300 MHz, CDCl3) δ ppm 1.41 (d, J=6.58 Hz, 3H) 2.34-2.48 (m, 2H) 2.49-2.60 (m, 2H) 2.66 (s, 3H) 2.81 (s, 3H) 3.13 (s, 3H) 3.39 (d, J=6.58 Hz, 1H) 3.72 (t, J=4.38 Hz, 4H) 6.75 (br. s., 1H) 7.45 (s, 1H) 8.01 (d, J=1.90 Hz, 1H) 8.30 (d, J=1.90 Hz, 1H) 8.52 (d, J=2.48 Hz, 1H) 8.76 (d, J=2.48 Hz, 1H) 12.43 (s, 1H).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[C:17]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:18][C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:20][C:9]1=2)(=O)=O.[CH2:31]([CH2:33][NH2:34])[OH:32]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[OH:32][CH2:31][CH2:33][NH:34][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[C:17]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:18][C:19]([N:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)=[N:20][C:9]1=2
Reactant: NCCO
Reactant: CS(=O)(=O)OCCn1c2ccccc2c2c(N3CCCC3)nc(N3CCCC3)nc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: OCCNCCn1c2ccccc2c2c(N3CCCC3)nc(N3CCCC3)nc21

Procedure:
A mixture of 9-(2-methanesulfonyloxyethyl)-2,4-di-1-pyrrolidinyl-9H-pyrimido[4,5-b]indole (IX, EXAMPLE 4, 1.3 g) and 15 ml of ethanolamine is heated to reflux for 4 hr, then cooled, and diluted with methylene chloride (100 mL) and aqueous saturated sodium bicarbonate. The phases are separated, and the aqueous phase is extracted again with methylene chloride/chloroform (1/1). The combined extracts are dried over sodium sulfate and concentrate under reduced pressure at 50°-60° to give a solid. The solid is recrystallized from ethyl acetate/hexane at 20°-250 to give the title compound, NMR (CDCl3) 1.5-1.7, 1.9-2.0, 2.84, 3.12, 3.56, 3.63, 3.92, 4.20, 7.10, 7.13-7.30 and 7.80 δ; MS (EI, m/z) 394 (M+), 363, 320 and 307.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[O:10]1[CH2:15][CH2:14][CH:13]([C:16](=O)[CH3:17])[CH2:12][CH2:11]1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[Br:9][C:5]1[CH:6]=[C:7]([NH:8][CH:16]([CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)[CH3:17])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: CC(=O)C1CCOCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(Nc1cc(Br)cnc1N)C1CCOCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 19.6 %

Procedure:
2,3-Diamino-5-bromopyridine (1.07 g) and 1-(tetrahydro-2H-pyran-4-yl)ethanone (0.80 g) were dissolved in methanol (20 ml), and acetic acid (0.98 ml) was added. After stirring at room temperature for a while, sodium cyanoborohydride (1.08 g) was added and the mixture was stirred at room temperature for 20 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by flash column chromatography (developed with ethyl acetate-hexane) to give the title compound (334 mg).
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Reaction time: 24 h
Yield: 52.7 %

Procedure:
To a suspension of 100 g of 2-methyl-3-nitrobenzoic acid, methyl ester and 100 g of N-bromosuccinimide in 1000 ml carbon tetrachloride was added 3 g of benzoyl peroxide and the mixture was stirred at reflux temperature for about 24 hours. Additional benzoyl peroxide was then added and refluxing was resumed for another 24 hours. The reaction mixture was cooled, filtered, and the filtrate concentrated in vacuo to afford an oil which crystallized upon cooling. This crude product was dissolved in diethyl ether and the organic layer was washed with saturated aqueous sodium sulfite (one 500-ml portion), water (two 500-ml portions), 2.5% aqueous sodium hydroxide solution (one 500-ml portion), water and brine. Drying and evaporation of the orgnaic layer in vacuo gave a yellow oil which crystallized on standing. Recrystallization from 350 ml n-butyl chloride/cyclohexane (2:1) gave 74 g of 2-(bromomethyl)-3-nitrobenzoic acid, methyl ester, m.p. 67°-70°.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2]1.[CH3:14][C:15]([NH2:26])([CH3:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>>[OH:1][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2][NH:26][C:15]([CH3:25])([CH3:14])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1
Reactant: CCCCCCCCCCC1CO1
Reactant: COc1ccc(CC(C)(C)N)cc1
Product: CCCCCCCCCCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Yield: 18.7 %

Procedure:
Using the method of Example 5, supra, 1,2-epoxydodecane (240 μL, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 68 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 363 (M+1, 0.2), 348 (2), 242 (100), 224 (8), 163 (7), 121 (20); 1H-NMR (CDCl3) δ 7.08 (2H, d, J=8.4), 6.83 (2H, d, J=8.4), 3.79 (3H, s), 3.50 (1H, m), 2.78 (1H, dd, J=11.8 and 3.1), 2.66 (2H, s), 2.41 (1H, dd, J=11.5 and 9.3), 1.26 (18 H, m), 1.07 (6H, s), 0.88 (3H, t, J=6.5); 13C-NMR (CDCl3) δ 158.2, 131.4, 129.9, 113.4, 76.9, 70.0, 55.2, 53.6, 47.8, 46.6, 35.1, 31.9, 29.7, 29.6, 29.3, 26.7, 26.5, 25.7, 22.7, 14.1; FT-IR (film) cm−1 3386, 1612, 1512, 1246, 1039, 824.