Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]([NH:23]S(C(C)(C)C)=O)[CH:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.C([O-])(O)=O.[Na+]>CO.O>[NH2:23][CH:9]([C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2])[CH:10]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)S(=O)NC(c1cccc(C#N)c1)C(c1cccnc1)c1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1cccc(C(N)C(c2cccnc2)c2cccnc2)c1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
N-[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]-2-methylpropane-2-sulfinamide (Diastereomer B, 1.567 g, 3.87 mmol) was dissolved in CH3OH (15 mL) and the solution was cooled to 0° C. HCl (4 M solution in dioxane, 2.905 mL, 11.62 mmol) was added drop-wise. The reaction was allowed to warm to RT and was stirred for 7 hr. The reaction was diluted with H2O and the pH was adjusted to pH=7 using saturated aqueous NaHCO3. The product was extracted with ethyl acetate (3×75 mL) followed by isobutanol (6×50 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to afford 3-(1-amino-2,2-dipyridin-3-ylethyl)benzonitrile as a foamy light yellow solid.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:37]1[NH:42][CH2:41][C:40](=[O:43])[N:39]2[CH2:44][CH2:45][CH2:46][C@H:38]12.C(=O)([O-])[O-].[K+].[K+].[NH4+].[Cl-]>CS(C)=O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:42]3[CH2:41][C:40](=[O:43])[N:39]4[CH2:44][CH2:45][CH2:46][C@@H:38]4[CH2:37]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CNC[C@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CC(=O)N3CCC[C@@H]3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 150 °C

Procedure:
The title compound was prepared starting from 250 mg (0.47 mmole) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO 2005/002577), (8aR)-hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one (D4), 164.4 mg (1.17 mmol), 130 mg of potassium carbonate (0.94 mmol); the reagents were dissolved in 1.5 ml of DMSO. The reaction mixture was heated at 150° C. overnight and then added to a saturated NH4Cl solution and back extracted with DCM; the crude material was purified on SPE cartridge (Silica) eluting with a gradient cyclohexane/ethyl acetate 9:1, to ethyl acetate 100% and affording 115 mg of the title compound as pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11](=[O:19])[N:12]([CH3:18])[C:13]([S:16][CH3:17])=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.Br.C([O-])(O)=O.[Na+].[OH-].[Na+]>CC(O)=O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11](=[O:19])[N:12]([CH3:18])[C:13]([S:16][CH3:17])=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(-c2cnc(SC)n(C)c2=O)cc1F
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CSc1ncc(-c2ccc(O)c(F)c2)c(=O)n1C
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
5-(3-Fluoro-4-methoxyphenyl)-3-methyl-2-methylthio-3H-pyrimidin-4-one (Step 4, 10.05 g, 35.85 mmol) was suspended in glacial HOAc (60 mL) and HBr (240 mL, 48%) was added. The reaction was put in an oil bath (110° C.) and stirred for 1.5 h. The reaction was heated to 120° C. and stirred for an additional 1.5 h, and which time LCMS showed very little starting material. The reaction was cooled to 0° C., and EtOAc (300 mL) was added. Saturated NaHCO3 (0.2 L) was added, the reaction was transferred to a 2 L Erlenmeyer flask, and 0.83 L saturated NaHCO3 was added. The reaction was stirred overnight, then more NaHCO3 (300 mL) and 5 N NaOH (100 mL) was added, and the reaction was stirred for 30 min then filtered. The solid was collected while the pH of the filtrate was adjusted to about 5 using 5 N NaOH and filtered again. The solid from both filtrations was combined and dried in vacuo to give title compound. MS (ESI pos. ion) m/z: 267. Calc'd for C12H11FN2O2S Mol. Wt.: 266.05.
Reaction SMILES: C(Cl)Cl.C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+].B#B.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(COC)OC.O1CCOCC1.O1CCCC1.CCOCC.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:15]
Reactant: c1ccncc1
Agent: B#B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCCCCCCCCCN

Procedure:
An alternative synthesis of 10 can be accomplished by first reacting the amine 6 with a suitable carboxylic acid (as a melt) or with an acid chloride in an inert solvent such as methylene chloride, chloroform, ether or toluene and with a base such as triethylamine, pyridine or sodium bicarbonate present. The intermediate amide is then reduced with a suitable reagent such as diborane in an inert solvent such as ether, tetrahydrofuran (THF), dioxane or dimethoxyethane to afford the desired amine 10.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=O)[CH2:7][C:6]2([CH3:16])[CH3:15].[C:17]([CH2:23][C:24]#[N:25])(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].C(O)(=O)CC.C([O-])(=O)C.[NH4+]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[C:23]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[C:24]#[N:25])[CH2:7][C:6]2([CH3:16])[CH3:15]
Reactant: COc1cc2c(cc1OC)C(C)(C)CC2=O
Reactant: CC(C)(C)C(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCC(=O)O
Solvent: Cc1ccccc1C
Product: COc1cc2c(cc1OC)C(C)(C)CC2=C(C#N)C(=O)C(C)(C)C
Temperature: 120 °C
Yield: 50 %

Procedure:
44 g (0.2 mol) of 5,6-dimethoxy-3,3-dimethyl-1-indanone, 25 g (0.2 mol) of pivaloylacetonitrile, 32 g of propionic acid and 17 g of ammonium acetate are mixed in 80 g of xylene and heated at 120° C. for 7 hours. After the system has been cooled to room temperature and the organic phase has been washed, the xylene is distilled off, and the crude product which remains is recrystallized in methanol. Yield: 50% theory; E1/1730 (λmax 373 nm).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[Si:12]([O:19][C@@H:20]([C@H:22]1[C:30](=[O:31])[N:29]2[C@@H:23]1[CH2:24][C:25](=[O:45])[CH2:26][CH:27]=[C:28]2[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33])[CH3:21])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>ClCCl>[C:8]([O:45][C:25]1[CH2:24][C@H:23]2[N:29]([C:30](=[O:31])[C@@H:22]2[C@H:20]([O:19][Si:12]([C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:14])[CH3:13])[CH3:21])[C:28]([C:32]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=2)=[O:33])=[CH:27][CH:26]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCC(=O)C[C@H]12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1=CC=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2C1
Reaction time: 0.08 h
Yield: 77.6 %

Procedure:
Triethylamine (1.1 ml, 7.5 mmol) followed by acetyl chloride (0.295 ml, 4.1 mmol) were added to a solution of 4-nitrobenzyl (7R,8S)-8-[(1R)-1-(tert-butyldimethylsilyloxy)-ethyl]-5,9-dioxo-1-azabicyclo[5.2.0]non-2-ene-2-carboxylate (1.67 g, 3.4 mmol) in anhydrous dichloromethane (220 ml) cooled with an ice bath. After 5 minutes, the reaction mixture was washed with water and dried over magnesium sulphate. The solvent was evaporated and the residue purified by flash chromatography, eluting with dichloromethane/ethyl acetate (95:5) to give 4-nitrobenzyl (7R,8S)-5-acetoxy-8-[(1R)-1-(tertbutyldimethyl-silyloxy)ethyl]-9-oxo-1-azabicyclo[5.2.0]non-2,4-diene-2-carboxylate (1.4 g, 77%).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[N:16]2[CH2:19][CH:18]([NH:20][CH2:21][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=3)[CH2:17]2)=[CH:11][CH:10]=1.[C:37](Cl)(=[O:39])[CH3:38]>ClCCl>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)[N:16]2[CH2:17][CH:18]([N:20]([CH2:21][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=3)[C:37](=[O:39])[CH3:38])[CH2:19]2)=[CH:31][CH:32]=1
Reactant: Fc1cc(F)cc(CNC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 0 °C

Procedure:
1.6 cm3 of triethylamine are added, at room temperature under an argon atmosphere, to a solution of 2 g of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorobenzyl)amine in 75 cm3 of dichloro-methane. The mixture is cooled to around 0° C. before adding dropwise thereto 0.66 cm3 of acetyl chloride, and then it is stirred at room temperature for 16 hours. The reaction mixture is diluted with 50 cm3 of dichloromethane and is then washed with twice 20 cm3 of distilled water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluent:dichloromethane/methanol (98/2 by volume)]. 1.2 g of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorobenzyl)acetamide are obtained in the form of a colorless oil [1H NMR spectrum (300 MHz, CDCl3, δ in ppm). A mixture of rotamers is observed. *2.06 and 2.14 (2s:3H in total); 2.97 (mt:2H); 3.43 (mt:2H); 4.20 and 4.25 (2s:1H in total); 4.54 and from 4.75 to 4.80 (mt:1H in total); 4.68 and 4.78 (broad 2s:2H in total); 6.70 (mt:3H); 7.24 (broad s :8H)].
Reaction SMILES: [C-:1]#[N:2].[K+].[Cl:4][C:5]1[C:6](F)=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.[F-]>O.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[Cl:4][C:5]1[C:6]([C:1]#[N:2])=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1
Reactant: [C-]#N
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Product: N#Cc1ncc(C(F)(F)F)cc1Cl
Yield: 90 %

Procedure:
A solution of potassium cyanide (71.6 g) in water (215 g) was added during 1 hour to a stirred mixture of 3-chloro-2-fluoro-5-trifluoromethylpyridine (199.5 g) and Aliquat 336 (tricaprylylmethylammonium chloride, 12.1 g) at 30° C. Stirring was maintained at this temperature for 4 hours at which time the amount of starting fluoride was less than 1% by hplc. The lower organic phase was separated and washed with aqueous sodium chloride solution and distilled to give 3-chloro-2-cyano-5-trifluoromethylpyridine (185.8 g, 90% yield) bp 90° C. at 15 mbar. The purity of this product was 98%.
Reaction SMILES: [N:1]1([C:6]2[C:7]([OH:12])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.CO[C:15]1(OC)[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:17][CH2:16]1.B(F)(F)F.CCOCC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH:11]1[C:6]2[N:1]3[CH:2]=[CH:3][CH:4]=[C:5]3[C:15]3([CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:22])[CH2:17][CH2:16]3)[O:12][C:7]=2[N:8]=[CH:9][CH:10]=1
Reactant: Oc1ncccc1-n1cccc1
Reactant: COC1(OC)CCN(C(=O)OCc2ccccc2)CC1
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(OCc1ccccc1)N1CCC2(CC1)Oc1ncccc1-n1cccc12
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3-pyrrol-1-ylpyridin-2-ol (481 mg, 3.00 mmol) and benzyl 4,4-dimethoxypiperidine-1-carboxylate (922 g, 3.3 mol) in CH2Cl2 (20 mL) at 40° C. was added BF3.OEt2 (407.3 μL, 3.300 mmol) drop-wise. The reaction mixture was stirred at 40° C. for 16 hours. The mixture was poured into sat. aq. Na2CO3 and was stirred for 5 min before it was extracted with EtOAc (3×). Organic layers were combined, washed with sat. aq. Na2CO3, water, brine, dried (Na2SO4) and evaporated to dryness. The residue was purified by column chromatography (1-30% EtOAc/CH2Cl2) to give benzyl spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate as an oil. ESI-MS m/z calc. 375.2. found 376.5 (M+1)+; Retention time: 1.70 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 8.10 (dd, J=7.7, 1.1 Hz, 1H), 8.00 (dd, J=4.9, 1.5 Hz, 1H), 7.60-7.52 (m, 1H), 7.42-7.36 (m, 4H), 7.36-7.29 (m, 1H), 7.16 (dd, J=7.8, 4.9 Hz, 1H), 6.33 (t, J=3.2 Hz, 1H), 6.20 (d, J=3.4 Hz, 1H), 5.11 (s, 2H), 3.97 (d br, J=13.2 Hz, 2H), 3.28 (s br, 2H), 1.98-1.92 (m, 4H).
Reaction SMILES: [C:1]([CH:4]([CH3:20])[CH2:5][CH2:6][CH2:7][C:8]1([CH3:19])[CH:14]2[O:15][C:11]([CH2:16][CH2:17][OH:18])([CH2:12][CH2:13]2)[CH2:10][O:9]1)([OH:3])=O.[H-].[Li+].[CH3:23][C:24]([CH3:28])=[CH:25][CH2:26][Li].C(=O)(O)[O-].[Na+]>CCOCC>[CH3:20][CH:4]([C:1](=[O:3])[CH2:26][CH:25]=[C:24]([CH3:28])[CH3:23])[CH2:5][CH2:6][CH2:7][C:8]1([CH3:19])[CH:14]2[O:15][C:11]([CH2:16][CH2:17][OH:18])([CH2:12][CH2:13]2)[CH2:10][O:9]1
Reactant: CC(CCCC1(C)OCC2(CCO)CCC1O2)C(=O)O
Reactant: [Li]CC=C(C)C
Agent: O=C([O-])O
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)=CCC(=O)C(C)CCCC1(C)OCC2(CCO)CCC1O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (1RS,4SR,5RS)-4-(4-carboxypentyl)-4-methyl-3,8-dioxabicyclo[3.2.1]octane-1-ethanol (58 mg, 0.2 mM), lithium hydride (10 mg, 1.25 mM) and ether (5 ml) is stirred at room temperature under nitrogen for two hours. An excess of 3-methyl-2-butenyl lithium is added to this mixture at room temperature. The resulting mixture is stirred for two hours and then treated with 5% sodium bicarbonate solution (5 ml) and extracted with ethyl acetate (3×20 ml). The combined organic layers are dried (Na2SO4), evaporated in vacuo and the residue is purified by column chromatography on silica gel (7 g) with ether to give (1RS,4SR,5RS)-4-(4,8-dimethyl-5-oxo-7-nonenyl)-4-methyl-3,8-dioxabicyclo[3.2.1]octane-1-ethanol (13 mg), 25%) as a colorless oil).
Reaction SMILES: [CH:1]([NH:3][C@H:4]1[C:7](=[O:8])[NH:6][C@@H:5]1[CH2:9][C:10]([O:16][CH3:17])=[CH:11][C:12]([O:14][CH3:15])=[O:13])=O.N1C(C)=CC=CC=1C.P(Cl)(Cl)(Cl)=O>ClCCl.C(OCC)(=O)C>[N+:3]([C@H:4]1[C:7](=[O:8])[NH:6][C@@H:5]1[CH2:9][C:10]([O:16][CH3:17])=[CH:11][C:12]([O:14][CH3:15])=[O:13])#[C-:1]
Reactant: COC(=O)C=C(C[C@H]1NC(=O)[C@@H]1NC=O)OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: [C-]#[N+][C@H]1C(=O)N[C@@H]1CC(=CC(=O)OC)OC
Reaction time: 4 h
Yield: 56.9 %

Procedure:
To a solution of methyl 4-[(2R,3R)-3-formamido-4-oxoazetidin-2-yl]-3-methoxybut-2-enoate[(E,Z)-isomeric mixture](133 mg) and 2,6-lutidine (0.96 ml) in dichloromethane (3 ml) was added phosphorus oxychloride (0.15 ml) at 0°. After stirring at the same temperature for four hours, the reaction mixture was diluted with ethyl acetate (20 ml), and washed with a dilute aqueous sodium chloride, dilute phosphoric acid, a dilute aqueous sodium chloride, ice-water, and a saturated aqueous solution of sodium chloride in turn. Drying over magnesium sulfate and removal of the solvent gave a brown oil, which was chromatographed on silica gel (2 g) eluting with 3% methanol in dichloromethane to give methyl 4-[(2R,3R)-3-isocyano-4-oxoazetidin-2-yl]-3-methoxybut-2-enoate[(E,Z)-isomeric mixture](70 mg) as a crystalline solid
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[C:3]#[CH:4].C([Li])CCC.C(O[C:15]1[CH:25]=[C:24](I)[CH:23]=[CH:22][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>[Cl-].[Zn+2].[Cl-].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.O1CCCC1>[F:1][C:2]([F:6])([F:5])[C:3]#[C:4][C:24]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:25]=1
Reactant: CCOC(=O)c1ccc(I)cc1OCC
Reactant: C#CC(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#CC(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 62.7 %

Procedure:
3,3,3-Trifluoro-1-propyne (approx. 0.6 mL, approx. 6 mmol) was condensed in a flame-dried Schlenk tube immersed in a dry ice/acetone bath. Tetrahydrofuran (3 mL) was added followed by a solution of butyllithium in hexanes (2.15 mL, 3.44 mmol, 1.6 M). After stirring 2.5 h at −78° C., zinc chloride (6.87 mL, 3.44 mmol, 0.5 M solution in tetrahydrofuran) was added to the reaction mixture and the reaction vessel was transferred to an ice-water bath and maintained at 0° C. for 30 min. Ethyl 2-ethoxy-4-iodobenzoate (1.00 g, 3.12 mmol, prepared as described in example 14) and tetrakis(triphenylphosphine)palladium(0) (0.18 g, 0.16 mmol) were then added. The reaction vessel was allowed to warm to room temperature and then after 1 h warmed to 50° C. for 18 h. After cooling, the reaction mixture was partitioned between brine (70 mL) and methylene chloride (2×100 mL), dried over magnesium sulfate and evaporated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 1/1 mixture of methylene chloride and hexanes) gave ethyl 4-trifluoroprop-1-ynylbenzoate as an off-white solid (0.474 g, 53%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]2=[O:28])[C:10](=[O:29])[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.NC1CCN(CCN2C3C=C(OC)C=CC=3COC2=O)CC1>>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]2=[O:28])[C:10](=[O:29])[CH2:9]1
Reactant: COc1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1=O)C(=O)CO2
Agent: COc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)OC2
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)N(CCN1CCC(N)CC1=O)C(=O)CO2

Procedure:
tert-Butyl{1-[2-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-2-oxopiperidin-4-yl}carbamate (Intermediate 115, 350 mg, 0.83 mmol) was reacted as described for Intermediate 106. The crude trifluoro acetate of the title compound was obtained as a black oil, 395 mg (quantitative), and used without further purification for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]([O:26]C)=O)=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21.C([NH2:30])=O.C[O-].[Na+]>CN(C)C=O.[Cl-].[NH4+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]([NH2:30])=[O:26])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)cc(Cl)cc1Cl
Reactant: NC=O
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1cc(Cl)cc(Cl)c1N1CCCn2c1nc1c(Cl)ccc(C(N)=O)c12
Temperature: 120 °C
Reaction time: 14 h

Procedure:
A mixture of methyl 9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (1.00 g, 2.35 mmol), formamide (0.937 mL, 2.35 mmol) and sodium methoxide (28% solution in methanol, 2.4 mL) in N,N-dimethylformamide (6 mL) was stirred at 120° C. for 14 hr. The mixture was diluted with aqueous saturated ammonium chloride. The resultant precipitate was collected by filtration, washed with water and diisopropyl ether to give the title compound as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([C:19](O)=[O:20])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.ClC(N(C)C)=C(C)C.[NH2:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]1[OH:37].C(N(C(C)C)C(C)C)C>ClCCl>[OH:37][C@@H:32]1[CH2:33][CH2:34][CH2:35][CH2:36][C@H:31]1[NH:30][C:19]([C:5]1[CH:4]=[N:3][C:2]([Br:1])=[C:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=2)[N:6]=1)=[O:20]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C(O)c1cnc(Br)c(-c2ccc(OC(F)(F)F)cc2)n1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Br)c(-c2ccc(OC(F)(F)F)cc2)n1
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To a solution of 1.0 g (0.0028 mol) of 5-bromo-6-(4-trifluoromethoxy-phenyl)-pyrazine-2-carboxylic acid in 80.0 ml dichloromethane was added at room temperature 0.4 ml (0.405 g 0.0030 mol) (1-chloro-2-methyl-propenyl)-dimethyl-amine and the mixture was stirred for 0.5 hours. To the resulting dark solution was added 0.35 g (0.0030 mol) (1R,2R)-2-amino-cyclohexanol and 0.94 ml (0.712 g, 0.0060 mol) N-ethyldiisopropylamine and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then partitioned between 10% aqueous citric acid and ethyl acetate. The phases were separated and the organic phase washed with 10% aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel with a gradient of 100% heptane to heptane with 40% ethyl acetate to yield 1.107 g of the tile compound as a white waxy solid. MS (ISP) (M+H+)=360.0 and 362.0.
Reaction SMILES: Cl.[C:2](=[NH:12])(OCC)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17]>CO.[OH-].[Na+]>[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH:17][C:2](=[NH:12])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=N)c1ccccc1
Reactant: COC(CN)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(CNC(=N)c1ccccc1)OC
Reaction time: 72 h
Yield: 104.5 %

Procedure:
(EX-1A) A solution of ethyl benzimidate hydrochloride (92.25 g, 496.9 mmol) in 300.0 mL dry methanol (1.68 M) was cooled to ca 0° C. and added a solution of aminoacetaldehyde dimethyl acetal (73.10 mL, 670.9 mmol) in dry methanol (75.0 mL, 9.0 M) drop wise at such a rate the temperature was kept below 5° C. The resulting solution was allowed to stir for 3 days with the temperature being maintained below 5° C. The reaction mixture was then concentrated under reduced pressure to give a yellow oil. The residue was dissolved in 1 N NaOH (750 mL) and extracted with dichloromethane (4×250 mL). The organic solutions were combined, dried (MgSO4), and concentrated to give 108.13 g crude N-(2,2-dimethoxyethyl)benzamidine as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1.Cl>CC(O)C>[ClH:11].[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:24][CH3:25])[N:15]=[CH:14][N:13]=[C:12]2[N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:10]=2)[CH2:6][CH2:7]1
Reactant: Cc1ccc2c(c1)NCC2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4ccc(C)cc43)c2cc1OC
Yield: 88 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 88% yield from 6-methyl-indoline (1.1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. The HCl salt was generated from the purified free base according to the procedure given in Example 2 (M.P. 231°-232° C.; LC-MS: 322 (MH+); anal. RP18-HPLC RT: 4.32 min.).