Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:32]=[CH:31][CH:30]=[CH:29][C:3]=1[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[N:7]=1)=[O:5].[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[NH2:1][C:2]1[C:3]([C:4]([C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:7]=2)=[O:5])=[CH:29][CH:30]=[CH:31][N:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3ccccc3c(C(=O)c3cccnc3N)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncccc1C(=O)c1nc(N2CCNCC2)cc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a solution of tert-butyl 4-(1-(2-aminonicotinoyl)isoquinolin-3-yl)piperazine-1-carboxylate (6 mg, 0.014 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (0.5 ml). The solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo and triturated twice with ether and dried to leave the compound as an orange solid (2 mg, 26% yield).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Cl[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=O>CN(C)C=O>[NH2:1][C:2]1[S:3][C:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[N:4]=1
Reactant: NC(N)=S
Reactant: O=C1CCCCC1Cl
Solvent: CN(C)C=O
Product: Nc1nc2c(s1)CCCC2
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Thiourea (123.3 g., 1.62 moles) was combined with 400 ml. of dimethylformamide and heated on a steam bath. After dissolution of the thiourea was complete, 2-chlorocyclohexanone (195.1 g., 1.47 moles) was added dropwise over 20 minutes, during which the temperature began to rise above 100° C., and external heating was discontinued. The temperature rose to a maximum of 128° C. After addition was complete, heating on the steam bath was resumed and was continued for 30 minutes. The reaction mixture was cooled to 5° C. and crude product recovered by filtration. The crude was partially dried to 242.4 g., and then dissolved by warming in a mixture of 1.4 l. of water, 100 ml. of methanol and 50 ml. of concentrated hydrochloric acid. The acidic solution was added dropwise to a stirred mixture of 150 ml. of concentrated ammonium hydroxide and ice and partially purified product (167.6 g.) recovered by filtration. Recrystallization from 1400 ml. of cyclohexane gave purified 2-aminio-4,5,6,7-tetrahydrobenzthiazole (150 g., m.p. 86°-87° C.).
Reaction SMILES: [N:1]1([S:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[C:18]4[N:19]([CH2:25][CH2:26][N:27]=4)[C:20]([NH2:24])=[N:21][C:22]=3[CH:23]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:28][C:29]1[N:34]=[CH:33][C:32]([C:35](O)=[O:36])=[CH:31][N:30]=1>>[NH2:28][C:29]1[N:34]=[CH:33][C:32]([C:35]([NH:24][C:20]2[N:19]3[CH2:25][CH2:26][N:27]=[C:18]3[C:17]3[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][CH2:10][S:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)(=[O:8])=[O:9])=[CH:23][C:22]=3[N:21]=2)=[O:36])=[CH:31][N:30]=1
Reactant: Nc1ncc(C(=O)O)cn1
Reactant: NC1=Nc2cc(OCCCS(=O)(=O)N3CCOCC3)ccc2C2=NCCN12
Product: Nc1ncc(C(=O)NC2=Nc3cc(OCCCS(=O)(=O)N4CCOCC4)ccc3C3=NCCN23)cn1

Procedure:
The procedure used for the preparation of Example 28, Step 2 was used to prepare the title compound from 8-[3-(morpholin-4-ylsulfonyl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Example 28, Step 1) and 2-aminopyrimidine-5-carboxylic acid. Yield 150 mg (45%). TLC Rf=0.47 in 10% MeOH/CH2Cl2, HPLC MS RT=0.76 min, MH+=515.4; 1H NMR (DMSO-d6) δ: 2.24 (2H, m), 3.21 (4H, m), 3.29 (2H, m), 3.67 (4H, m), 4.20 (2H, t), 4.30 (2H, t), 4.53 (2H, t), 7.20 (1H, d), 7.70 (1H, br s), 7.97 (1H, s), 8.13 (1H, d), 9.02 (2H, s).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][N:11]([CH3:31])[S:12]([N:15]1[CH:19]=[C:18]([CH2:20][N:21]([C:24]2[CH:29]=[CH:28][N:27]=[C:26](Cl)[N:25]=2)[CH2:22][CH3:23])[N:17]=[CH:16]1)(=[O:14])=[O:13]>CN(C)C=O>[CH3:10][N:11]([CH3:31])[S:12]([N:15]1[CH:19]=[C:18]([CH2:20][N:21]([CH2:22][CH3:23])[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([O:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[N:25]=2)[N:17]=[CH:16]1)(=[O:13])=[O:14]
Reactant: Oc1ccccc1
Reactant: CCN(Cc1cn(S(=O)(=O)N(C)C)cn1)c1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(Cc1cn(S(=O)(=O)N(C)C)cn1)c1ccnc(Oc2ccccc2)n1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To sodium hydride (0.194 g, 55% in mineral oil, 4.4 mmol) in dimethylformamide (1.5 ml) was added phenol (0.418 g, 4.4 mmol) and stirring was continued for 15 min at room temperature. To this reaction mixture 4-{[(2-chloro-pyrimidin-4-yl)-ethyl-amino]-methyl}-imidazole-1-sulfonic acid dimethylamide (0.153 g, 0.44 mmol) was added. After stirring and heating to 80° C. overnight the solvent was evaporated. Water was added (5 ml) and the mixture was extracted with ethyl acetate (20 ml) twice. The combined organic layers were washed with water, dried over magnesium sulphate and evaporated. The residue was purified using flash chromatography (SiO2; eluent: heptane/ethyl acetate=95:5) to yield the title compound as a colourless gum, MS (ISP): 403.4 ((M+H)+.).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:30][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH:21][C@@H:22](C4C=CC=CC=4)[CH3:23])[C:15]=3[CH:14]=2)=[CH:9][CH:8]=1)=[O:4].N.ClCCl.[CH3:35][OH:36]>>[CH2:35]([O:36][C:14]1[CH:15]=[CH:16][C:22]([NH:21][C:20]2[C:15]3[CH:14]=[C:13]([C:10]4[CH:9]=[CH:8][C:7]([CH2:6][NH:5][C:3](=[O:4])[CH2:2][Cl:1])=[CH:12][CH:11]=4)[NH:30][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:23][CH:13]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CNC(=O)CCl)cc3)cc12)c1ccccc1
Reactant: CO
Agent: N
Solvent: ClCCl
Product: O=C(CCl)NCc1ccc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3[nH]2)cc1

Procedure:
This compound is synthesized using an analogous sequence as described for 2-chloro-N-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide (steps 40.4 to 40.6); Rf (dichloromethane/methanol/conc. ammonia 90:10:1)=0.40; MS-ES+: (M+H)+=498.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[CH3:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1.[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]1[N:34]=[C:33]([C:32]2[CH:35]=[CH:36][C:29]([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])=[CH:30][CH:31]=2)[N:2]([CH3:1])[N:3]=1
Reactant: CN(N=C(Cl)c1ccccc1Cl)S(=O)(=O)c1ccccc1
Reactant: CCCCCCCc1ccc(C#N)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: CCCCCCCc1ccc(-c2nc(-c3ccccc3Cl)nn2C)cc1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
A mixture of 2.06 g of N-methyl-N-phenylsulfonyl-2-chlorobenzohydrazonoyl chloride, 1.30 g of 4-(6-methylhexyl) benzonitrile, 0.93 g of anhydrous aluminum chloride and 5 ml of o-dichlorobenzene was stirred in an oil bath at a temperature of 140° C. for 30 minutes. After the cooling, the resulting solution was dissolved in 200 ml of chloroform, washed with diluted hydrochloric acid solution, diluted sodium hydroxide aqueous solution and saline water in this order, dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. The resulting concentrate was purified through a chromatography of silica gel column using a mixed solution of hexane and ethyl acetate as a developing solvent to obtain 1.52 g of the given compound (melting point: 64.0°-67.0° C.).
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([OH:14])[C:5]2[O:6][C:7]([CH3:11])([CH3:10])[O:8][CH2:9][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[F:1][C:2]1[CH:13]=[C:12]([O:14][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:5]2[O:6][C:7]([CH3:11])([CH3:10])[O:8][CH2:9][C:4]=2[CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)OCc2cc(F)cc(O)c2O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc(F)cc(OCc3ccccc3)c2O1
Yield: 74.1 %

Procedure:
A solution of 6-fluoro-2,2-dimethyl-4H-1,3-benzodioxin-8-ol (21.4 g, 108 mmol) in DMF (200 mL) was treated with cesium carbonate (70.4 g, 216 mmol) and benzyl bromide (14.1 mL, 119 mmol) for 1 h 45 min at rt. Water was added and the resulting aqueous mixture was extracted twice with ethyl acetate. The organic extracts were combined, washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was recrystallized from ethanol. The recovered white crystalline product was rinsed with hexanes providing 6-fluoro-2,2-dimethyl-8-[(phenylmethyl)oxy]-4H-1,3-benzodioxine (23.04 g, 80 mmol, 74% yield). 1H NMR (400 MHz, CDCl3): δ7.43-7.29 (m, 5H), 6.51 (dd, 1H), 6.31 (dd, 1H), 5.15 (s, 2H), 4.80 (s, 2H), 1.59 (s, 6H); GCMS for C17H17FO3: 288 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl.[CH3:31][NH:32][O:33][CH3:34]>C(Cl)Cl>[F:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([N:32]([O:33][CH3:34])[CH3:31])=[O:7])=[CH:3][C:2]=1[OH:1]
Reactant: CNOC
Reactant: O=C(O)c1ccc(F)c(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(F)c(O)c1
Temperature: 78 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
To a 5 L four necked round bottom flask was added 3-hydroxy-4-fluorobenzoic acid (100 g, 0.64 mol) and CH2Cl2 (2.3 L). Triethylamine (107 mL, 0.768 mol) was then added to the suspension. The solution was cooled to 78° C., and EDCI (184.2 g, 0.961 mol) was added portion wise followed by the addition of N,O-dimethylhydroxyamine hydrochloride (93.6 g, 0.96 mol). The reaction mixture was stirred at −78° C. for 1 h and then allowed to warm to 0° C. over a period of 2 h. The reaction mixture was transferred to a separatory funnel and washed water (2×1.2 L). The organic portion was dried over Na2SO4, filtered and concentrated in vacuo to give 4-fluoro-3-hydroxy-N-methoxy-N-methylbenzamide as a white solid (94.4 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[C:11]([OH:14])[C:10]=1[CH:15]([CH3:17])[CH3:16].[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27]O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27][O:14][C:11]1[C:10]([CH:15]([CH3:17])[CH3:16])=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[O:13][N:12]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)c1c(O)noc1-c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)c1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccc(Cl)cc1Cl
Yield: 85.2 %

Procedure:
5-(2,4-Dichlorophenyl)-3-hydroxy-4-isopropylisoxazole (0.06 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.04 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.078 g, 86%) as a colorless oil.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:17]=[C:18]([CH:24]2[CH2:29][NH:28][C:27](=[O:30])[NH:26][CH2:25]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:50]1([CH2:56][CH2:57][CH2:58][CH2:59]O)[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>O1CCCC1.C(OCC)(=O)C>[C:50]1([CH2:56][CH2:57][CH2:58][CH2:59][O:15][C:16]2[CH:17]=[C:18]([CH:24]3[CH2:25][NH:26][C:27](=[O:30])[NH:28][CH2:29]3)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: OCCCCc1ccccc1
Reactant: COc1ccc(C2CNC(=O)NC2)cc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C2CNC(=O)NC2)cc1OCCCCc1ccccc1
Temperature: 25 °C
Yield: 31.3 %

Procedure:
Diisopropylazodicarboxylate (1.1 ml, 5.70 mmol, 1.2 eq) was added to a mixture of (1.06 g, 4.75 mmol, 1.0 eq) tetrahydro-5-(3-hydroxy-4-methoxyphenyl)-2(1H)-pyrimidinone, (1.37 g, 5.23 mmol, 1.1 eq) triphenylphosphine, and (714 mg, 4.75 mmol, 1.0 eq) 4-phenyl-1-butanol in 20 ml of anhydrous tetrahydrofuran. After heating to reflux for 18 hours, the reaction mixture was cooled to room temperature, diluted with 350 ml ethyl acetate, washed twice with 1N NaOH, once with H2O, once with brine, dried over Na2SO4, and concentrated to yield an orange solid. Silica gel chromatography eluting with 4% CH3OH--CH2Cl2 yielded 527 mg of a white solid, which was recrystallized from ethyl acetate to afford 480 mg, 29%, of white needles. M.P.: 142°-143° C. Elemental Analysis Calc'd for C21 H26N2O3 : Calc'd: C, 71.17; H, 7.40; N, 7.90. Found: C, 71.12; H, 7.32; N, 7.75.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)=[N:11][CH:12]=1.CN([CH:27]=[O:28])C>C1COCC1>[F:21][C:20]([F:23])([F:22])[O:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[N:9]=[CH:8][C:7]([CH:27]=[O:28])=[CH:12][N:11]=2)=[CH:14][CH:15]=1
Reactant: FC(F)(F)Oc1ccc(-c2ncc(Br)cn2)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cnc(-c2ccc(OC(F)(F)F)cc2)nc1
Reaction time: 0.01 h
Yield: 74 %

Procedure:
n-BuLi (2.5 M, 1.88 mL, 4.7 mmol) was added to a solution of bromide 89 (1.252 g, 3.92 mmol) in THF (40 mL) at −95° C. The solution was stirred for 30 s and then DMF (5 mL) was added. The reaction was stirred at −90° C. for 20 min and then quenched with aqueous NH4Cl. The resulting mixture was partitioned between EtOAc and water, and then column chromatography of the organic portion on silica gel (eluting with 1:7 EtOAc/hexanes) gave 2-[4-(trifluoromethoxy)phenyl]-5-pyrimidinecarbaldehyde (90) (0.778 g, 74%) as a white solid: mp 114-115° C.; 1H NMR (CDCl3) δ 10.16 (s, 1H), 9.22 (s, 2H), 8.62 (d, J=9.0 Hz, 2H), 7.36 (d, J=9.0 Hz, 2H). APCI MS m/z 269 [M+H]+, 301 [M+H+MeOH]+.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([S:21]([C:24]1[CH:25]=[CH:26][CH:27]=[C:28]3[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]3)(=[O:23])=[O:22])[C:16](=[O:34])[C:15]2([OH:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH3:42]>N1C=CC=CC=1>[C:5]1([O:4][C:2](=[O:3])[O:43][C:15]2([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])[C:14]3[C:18](=[CH:19][CH:20]=[C:12]([Cl:11])[CH:13]=3)[N:17]([S:21]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]4[C:33]=3[N:32]=[CH:31][CH:30]=[CH:29]4)(=[O:23])=[O:22])[C:16]2=[O:34])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccccc1C1(O)C(=O)N(S(=O)(=O)c2cccc3cccnc23)c2ccc(Cl)cc21
Solvent: c1ccncc1
Product: COc1ccccc1C1(OC(=O)Oc2ccccc2)C(=O)N(S(=O)(=O)c2cccc3cccnc23)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
Phenyl chloroformate (0.35 ml, 2.79 mmol) was added dropwise to a solution of example 64 (300 mg, 0.624 mmol) in pyridine (6 ml) while cooling slightly. The reaction mixture was stirred at room temperature overnight. After addition of ice-water, the mixture was extracted with ethyl acetate, and the organic phase was washed several times with dilute citric acid solution and water. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated with diethyl ether, and the resulting precipitate was filtered off, washed with diethyl ether and dried. 310 mg of the desired intermediate were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Cl:9][C:10]1(Cl)[CH2:15][O:14][CH2:13][CH2:12][O:11]1>>[Cl:9][CH2:10][CH2:15][O:14][CH2:13][C:12]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=1)=[O:11]
Reactant: ClC1(Cl)COCCO1
Reactant: Nc1cccc(F)c1
Product: O=C(COCCCl)Nc1cccc(F)c1
Temperature: 100 °C

Procedure:
A mixture of 12.0 g (108 mmol) of 3-fluoraniline and 16 g of 2-chlorodioxene (contains 6% of 2,2-dichlorodioxane) is heated at 100° C. for 24 hours. The mixture is allowed to cool, and excess 2-chlorodioxene is removed under reduced pressure, giving 25 g of 2-(2-chloroethoxy)-N-(3-fluorophenyl)acetamide as brown oil; ESI 232. This oil is dissolved in 400 ml of acetonitrile, and 84.7 g (260 mmol) of caesium carbonate are added. The suspension formed is stirred at room temperature for 18 hours. The reaction mixture is filtered, and the filtrate is evaporated, giving 21.0 g of 4-(3-fluorophenyl)morpholin-3-one as brown oil; ESI 196. 1H-NMR (d6-DMSO): δ=3.77 (t, J=5 Hz; 2H), 3.97 (t, J=5 Hz; 2H), 4.23 (s; 2H), 7.11 (dddd, J1=8 Hz, J2=8 Hz, J3=2 Hz, J4=0.5 Hz, 1H), 7.26 (ddd, J1=8 Hz, J2=2 Hz, J3=0.5 Hz, 1H), 7.34 (ddd, J1=10 Hz, J2=2 Hz, J3=2 Hz, 1H), 7.45 (ddd, J1=8 Hz, J2=8 Hz, J3=7 Hz, 1H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH:6]([CH3:11])[CH2:5]1)(=[O:3])[CH3:2].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C@H:7]1[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][C@H:6]1[CH3:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)N1CCC(=O)C(C)C1
Reactant: NCc1ccccc1
Product: CC(=O)N1CC[C@H](NCc2ccccc2)[C@H](C)C1

Procedure:
Racemic cis 1-(4-benzylamino-3-methyl-piperidin-1-yl)-ethanone was prepared in the same manner from racemic 1-acetyl-3-methyl-piperidin-4-one. In this instance, benzylamine was used instead of (R)-1-phenylethylamine.
Reaction SMILES: [C:1]([C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].[N:14]([CH:17]1[CH2:36][N:21]2[C:22]3[C:27]([C:28]([CH2:29][C:30]([O:32]CCC)=[O:31])=[C:20]2[CH2:19][CH2:18]1)=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N+:15]=[N-:16].[N-]=[N+]=[N-]>>[C:8]1([C:3]2([C:1]3[N:14]([CH:17]4[CH2:36][N:21]5[C:22]6[C:27]([C:28]([CH2:29][C:30]([OH:32])=[O:31])=[C:20]5[CH2:19][CH2:18]4)=[CH:26][CH:25]=[CH:24][CH:23]=6)[N:15]=[N:16][CH:2]=3)[CH2:7][CH2:6][CH2:5][CH2:4]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C#CC1(c2ccccc2)CCCC1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Agent: [N-]=[N+]=[N-]
Product: O=C(O)Cc1c2n(c3ccccc13)CC(n1nncc1C1(c3ccccc3)CCCC1)CC2

Procedure:
The title compound was prepared using analogous procedures described in EXAMPLE 3 from (1-ethynylcyclopentyl)benzene and enantiomerically pure propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate, prepared by resolution of the racemic azide on a 4.6×250 mm ChiralCel OD column eluting with 15% MeOH, 15% iPrOH, 69.75% Hexanes and 0.25% Et3N at 1 mL/min and 254 nm. Retention times=10.3 and 11.5 min. EXAMPLE 6.1 and 6.2 were prepared from the chiral azide with the retention time of 10.3 and 11.5 min respectively. 1H NMR data of EXAMPLE 6.1: 1H NMR (400 MHz, DMSO-d6): δ 12.13 (s, 1H), 7.93 (s, 1H), 7.42 (d, 1H), 7.36 (dd, 2H), 7.31-7.23 (m, 3H), 7.13 (d, 1H), 7.07-6.97 (m, 2H), 4.59 (s, 1H), 3.98-3.89 (m, 1H), 3.58-3.46 (m, 2H), 3.03-2.92 (m, 1H), 2.29-2.20 (m, 1H), 2.10-2.01 (m, 1H), 1.54-1.43 (m, 1H). MS (+ESI) m/z: 441.2.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:21]1[N:26]=[C:25]([Cl:27])[CH:24]=[CH:23][N:22]=1.O>CN(C=O)C>[CH2:1]([S:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:21]1[N:26]=[C:25]([Cl:27])[CH:24]=[CH:23][N:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: c1ccc(CSc2cccc3[nH]ccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccnc(-n2ccc3c(SCc4ccccc4)cccc32)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 13.9 %

Procedure:
4-Benzylsulfanyl-1H-indole (5.00 g, 21 mmol) (Can. J. Chem. 1962, 40, 511) was slowly added to a suspension of NaH (60% dispersion in mineral oil, 1.37 g, 34 mmol) in DMF (40 mL) at 0° C. The reaction mixture was stirred for 15 min until the gas evolution ceased, then 2,4-di-chloropyrimidine (3.03 g, 20 mmol) was added portionwise, followed by an additional aliquot of DMF (10 mL). The resulting mixture was slowly warmed to RT, then poured onto a slurry of ice and water and extracted with EtOAc. The organic layer was washed twice with a mixture of water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexanes, gradient from 10:90 to 50:50) to give 4-benzylsulfanyl-1-(4-chloropyrimidin-2-yl)-1H-indole (979 mg, 14% yield) as a pale-yellow waxy solid and a mixture of 4-benzylsulfanyl-1-(2-chloropyrimidin-4-yl)-1H-indole and the bisubstituted product (691 mg) after precipitation from DCM/EtOAc. This mixture was repurified by flash chromatography (EtOAc/hexanes, 20:80) to give 4-benzylsulfanyl-1-(2-chloropyrimidin-4-yl)-1H-indole (270 mg, 4% yield) as an off-white solid. MS=352 [M+H]+; MP=159.0-161.2° C.
Reaction SMILES: [C:1]1([P:7]2(=[O:22])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][N:8]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.F[B-](F)(F)F.[O:31]=[N+:32]=[O:33]>C(OCC)C>[C:1]1([P:7]2(=[O:22])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][N:8]2[C:16]2[CH:17]=[CH:18][C:19]([N+:32]([O-:33])=[O:31])=[CH:20][CH:21]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]=O
Reactant: O=P1(c2ccccc2)c2ccccc2CN1c1ccccc1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(N2Cc3ccccc3P2(=O)c2ccccc2)cc1
Temperature: 26 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
Under a static nitrogen atmosphere, a solution of 1,2-diphenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (1.0 g, 0.0033 mol) in 10 ml. of methylene chloride was dropwise added to a constantly stirred suspension of nitronium tetrafluoroborate (0.47 g, 0.0035 mol) in 25 ml. of methylene chloride while maintaining the temperature between -5° C. and 5° C. The reaction mixture was stirred for 3 hours at 26° C. and then added to 40 ml. of ice water. The layers were separated and the aqueous layer was extracted with methylene chloride. The methylene chloride layers were combined, dried over magnesium sulfate, and concentrated in vacuo to yield a residue which was purified on a silica gel column using ethyl acetate as the eluant. Fractions containing the benzazaphosphole were combined and concentrated in vacuo to produce a crude product. The crude product was slurried in diethyl ether to yield 1-phenyl-2-(4-nitrophenyl)-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (0.9 g, 78% yield) as a yellow solid having a melting point of 255°-257° C. and the following analysis:
Reaction SMILES: C=O.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([NH:17][C:18]2[N:19]=[C:20]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)[C:21]3[CH2:27][NH:26][CH2:25][CH2:24][C:22]=3[N:23]=2)[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1.[C:37]([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([NH:17][C:18]2[N:19]=[C:20]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)[C:21]3[CH2:27][N:26]([CH3:37])[CH2:25][CH2:24][C:22]=3[N:23]=2)[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1
Reactant: COc1cccc(Cc2nc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc3c2CNCC3)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cccc(Cc2nc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc3c2CN(C)CC3)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Formaldehyde (3.15 μL, 0.04 mmol) was added to a solution of N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4-(3-methoxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (13.70 mg, 0.03 mmol) in methanol (1.5 mL). Sodium cyanoborohydride (0.943 mg, 0.02 mmol) and acetic acid (1.030 μL, 0.02 mmol) was added and the reaction mixture stirred for 2 h at rt and purified by preparative HPLC to afford the titled compound.