Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.CCN(C(C)C)C(C)C.[NH2:20][C@@H:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1>C(O)CCC>[C@@H:21]1([NH:20][C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1
Reactant: N[C@H]1CCc2ccccc21
Reactant: Clc1nc[nH]c2nccc1-2
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2c(c1)CC[C@@H]2Nc1ncnc2[nH]ccc12
Temperature: 25 °C
Yield: 79.9 %

Procedure:
A solution of 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (2.10 g, 13.6 mmol), DIPEA (3.57 mL, 20.5 mmol) and (S)-(+)-1-aminoindan (1.93 mL, 15.0 mmol) in 1-butanol (60.0 mL) and was heated to reflux for 60 hours, cooled down to room temperature and concentrated. The residue was purified by flash chromatography (0 to 100% EtOAc/DCM) to afford the title compound (2.72 g, 80%).
Reaction SMILES: [NH2:1][CH:2]([C:5]1([CH2:10][CH2:11][CH3:12])[CH2:9][CH:8]=[CH:7][CH2:6]1)[CH2:3][CH3:4].B.[OH:14]O.[OH-].[Na+]>C1COCC1.O>[NH2:1][CH:2]([C:5]1([CH2:10][CH2:11][CH3:12])[CH2:9][CH2:8][CH:7]([OH:14])[CH2:6]1)[CH2:3][CH3:4]
Reactant: CCCC1(C(N)CC)CC=CC1
Reactant: OO
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCC1(C(N)CC)CCC(O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(1-aminopropyl)-1-propylcyclopent-3-ene (63, 1.4 g, 8.25 mmol) was dissolved in THF (15 mL) at 0° C. under argon. Borane (9.1 mL, 9.07 mmol, 1M in THF) was added dropwise over 10 minutes. The reaction mixture was allowed to warm to room temperature before stirring overnight. After cooling to 0° C., water was added (4 mL), followed by hydrogen peroxide (5.8 mL, 30% solution in water) and sodium hydroxide solution (9.1 mL, 1M aqueous solution). After stirring for 5 minutes the mixture was extracted with ethyl acetate, dried over sodium sulphate and evaporated to give 1.54 g of desired product as a mixture of isomers. Rt=0.81, 0.84, 0.88 min (Method M). Detected mass: 186.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]([CH3:8])[C:6]=1[CH3:7].[OH:16][C:17]1[CH:18]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:20]=[CH:21][CH:22]=1.N>O.CC(O)C.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[CH3:8][N:5]1[C:6]([CH3:7])=[C:2](/[N:1]=[C:20]2\[CH:21]=[CH:22][C:17](=[O:16])[CH:18]=[C:19]\2[NH:23][C:24](=[O:26])[CH3:25])[C:3](=[O:15])[N:4]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1c(N)c(=O)n(-c2ccccc2)n1C
Reactant: CC(=O)Nc1cccc(O)c1
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: N
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CC(=O)NC1=CC(=O)C=C/C1=N\c1c(C)n(C)n(-c2ccccc2)c1=O

Procedure:
10 mmol of 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one was dissolved in 30 ml of water. This solution was admixed with 10 mmol of N-(3-hydroxyphenyl)acetamide in solution in 30 ml of 2-propanol, 3 ml of 20% aqueous ammonia and 22 mmol of potassium ferricyanide at a temperature ranging from 5 to 10° C.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[C:13](Cl)(=O)[CH3:14]>C(O)C1C=CC=CC=1>[CH:5]1[CH:7]=[CH:9][C:13]([CH2:14][O:1][CH:2]2[O:10][CH:9]([CH2:11][OH:12])[CH:7]([OH:8])[CH:5]([OH:6])[CH:3]2[OH:4])=[CH:2][CH:3]=1
Reactant: CC(=O)Cl
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: OCc1ccccc1
Product: OCC1OC(OCc2ccccc2)C(O)C(O)C1O
Temperature: 50 °C
Yield: 130 %

Procedure:
D-Mannose (30 g, 167 mmol) and acetyl chloride (13 mL, 167 mmol) was dissolved in benzyl alcohol (250 mL) and heated to 50° C. for 1 h. The resulting solution was concentrated by low pressure distillation. The resulting residue was purified by flash column chromatography (ethyl acetate/methanol, 9:1) and recrystallised from isopropanol/petrol to afford the title compound (29.34 g, 70%) as a white crystalline solid m.p. 126-127° C. [Lit 128-129° C.]; [α]D26+102.0 (c, 1.1 in MeOH); [Lit. [α]D18+73.1 (c, 1.4 in H2O)]; δH (400 MHz, CD3OD) 3.62 (1H, ddd, J4,5 9.5 Hz, J5,6 2.3 Hz, J5,6′ 5.5 Hz, H-5), 3.68 (1H, at, J9.3 Hz, H-4), 3.73-3.78 (2H, m, H-3, H-6), 3.85-3.88 (2H, m, H-2, H-6′), 4.75, 4.52 (2H, ABq, J11.6 Hz, CH2), 4.86 (1H, d, J1,2 1.8 Hz, H-1), 7.28-7.38 (5H, m, ArH).
Reaction SMILES: [F:1][C:2]1[CH:47]=[CH:46][C:5]([C:6]([NH:8][C:9]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41][C:42]([F:45])([F:44])[F:43])[CH:36]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:13][CH:12]=2)=[O:7])=[CH:4][C:3]=1[C:48]([F:51])([F:50])[F:49].[Li+].[OH-].CO>C1COCC1>[F:1][C:2]1[CH:47]=[CH:46][C:5]([C:6]([NH:8][C:9]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41][C:42]([F:43])([F:44])[F:45])[CH:36]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=2)[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:16]=2)=[O:7])=[CH:4][C:3]=1[C:48]([F:49])([F:50])[F:51]
Reactant: CCOC(=O)CCc1ccc(CC(NC(=O)c2ccc(F)c(C(F)(F)F)c2)(c2cccc(OC(F)(F)F)c2)c2cccc(OC(F)(F)F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(CC(NC(=O)c2ccc(F)c(C(F)(F)F)c2)(c2cccc(OC(F)(F)F)c2)c2cccc(OC(F)(F)F)c2)cc1
Temperature: 50 °C

Procedure:
To a solution of ethyl 3-(4-(2-(4-fluoro-3-(trifluoromethyl)benzamido)-2,2-bis(3-(trifluoromethoxy)phenyl)ethyl)phenyl)propanoate (11 mg, 0.015 mmol) in THF (0.75 mL) was added 1 N LiOH (0.15 mL) and methanol (0.30 mL). The reaction mixture was heated at 50° C. for 0.5 h. The solvents were removed under a stream of nitrogen then 1 N HCl (2 mL) was added to the residue and the mixture was extracted with CH2Cl2 (2×5 mL). The combined organics were dried over Na2SO4, filtered and the volatiles removed. The resulting residue was purified on ISCO silica gel eluting with 0 to 10% MeOH/CH2Cl2 to give 3-(4-(2-(4-fluoro-3-(trifluoromethyl)benzamido)-2,2-bis(3-(trifluoromethoxy)phenyl)ethyl)phenyl)propanoic acid (Example 277) as a clear, colorless oil (9 mg, 85% yield). LCMS: RT=2.18 min [M+H] 704.1 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) δ ppm 2.55 (t, J=7.69 Hz, 2H), 2.82 (t, J=7.69 Hz, 2H), 3.83 (s, 2H), 6.54 (d, J=8.35 Hz, 2H), 6.60 (s, 1H), 6.93 (d, J=7.91 Hz, 2H), 6.97 (s, 2H), 7.08-7.14 (m, 4H), 7.17-7.23 (m, 1H), 7.28-7.33 (m, 2H), 7.73-7.77 (m, 1H), 7.83-7.86 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([C:17]([O:19][CH3:20])=[O:18])[CH:3]=1.Cl[CH2:22][CH2:23][O:24][CH2:25][CH2:26]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C>[CH3:20][O:19][C:17]([C:4]1[CH:3]=[C:2]([N:1]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:16]=[CH:15][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:18]
Reactant: ClCCOCCCl
Reactant: CCOC(=O)CCCOc1ccc(N)cc1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(N2CCOCC2)cc1C(=O)OC
Temperature: 70 °C
Reaction time: 24 h
Yield: 79.4 %

Procedure:
A mixture of ethyl 4-(4-amino-2-methoxycarbonyl-phenoxy)butyrate (2.20 g), bis(2-chloroethyl)ether (0.915 ml, 7.81 mmol), potassium carbonate(3.24 g, 23.4 mmol), sodium iodide (2.34 g, 15.6 mmol) and DMF (20 ml) was stirred at 70° C. for 24 hours, and the mixture was concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (silica gel 30 g,.ethyl acetate/hexane=1/4), and the desired fraction was concentrated under reduced pressure to give ethyl 4-(2-methoxycarbonyl-4-morpholinophenoxy)butyrate (2.18 g). IR (KBr): 1732 cm−1.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1.[CH3:15][NH2:16].[O-2].[Ca+2]>C1COCC1>[Cl:14][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[Cl:13])[O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:16][CH3:15]
Reactant: Clc1ccc(OCCCCBr)cc1Cl
Reactant: CN
Agent: [Ca+2]
Agent: [O-2]
Solvent: C1CCOC1
Product: CNCCCCOc1ccc(Cl)c(Cl)c1
Temperature: 125 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
A mixture of 4-(4-bromobutoxy)-1,2-dichlorobenzene (0.03 mol), methylamine (20 g) and calciumoxide (7 g) in THF (100 ml) was stirred at 125° C. overnight in an autoclave. The mixture was filtered over dicalite and the filtrate was evaporated. The residue was taken up in DIPE and the mixture was filtered over dicalite. The filtrate was converted into the hydrochloric acid salt (1:1) with HCl/2-propanol. The precipitate was filtered off and dried, yielding 6 g (70.3%) of 4-(3,4-dichlorophenoxy)-N-methyl-1-butanamine (intermediate 4, mp. 132° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[S:14][C:13]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[N:12][C:11]=2[CH3:20])=[O:9])=[CH:4][C:3]=1[N+:21]([O-])=O>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[S:14][C:13]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[N:12][C:11]=2[CH3:20])=[O:9])=[CH:4][C:3]=1[NH2:21]
Reactant: Cc1nc(NCC(C)C)sc1C(=O)c1ccc(N)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Product: Cc1nc(NCC(C)C)sc1C(=O)c1ccc(N)c(N)c1

Procedure:
7 g of 1-amino-2-nitro-4-(4-methyl-2-isobutylamino-5-thiazoloyl)-benzene are reduced with 40 g of stannous chloride in 150 ml of acetic acid analogously to Example 1. Oily 1,2-diamino-4-(4-methyl-2-isobutylamino-5-thiazoloyl)-benzene is obtained and this is used in the following step.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:8].Cl[C:19]1[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=1>C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:25][C:22]1[CH:21]=[N:20][C:19]([C:12]2[CH:13]=[CH:14][C:9]([CH:7]=[O:8])=[CH:10][CH:11]=2)=[N:24][CH:23]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-c2ncc(F)cn2)cc1
Temperature: 25 °C
Yield: 51.7 %

Procedure:
A suspension of 2M aq. Na2CO3 (7 mL) and 4-formylphenylboronic acid (1.35 g, 9.0 mmol) in ethanol (4 mL) was added to a solution of 2-chloro-5-fluoropyrimidine (922 mg, 7.0 mmol, prepared as described in Org. Prep. Proc. Int. 1995, 27, 600), and [1,4-bis(diphenylphosphino)butane]palladium(II) dichloride (0.209 g, 0.35 mmol) in toluene (15 mL). The reaction mixture was heated to reflux for 6 h, cooled to room temperature, diluted with ethyl acetate, washed with sat. aq. NaHCO3 and brine, dried with Na2SO4, and concentrated in vacuo. Purification by medium pressure liquid chromatography (SiO2, 20:1 hexanes/ethyl acetate) gave 732 mg (52%) of the title compound. MS 203 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]4[O:24][CH2:25][O:26][C:18]=34)=[N:11][CH:12]=[N:13]2)=[C:8]([O:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:7]=1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:23][C:22]1[C:17]([NH:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[CH:7][C:8]=3[O:27][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:13]=[CH:12][N:11]=2)=[C:18]2[O:26][CH2:25][O:24][C:19]2=[CH:20][CH:21]=1
Reactant: C1CCNCC1
Reactant: Clc1ccc2c(c1Nc1ncnc3cc(OCCCBr)cc(OC4CCOCC4)c13)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc2c(c1Nc1ncnc3cc(OCCCN4CCCCC4)cc(OC4CCOCC4)c13)OCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 7-(3-bromopropoxy)-4-(6-chloro-2,3-methylenedioxyanilino)-5-tetrahydropyran-4-yloxyquinazoline (0.536 g), piperidine (0.12 ml), potassium carbonate (0.4 g) and DM (2 ml) was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was triturated under methylene chloride. The mixture was filtered and the filtrate was purified by column chromatography on silica using initially a 1:1 mixture of ethyl acetate and methylene chloride and then a 10:9:1 mixture of ethyl acetate, methylene chloride and a saturated methanolic ammonia solution as eluent. There was thus obtained the title compound (0.53 g); NMR Spectrum: (CDCl3) 1.4-1.5 (m, 2H), 1.55-1.7 (m, 4H), 1.9-2.1 (m, 4H), 2.2-2.3 (m, 2H), 2.4 (m, 4H), 2.5 (m, 2H), 3.6-3.7 (m, 2H), 4.04.1 (m, 2H), 4.15 (m, 2H), 4.8 (m, 1H), 6.08 (s, 2H), 6.52 (d, 1H), 6.75 (d, 1H), 6.85 (d, 1H), 7.0 (d, 1H), 8.55 (s, 1H), 9.35 (s, 1H); Mass Spectrum: M+H+ 541 and 543.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:7]1[CH2:23][CH:8]1[CH2:9][O:10][C:11]1[C:15]([CH3:16])=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:13][N:12]=1>C(O)C>[OH:7][CH:8]([CH2:23][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[CH2:9][O:10][C:11]1[C:15]([CH3:16])=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:13][N:12]=1
Reactant: C1COCCN1
Reactant: Cc1c(OCC2CO2)noc1-c1ccccc1
Solvent: CCO
Product: Cc1c(OCC(O)CN2CCOCC2)noc1-c1ccccc1
Yield: 90.8 %

Procedure:
1.40 g of morpholine was added to a solution of 3.00 g of 3-(2,3-epoxypropoxy)-4-methyl-5-phenylisoxazole (prepared as described in Preparation 3) in 50 ml of ethanol, and the mixture was heated under reflux for 3 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting solid residue was recrystallized from diethyl ether, to give 3.75 g (yield 90.7%) of the title compound as a colorless powder, melting at 94°-95° C.
Reaction SMILES: [C-:1]#[N:2].[K+].C1OCCOCCOCCOCCOCCOC1.O[CH2:23][CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([CH:35]=[CH:36][CH:37]=1)[O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].C(P(CCCC)CCCC)CCC>C(#N)C.CCOCC.C(Cl)(Cl)(Cl)Cl>[C:1]([CH2:23][CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([CH:35]=[CH:36][CH:37]=1)[O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])#[N:2]
Reactant: [C-]#N
Reactant: COC(=O)COc1cccc(CCCO)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CCCCP(CCCC)CCCC
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)COc1cccc(CCCC#N)c1
Reaction time: 0.25 h
Yield: 70.7 %

Procedure:
A mixture of potassium cyanide (1.16 g), 18-crown-6 (236 mg) and acetonitrile (18 ml) was stirred for 15 min under an atmosphere of argon. A mixture of methyl 3-(3-hydroxypropyl)phenoxyacetate (2.0 g) and tributylphosphine (1.99 g) in acetonitrile (10 ml) was added to the reaction mixture, followed by the dropwise addition of a solution of carbon tetrachloride (0.95 ml) in an acetonitrile (10 ml) with cooling in ice bath. The mixture was stirred overnight at room temperature. The mixture was diluted with ether, and washed with aqueous 10% citric acid. After the addition of carbon tetrachloride (10 ml), the mixture was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=9:1) to give the title compound (1.47 g) having the following physical data.
Reaction SMILES: N.Br[C:3]1(Br)[C:5]([CH3:7])([CH3:6])[CH:4]1[CH2:8][CH2:9][C:10]([CH3:14])([OH:13])[C:11]#[CH:12].[Na]>C(OCC)C>[CH3:6][C:5]1([CH3:7])[CH2:3][CH:4]1[CH2:8][CH2:9][C:10]([CH3:14])([OH:13])[C:11]#[CH:12]
Reactant: C#CC(C)(O)CCC1C(C)(C)C1(Br)Br
Agent: N
Agent: [Na]
Solvent: CCOCC
Product: C#CC(C)(O)CCC1CC1(C)C
Reaction time: 4 h
Yield: 48.8 %

Procedure:
Ammonia (54.5 ml) is placed in a reaction flask. A solution of 109.5 g (0.338 mol) of 5-(2',2'-dibromo-3',3'-dimethylcyclopropyl)-3-methyl-1-pentyn-3-ol dissolved in 415 ml of diethyl ether is added. Sodium (37.4 g, 1.662 mol) in small portions is added at -42° to -36° within 11/2 hours. The mixture is stirred for 13/4 h, the ammonia is evaporated and 830 ml of hexane are added dropwise. The mixture is then stirred for 30 minutes and 60 ml of ethanol are added dropwise. The mixture is then poured into a mixture of ice and acetic acid, extracted with ether, washed neutral and evaporated. The crude product (52.9 g) is distilled at 0.06 Torr. In this manner there are obtained 27.4 g (48%) of 5-(2',2'-dimethylcyclopropyl)-3-methyl-1-pentyn-3-ol (purity 75%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]#[N:12])[C:5]2[CH:6]=[CH:7][NH:8][C:9]=2[CH:10]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=2)[N:17]=[C:16]([CH3:25])[C:15]=1[CH3:26]>>[Br:1][C:2]1[CH:3]=[C:4]([C:11]#[N:12])[C:5]2[CH:6]=[CH:7][N:8]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=4)[N:17]=[C:16]([CH3:25])[C:15]=3[CH3:26])[C:9]=2[CH:10]=1
Reactant: N#Cc1cc(Br)cc2[nH]ccc12
Reactant: Cc1nc2ccc(Cl)cc2c(Cl)c1C
Product: Cc1nc2ccc(Cl)cc2c(-n2ccc3c(C#N)cc(Br)cc32)c1C

Procedure:
Prepared according to procedure U using 6-bromo-1H-indole-4-carbonitrile (0.5 g, 2.26 mmol) and 4,6-dichloro-2,3-dimethylquinoline (0.5626 g, 2.49 mmol) to give 6-bromo-1-(6-chloro-2,3-dimethylquinolin-4-yl)-1H-indole-4-carbonitrile as a yellow solid: Mass Spectrum (ESI) m/e=410.0 [M+1 (79Br)] and 412.0 [M+1 (81Br)].
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.[CH:39]12[CH2:47][CH2:46][CH:43]([CH2:44][CH2:45]1)[CH2:42][N:41]([C:48](=O)[CH2:49]Cl)[CH2:40]2>>[CH:43]12[CH2:46][CH2:47][CH:39]([CH2:45][CH2:44]1)[CH2:40][N:41]([CH2:48][CH2:49][O:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:8]([CH:34]([CH3:35])[CH3:36])[C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=3[CH:17]3[CH2:26][CH2:25][C:24]4[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=4[CH2:18]3)=[CH:4][CH:3]=1)[CH2:42]2
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Reactant: O=C(CCl)N1CC2CCC(CC2)C1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CC4CCC(CC4)C3)cc2)C(C)C)c1
Yield: 34.5 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 1-(3-azabicyclo[3.2.2]non-3-yl)-2-chloroethanone (17 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.0 mg) was obtained.
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[N+:17]([O-:19])=[O:18]>>[F:1][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: [F-]
Agent: [K+]
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1F

Procedure:
reacting potassium fluoride with 4-chloro-3,5-dinitrobenzotrifluoride in the liquid phase, at a temperature of about 75° to about 160° Celsius to form 4-fluoro-3,5-dinitrobenzotrifluoride; and
Reaction SMILES: [C:1]([Li])(C)(C)C.[C:6]([O:10][C:11](=[O:20])[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1)([CH3:9])([CH3:8])[CH3:7].CI>C1COCC1>[C:6]([O:10][C:11](=[O:20])[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[C:14]=1[CH3:1])([CH3:9])([CH3:7])[CH3:8]
Reactant: [Li]C(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(NC(=O)OC(C)(C)C)ccnc1Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
tert-Butyllithium (29 mL of 1.7M in pentane, 50 mmol) was added dropwise to a vigorously stirring solution of (2-chloropyridin-4-yl)carbamic acid tert-butyl ester (4.57 g, 20 mmol) in THF (150 mL) at −78° C. under nitrogen. The reaction mixture was kept at this temperature for 4 hours before adding a solution of methyl iodide (3.41 g, 24 mmol) in THF (20 mL). Warmed the reaction mixture to 0° C. over 2 hours, and quenched the reaction with saturated aqueous ammonium chloride solution (100 mL). Extracted into ethyl acetate, washed with brine, dried over magnesium sulfate, and concentrated to dryness. Flash column chromatography on silica gel gave the product as a white solid (2.93 g, 12 mmol). 1H NMR (CDCl3) δ 8.11 (d, 1H), 7.98 (d, 1H), 6.58 (br s, 1H), 2.30 (s, 3H), 1.52 (s, 9H). ESI MS (M+1)+: 243, 245 (Cl).
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[CH2:11]([N:18]1[CH2:23][NH:22][C:21](=[S:24])[NH:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(C)=O>[CH2:11]([N:18]1[CH2:23][N:22]2[C:2]([OH:3])([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:1][S:24][C:21]2=[N:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: S=C1NCN(Cc2ccccc2)CN1
Solvent: CC(C)=O
Product: OC1(c2ccccc2)CSC2=NCN(Cc3ccccc3)CN21
Reaction time: 2 h

Procedure:
A solution of 5.0 grams (0.025 moles) of phenacyl bromide in 40 milliliters of acetone was mixed with a solution of 5.2 grams (0.025 moles) of 5-benzyl-3,4,5,6-tetrahydro-s-triazine-2(1H)-thione in 1200 milliliters of the same solvent and left for 2 hours at room temperature. The solution was then concentrated to 300 milliliters and left overnight. 3-Benzyl-6-hydroxy-6-phenyl-3,4,6,7-tetrahydro-2H-thiazolo[3,2-a]-s-triazine hydrobromide acetonate crystallized as a pale brown solid, m.p. 97°-99° C. The yield was 9.5 grams (82%).
Reaction SMILES: OC(C(F)(F)F)=O.[N:8]1([CH2:14][C:15]2[N:16]=[N:17][C:18]3[C:19](=[C:21]([NH2:26])[N:22]=[C:23]([NH2:25])[N:24]=3)[N:20]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Cl.C(=O)([O-])[O-].[K+].[K+].CC#N.O>CN(C=O)C>[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][N:11]1[CH2:12][CH2:13][N:8]([CH2:14][C:15]2[N:16]=[N:17][C:18]3[C:19](=[C:21]([NH2:26])[N:22]=[C:23]([NH2:25])[N:24]=3)[N:20]=2)[CH2:9][CH2:10]1
Reactant: Fc1cccc(CCl)c1
Reactant: Nc1nc(N)c2nc(CN3CCNCC3)nnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(N)c2nc(CN3CCN(Cc4cccc(F)c4)CC3)nnc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.2 %

Procedure:
To a stirred solution of 3-Piperazin-1-ylmethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine TFA salt 5 (50 mg; 0.08 mmol; prepared in EXAMPLE 4) in dry DMF (1.0 mL) was added m-fluorobenzyl chloride (0.0143 mL; 0.12 mmol) followed by potassium carbonate (55 mg; 0.40 mmol). The mixture was allowed to stir for 24 h at room temperature then taken up into CH3CN/H2O/0.1% TFA. The mixture was purified by reverse phase HPLC (Rainin C18, 0% CH3CN to 50% CH3CN gradient, CH3CN/H2O, 0.1% TFA) and the bright yellow fractions containing the product were lyophilized after removal of CH3CN in vacuo to give 11 mg of yellow colored 3-[4-(3-Fluoro-benzyl)-piperazin-1-ylmethyl]-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine as the trifluoroacetate salt.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][C:37](=[O:54])[CH2:38][C:39]1[CH:44]=[C:43](OS(C(F)(F)F)(=O)=O)[CH:42]=[C:41]([F:53])[CH:40]=1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:54])[CH2:38][C:39]1[CH:44]=[C:43]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:19])[F:20])=[CH:17][C:12]=2[CH2:11][N:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:33])[CH2:31][CH3:32])[CH:42]=[C:41]([F:53])[CH:40]=1)[CH3:35]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Reactant: CCOC(=O)Cc1cc(F)cc(OS(=O)(=O)C(F)(F)F)c1
Product: CCOC(=O)Cc1cc(F)cc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid benzyl ester and (3-fluoro-5-trifluoromethanesulfonyloxy-phenyl)-acetic acid ethyl ester.