Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:27]=[CH:26]C3C(=CC=C(C=O)C=3)N=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.C[Mg]Br.O.C([O:37][CH2:38][CH3:39])(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:5]3[C:4](=[CH:3][CH:2]=[C:7]([CH:38]([OH:37])[CH3:39])[CH:6]=3)[N:17]=[CH:26][N:27]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CCOC(C)=O
Reactant: O=Cc1ccc2nc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)ncc2c1
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1

Procedure:
In 30 mL of tetrahydrofuran was dissolved 620 mg of 4 (3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-formylquinazoline (IV-1), the solution was cooled to 0° C. under the nitrogen atmosphere, and 4.9 mL of methylmagnesium bromide (0.93M tetrahydrofuran solution) was added dropwise. After the reaction at 0° C. for 1 hour under the nitrogen atmosphere, water and ethyl acetate were added to separate the layers. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After concentration, the resulting crystal was washed with chloroform to obtain 330 mg of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-hydroxyethan-1-yl)quinazoline (VI-1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22]([C:24]1[S:25][C:26]([N+:30]([O-:32])=[O:31])=[C:27](Br)[CH:28]=1)=[O:23].[CH3:33][C:34]1[C:39]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:38][C:37]([SH:46])=[CH:36][CH:35]=1>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:20][O:21][C:22]([C:24]1[S:25][C:26]([N+:30]([O-:32])=[O:31])=[C:27]([S:46][C:37]2[CH:38]=[C:39]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:34]([CH3:33])=[CH:35][CH:36]=2)[CH:28]=1)=[O:23]
Reactant: Cc1ccc(S)cc1-c1ccccc1
Reactant: COC(=O)c1cc(Br)c([N+](=O)[O-])s1
Agent: CN(C)c1ccncc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Sc2ccc(C)c(-c3ccccc3)c2)c([N+](=O)[O-])s1
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of triphenylphosphine (0.67 g, 2.55 mmol), 4-bromo-5-nitro-thiophene-2-carboxylic acid methyl ester ((Example 114, step c) 1 g, 3.76 mmol) and 4-(dimethyl)aminopyridine resin (1 eq) in THF was added 6-methyl-biphenyl-3-thiol from above step b. This mixture was stirred for 3 hrs. The reaction mixture was filtered and the solvents were removed in vacuo. The residue was purified via column chromatography (SiO2, 15% ethyl acetate/hexane) to afford a yellow glass (600 mg, 61%), which was used in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[O:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C@@H:13]([CH3:49])[CH2:14][O:15][C:16]2[CH:48]=[CH:47][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[N:23](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:22]3=[O:46])=[CH:18][CH:17]=2)[CH2:8]1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[O:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C@@H:13]([CH3:49])[CH2:14][O:15][C:16]2[CH:48]=[CH:47][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:46])=[CH:18][CH:17]=2)[CH2:8]1
Reactant: C[C@@H](COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)N1C[C@H](COc2cccc(Cl)c2)OC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](COc1ccc(CC2SC(=O)NC2=O)cc1)N1C[C@H](COc2cccc(Cl)c2)OC1=O
Yield: 79.8 %

Procedure:
A procedure similar to that described in Example 1 was repeated, except that 0.73 g of 5-[4-{2(S)-[5(R)-(3-chlorophenoxymethyl)-2-oxooxazolidin-3-yl]-propoxy}benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 37), 4 ml of methylene chloride and 4 ml of trifluoroacetic acid were used, to give 0.39 g of the title compound having a melting point of 55° C. to 60° C. (softening) and having [α]D =-52.4° (methanol, c=0.990).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)=[CH:8]2)=[O:4].[NH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:33])[C:5]([C:3]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[CH:24]=2)[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3cccc(C(F)(F)F)c3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3cccc(C(F)(F)F)c3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(3-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (55 mg, 0.12 mmol), β-alanine (863 mg, 9.7 mmol) and NaOMe solution (14.5 mL, 7.3 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3. The organic layer was washed with brine, dried over MgSO4, and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 46 mg of the title compound. MS: (+) m/z 512.27 (M+1).
Reaction SMILES: C1C=C(C(O)=[O:8])C(C(OO)=O)=CC=1.[C:14]1([S:20][CH2:21][C:22]2[NH:23][C:24]([CH3:47])=[C:25]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=3)[C:27]=2[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>CCOC(C)=O>[C:14]1([S:20]([CH2:21][C:22]2[NH:23][C:24]([CH3:47])=[C:25]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=3)[C:27]=2[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:8])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)c1ccccc1C(=O)OO
Reactant: CCOC(=O)C1=C(C)NC(CSc2ccccc2)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C)NC(CS(=O)c2ccccc2)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of monoperphtalic acid in AcOEt (0.37 M solution; 20 ml) is added at 0° C. to a mixture of 2-(phenylthio) methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine (3.5 g) and NaHCO3 (3 g) in AcOEt (20 ml). After 30 minutes the mixture is filtered and the eluate is washed with 1N solution of sodium thiosulfate (2×20 ml) and then with water (3×10 ml). The organic layer is dried on Na2SO4 and evaporated to dryness; the residue is purified by chromatography on SiO2 (hexane/AcOEt 85/15, as eluent) to give 3.5 g of 2-(phenylsulfinyl)methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine, m.p. 160°-162° C.
Reaction SMILES: Cl[C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]=1.[Br:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([NH:14][NH2:15])=[O:13].[OH-].[Na+].C(OCC)C>C1C=CC=CC=1>[N:8]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=1[NH:15][NH:14][C:12](=[O:13])[C:11]1[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=1[Br:9]
Reactant: ClC1=NCCCCC1
Reactant: NNC(=O)c1ccccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=C(NNC1=NCCCCC1)c1ccccc1Br
Yield: 38.7 %

Procedure:
To a solution of 7-chloro-3,4,5,6-tetrahydro-2H-azepine (1.32 g, 10 mmol, J. Med. Chem. 30, 1543-49) in benzene (20 ml) was added 2-bromo-benzoic acid hydrazide (1.08 g, 5 mmol) and the mixture was stirred at reflux temperature for 5 hrs. To the cooled reaction mixture was added 10% sodium hydroxide (10 ml) and diethyl ether (20 ml). The mixture was stirred for 30 min., the precipitate filtered off and dried in vacuo at 50° C. for 1 hr. affording 0.6 g of 2-bromo-benzoic acid-N′-(4,5,6,7-tetrahydro-3H-azepin-2-yl)-hydrazide which was dissolved in ethanol (20 ml) followed by addition of TEA (5 ml) and refluxed for 16 hrs. The volatiles were evaporated in vacuo and to the residue was added diethyl ether (10 ml) and ethyl acetate (5 ml). The precipitate was filtered off and dried in vacuo at 50° C. for 1 hr affording 0.35 g (24%) of the title compound as a solid.
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4]([CH3:17])=[CH:5][CH:6]=[N:7]2.[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].CN(C)P(=O)(N(C)C)N(C)C.C1OC1C>C(N(CC)CC)C>[CH2:18]([O:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4]([CH3:17])=[CH:5][CH:6]=[N:7]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1O
Reactant: CCCCCCCBr
Agent: CC1CO1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCN(CC)CC
Product: CCCCCCCOc1c(OC)cc([N+](=O)[O-])c2nccc(C)c12
Yield: 52 %

Procedure:
A stirred mixture of 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline [from Example 7B]--14.0 g, 0.06 mole - n-heptyl bromide (7.5 g, 0.045 mole) and hexamethylphosphoric triamide (12 ml) was heated at 120°, under N2, while a mixture of triethylamine (1 ml) and propylene oxide (6 ml) was added in small portions during 6 hr. Additional propylene oxide (4 ml) was added during 4 hr and the mixture was cooled and filtered and the dull red solid was washed with acetone to return 7.5 g of starting material. The combined filtrate and washings were diluted with water and the resulting solid was extracted with diethyl ether. The extract was washed with 5% sodium hydroxide and water, treated with carbon, dried (sodium sulfate) and evaporated to dryness. Trituration of the dark brown residual oil with petroleum ether (20°-40°) produced a tan solid which was extracted with additional petroleum ether (700 ml). Concentration of the extract to 300 ml and cooling in a Dry-Ice bath gave 7 g (52%) of 5-heptoxy-6-methoxy-4-methyl-8-nitroquinoline as a pale yellow solid, mp 52°-55°. Recrystallization from petroleum ether (20°-40°) provided the analytical sample as glistening pale yellow crystals, mp 56°-57°.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+]>O1CCCC1.CO>[CH:12](=[C:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCCc2ccccc21
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1C(=Cc2ccccc2)CCc2ccccc21
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A 250 mL flask was charged with tetralone (4 g, 27.4 mmol) and benzaldehyde (3.88 g, 36.6 mmol). This was dissolved in warm tetrahydrofuran (15 mL), and to this yellow solution was slowly added a 4 wt % solution of KOH in methanol (125 mL). The reaction was stirred for 4 days at room temperature. The solvent was then removed under reduced pressure, and it was poured into 150 mL of water and extracted with methylene chloride. The organic extract was dried over magnesium sulfate and filtered, and the solvent was removed at reduced pressure to afford 4.1 g (64%) as white powder.
Reaction SMILES: C1(PC2C=CC=CC=2)C=CC=CC=1.C([Li])CCC.CCCCCC.[ClH:25].Cl.[CH:27]1([CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][N:41]([C:44]3[CH:49]=[CH:48][C:47]([O:50]C)=[CH:46][CH:45]=3)[CH2:40][CH2:39]2)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1>C1COCC1>[ClH:25].[ClH:25].[CH:27]1([CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][N:41]([C:44]3[CH:45]=[CH:46][C:47]([OH:50])=[CH:48][CH:49]=3)[CH2:40][CH2:39]2)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1
Reactant: COc1ccc(N2CCN(CCC3CCc4ccccc43)CC2)cc1
Agent: Cl
Agent: [Li]CCCC
Agent: c1ccc(Pc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Oc1ccc(N2CCN(CCC3CCc4ccccc43)CC2)cc1
Reaction time: 0.17 h

Procedure:
A solution of diphenylphosphine (8.7 ml, 50 mmol) in THF (60 ml) is cooled to 0° under a nitrogen atmosphere and treated with n-butyllithium in hexane (1.6M, 31.3 ml, 50 mmol). After stirring for 10 min, a solution of 4-[2-(indan-1-yl)ethyl]-1-(4-methoxyphenyl)piperazine (CXII, EXAMPLE 70, 6.73 g, 20 mmol) in THF (20 ml) is added. The mixture is refluxed for 24 hr, quenched with water and extracted with ethyl acetate (2×800 ml). The organic phase is washed with water, saline, dried (magnesium sulfate), filtered and concentrated under reduced pressure. The concentrate is purified by liquid chromatography on silica gel 60 (230-400 mesh, 400 g), eluting with hexane/acetone (2/1). The appropriate fractions homogeneous by TLC are combined and concentrated to give the free base of the title compound. This free base is converted into the hydrochloric acid salt and recrystallized from ethyl acetate/methanol to give the title compound, mp 215°-216°, NMR (DMSO-d6, TMS) 7.30-6.68 and 3.68-1.60 δ.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1>N1C=CC=CC=1.C[Si](OS(O[Si](C)(C)C)(=O)=O)(C)C.ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][O:13]1
Reactant: OCCCCCCCCCCBr
Reactant: C1=COCCC1
Agent: C[Si](C)(C)OS(=O)(=O)O[Si](C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: BrCCCCCCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 42.8 %

Procedure:
A mixture of 100 g 1-bromodecan-10-ol, 2.1 g bis(trimethylsilyl)sulphate, 43 g 3,4-dihydro-2H-pyran and 500 ml dichloromethane is stirred for 6 hours at room temperature. Several drops of pyridine are added and the reaction mixture evaporated down. The residue is purified by column chromatography on silica gel using hexane/ethyl acetate (1/1 v/v) as eluent to yield 58 g of 1-bromo-10-[tetrahydropyranyloxy]decane.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][NH:5][CH3:6].C(N(CC)CC)C.[CH:14]([N:17]=[C:18]=[O:19])([CH3:16])[CH3:15]>O1CCCC1>[CH:14]([NH:17][C:18]([N:4]([CH3:3])[NH:5][CH3:6])=[O:19])([CH3:16])[CH3:15]
Reactant: CC(C)N=C=O
Reactant: CNNC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNN(C)C(=O)NC(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
To a solution of N,N'-dimethylhydrazine dihydrochloride (1.33 g) and triethylamine (2.02 g) in dry tetrahydrofuran (20 ml) which was cooled to 0° C., was added isopropyl isocyanate (851 mg). The mixture was stirred at 0° C. for 2 hours. After evaporation of the solvent, the residue was dissolved in ethyl acetate (50 ml). The solution was washed with 1 M sodium bicarbonate solution and water successively, and dried over magnesium sulfate. The solvent was evaporated to give N-(isopropylcarbamoyl)-N,N'-dimethylhydrazine (771 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[CH3:20][N:21]1[CH2:26][CH2:25][CH:24]([CH:27]=O)[CH2:23][CH2:22]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:13])[CH2:27][CH:24]3[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CN1CCC(C=O)CC1
Product: CN1CCC(CN(C)Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction between (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amine and 1-methylpiperidine-4-carbaldehyde using standard reductive amination conditions yielded (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-(1-methyl-piperidin-4-ylmethyl)-amine, which was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Acid/base work-up and trituration with ether yielded 335. 400 MHz 1H NMR CDCl3: 9.30 (s, 2H), 7.26 (s, 1H), 5.30 (br s, 2H, NH2), 4.04 (t, 4H, J 4.5), 3.90 (t, 4H, J 4.5), 3.80 (s, 2H), 2.87 (d, 2H, J 11.5), 2.33 (d, 2H, J 7.1), 2.30 (s, 3H), 2.28 (s, 3H), 1.93 (t, 2H, J 11.7), 1.83 (d, 2H, J 13.1), 1.57-1.51 (m, 1H), 1.32-1.22 (m, 2H). LC-MS (m+1)=469.35
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:11]1([NH:17][CH3:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(O)(C)(C)C.Cl>O>[CH:11]1([N:17]([CH3:18])[C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CNC1CCCCC1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: O
Product: CN(c1ncnc2[nH]ccc12)C1CCCCC1
Yield: 87.8 %

Procedure:
A mixture of 200 mg (1.30 mmol) of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (prepared by the method of Davoll, J. Am. Chem. Soc., (1960). 82, 131), the product from Method A (589 mg/5.21 mmol) and 3 mL of tert-butanol was stirred in a sealed tube at 100° C. for 24 h. The reaction mixture was added to water, acidified to pH 1 with 1 N HCl (aq), washed twice with diethylether (ether) and basified to pH 14 with 1 N sodium hydroxide (NaOH). The resulting precipitate was filtered and dried in vacuo to obtain 263 mg (88%) of the title compound, mp 177-180° C. 1H NMR (400 MHz, CDCl3): δ1.11-1.22 (m, 1H), 1.43-1.63 (m, 4H), 1.73 (br d, 1H, J=13.3 Hz), 1.83-1.90 (m, 4 H), 3.23 (s, 3H), 4.69 (br, 1H), 6.53 (d, 1H, J=3.5 Hz), 7.03 (d, 1H, J=3.5 Hz), 8.30 (s, 1H), 10.6 (br, 1H). LRMS: 231 (M+1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][CH:11]3[CH2:16][CH2:15][CH:14]([N:18]4[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=5)=[O:24])[CH2:19]4)[CH2:13][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C1CCC(Oc2ccc3c(c2)OCO3)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(Oc3ccc4c(c3)OCO4)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(benzo[1,3]dioxol-5-yloxy)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[C:10]([Cl:12])[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=1)[CH2:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C(#N)C>[Cl:12][C:10]1[N:9]=[CH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:23][C:22]3[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]4[CH:26]=[CH:27][CH:28]=[C:14]([F:13])[CH:15]=4)=[CH:25][CH:24]=3)[C:3]=2[CH:11]=1
Reactant: Clc1cc2c(Cl)ncnc2cn1
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Solvent: CC#N
Product: Fc1cccc(COc2ccc(Nc3ncnc4cnc(Cl)cc34)cc2)c1

Procedure:
4,6-Dichloro-pyrido[3,4-d]pyrimidine (1 g) and 4-(3-fluorobenzyloxy)aniline (1.08 g) in acetonitrile (70 ml) were reacted together as in Procedure A. The product was collected by filtration as a yellow solid (1.86 g); m/z 381 (M+1)+.
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[C:6](O)=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:4]1(=[O:17])=[O:16])[CH3:2].CN(C=O)C.C(Cl)(=O)C([Cl:26])=O>C(Cl)Cl>[Cl:26][C:6]1[C:7](=[O:8])[N:3]([CH2:1][CH3:2])[S:4](=[O:17])(=[O:16])[C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCN1C(=O)C(O)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Temperature: 0 °C
Yield: 292.4 %

Procedure:
2-Ethyl-4-hydroxy-5-phenylisothiazol-3(2H)-one 1,1-dioxide (5 g, 19.76 mmol) was dissolved in dry DCM (250 mL) and cooled to 0° C. under N2. Dry DMF (15 mL) was added, followed by oxalyl chloride (3 mL, 34.4 mmol). The ice-bath was removed and the mixture was refluxed at 50° C. under N2 for 4 h. The reaction mixture was evaporated and the residue was diluted with EtOAc and washed with water (3×25 mL) and brine, dried over Na2SO4 and evaporated. Another (16 g, 63.24 mmol) of 2-ethyl-4-hydroxy-5-phenylisothiazol-3(2H)-one 1,1-dioxide was dissolved in dry DCM (500 mL) and cooled to 0° C. under N2. Dry DMF (20 mL) was added followed by oxalyl chloride (9 mL, 103.2 mmol). The ice-bath was removed and the mixture was refluxed at 50° C. under N2 for 4 h. The reaction mixture was evaporated and the residue was diluted with EtOAc and washed with water (3×50 mL) and brine, dried over Na2SO4 and evaporated where by red solid was obtained. The crude material from both batches were combined and purified by column chromatography on silica gel using 2.5-3% EtOAc in petroleum ether as eluant, and recrystallised from MeOH to give the title compound (15.7 g, 70%) as a white solid; 1H NMR (400 MHz, CD3OD) δ 1.42 (t, 3H, J=7.3 Hz), 3.84 (q, 2H, J=7.3 Hz), 7.6-7.7 (m, 3H), 7.9-8.0 (m, 2H); Mass Spectrum: M+H+ 272.
Reaction SMILES: [Cl:1][C:2]1[C:7]2=[CH:8][CH:9]=[CH:10][N:6]2[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.O1CCCC1.[Br:18]N1C(=O)CCC1=O>CO>[Br:18][C:10]1[N:6]2[C:7]([C:2]([Cl:1])=[N:3][C:4]([S:11][CH3:12])=[N:5]2)=[CH:8][CH:9]=1
Reactant: CSc1nc(Cl)c2cccn2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: C1CCOC1
Product: CSc1nc(Cl)c2ccc(Br)n2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a Round bottom flask, [A] 4-Chloro-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (25.47 g, 0.1276 mol), Tetrahydrofuran (1000 mL), and Methanol (640 mL) were added. N-Bromosuccinimide (22.7 g, 0.128 mol) was added portionwise to the reaction for 1 hour at 0° C. The reaction was stirred at room temperature for 1 hour and the solvent was removed under vacuum. The solid was partitioned with water and DCM (500 mL). The organic was separated, washed with Brine, and dried over magnesium sulfate. The solid was filtered and washed with DCM. The filtrate was then reduced under vacuum to afford 7-Bromo-4-chloro-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine as a yellow solid. 7-Bromo-4-chloro-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine was suspended in Isopropyl alcohol (410 mL) at 55° C. Sodium borohydride (10.1 g, 0.268 mol) was added and heated at 60° C. for 3 hours. The reaction was allowed to cool to RT. The solid was filtered and washed with DCM. The solvent was partially removed to ensure the intermediate stayed in solution. (The intermediate is not stable out of solution). Methylene chloride (800 mL) was added to the viscous oil. Dichlorodicyanoquinone (31.8 g, 0.140 mol) was then added portion wise over 15 minutes. The mixture was stirred for 30 minutes. The solid was filtered through Celite, washed with DCM and the filtrate was removed under vacuum. The crude reaction mixture was purified via ISCO column chromatography with hexane and EtOAc as an eluant (0 to 8% EtOAc). The collected fractions afforded 12.2 grams of 7-Bromo-4-chloro-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine as a light yellow solid. 1H NMR (400 MHz, DMSO, d6) δ 8.95 (s, 1H), 7.09 (s, 2H), 2.55 (s, 3H).