Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([S:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[C:5]([CH3:15])[N:6]2[CH2:11][C:12]([OH:14])=[O:13].ClC1C=CC(S[C:32]2[C:40]3[C:35](=CC=C[C:39]=3I)N(CC(O)=O)C=2C)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[C:53]1(B(O)O)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>C(O)C.C1(C)C=CC=CC=1.O.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>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([S:16][C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[N:6]([CH2:11][C:12]([O:14][C:40]([CH3:35])([CH3:32])[CH3:39])=[O:13])[C:5]=2[CH3:15])=[CH:18][CH:19]=1
Reactant: Cc1c(Sc2ccc(Cl)cc2)c2c(I)cccc2n1CC(=O)O
Reactant: OB(O)c1ccccc1
Reactant: Cc1c(Sc2ccc(Cl)cc2)c2c(Br)cccc2n1CC(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1c(Sc2ccc(Cl)cc2)c2c(-c3ccccc3)cccc2n1CC(=O)OC(C)(C)C

Procedure:
To a solution of the product of example 22 part (ii) (0.5 g) in ethanol (0.8 ml) and toluene (3 ml) was added 2M sodium carbonate solution in water (1.4 ml), phenylboronic acid (0.131 g) and tetrakis(triphenylphosphine)palladium(0) (1.2 g). The reaction was heated to reflux for 2 hours, cooled and concentrated in vacuo. The residue was purified by flash column chromatography to give the sub-title compound (0.4 g). This was used in step (ii) without further characterisation.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:20]([O:24][C:25]([N:27]1[CH:32]2[CH2:33][CH2:34][CH:28]1[CH2:29][N:30]([C:35]([C:37]1[CH:38]=[N:39][C:40]([NH2:43])=[CH:41][CH:42]=1)=[O:36])[CH2:31]2)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH:28]2[CH2:34][CH2:33][CH:32]1[CH2:31][N:30]([C:35]([C:37]1[CH:38]=[N:39][C:40]([NH:43][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[NH:2][CH3:1])[N:14]([CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:41][CH:42]=1)=[O:36])[CH2:29]2)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CNC(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nc1)C2
Product: CNC(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1

Procedure:
Following general N—C coupling procedure 1, 2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methylamide, see WO 2010020675, (0.150 g, 0.538 mmol) was combined with 3-(6-amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.188 g, 0.565 mmol, 1.05 eq), which gave 3-[6-(7-cyclopentyl-6-methylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester as a yellow solid and was used directly in step 3. MS m/z 575.9 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH3:7][O-:8].[Na+].C(O)[CH2:11][CH2:12][CH3:13]>>[CH3:7][O:8][CH2:2][C:3]([O:5][CH2:6][CH2:11][CH2:12][CH3:13])=[O:4]
Reactant: CCCCO
Reactant: C[O-]
Reactant: COC(=O)CCl
Agent: [Na+]
Product: CCCCOC(=O)COC
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 75 %

Procedure:
542.5 g (5.0 mol) of methyl chloroacetate are initially introduced and stirred at 25° C. 945.4 g (5.25 mol) of 30% strength sodium methoxide solution are added dropwise in the course of 2.5 h such that a reaction temperature of 65° C. is not exceeded. After the addition, stirring is continued at reflux temperature for a further 3 h. 518.8 g of methanol are then removed from the reaction mixture by distillation. 741.2 g (10 mol) of n-butanol are added to the residue and the mixture is heated under reflux. In the course of this, methanol is removed through a 0.5 m long Multifil column at a reflux ratio of approximately 1:1 (398.7 g of distillate). After 6.5 h, the conversion of the methyl methoxyacetate to the n-butyl methoxyacetate is >98%. After cooling, the reaction mixture is filtered off with suction and the residue is washed with 277 g of n-butanol. The liquid phase (filtrate and wash liquid) of 1,132.9 g is fractionated through a 0.5 m long Multifil column. n-Butyl methoxyacetate (548.1 g, yield 75%) is obtained as the main fraction with a purity >99%, a chlorine content of 10 ppm and a water content of <0.05%.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[C:42]([O:45][CH:46]4[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1.C(N(C(C)C)CC)(C)C.[O:64]1[C:68]([C:69](O)=[O:70])=[CH:67][CH:66]=[N:65]1>C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[C:42]([O:45][CH:46]4[CH2:47][CH2:48][N:49]([C:69]([C:68]5[O:64][N:65]=[CH:66][CH:67]=5)=[O:70])[CH2:50][CH2:51]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Reactant: O=C(O)c1ccno1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)c2ccno2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35 %

Procedure:
HATU (0.31 g) was added to a solution of N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and isoxazole-5-carboxylic acid (0.1 g) in methylene chloride (9 ml). The resulting mixture was stirred at room temperature for 2.5 hrs. Methylene chloride (20 ml) was added and the organics washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The crudes were then purified by flash column chromatography eluting with methanol/methylene chloride (2.5/97.5). Fractions containing the desired product were evaporated to a white foam which was triturated with diethyl ether (20 ml) to give N-(3-chloro-2-fluorophenyl)-6-{[1-(isoxazol-5-ylcarbonyl)piperidin-4-yl]oxy}-7-methoxyquinazolin-4-amine as a white solid (0.110 g). 1H NMR Spectrum: (DMSO d6 373K) 1.88 (m, 2H), 2.09 (m, 2H), 3.61 (m, 2H), 3.84 (m, 2H), 3.96 (s, 3H), 4.78 (m, 1H), 6.87 (s, 1H), 7.29 (m, 1H), 7.29 (s, 1H), 7.42 (m, 1H), 7.59 (m, 1H), 7.93 (s, 1H), 8.39 (s, 1H), 8.64 (s, 1H), 9.28 (br s, 1H); Mass Spectrum: (M+H)+ 498.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:16]=1)[C:8](N(OC)C)=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Mg]Br.Cl>C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([C:8](=[O:9])[CH3:22])[CH:14]=[C:15]([O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:16]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCOc1cc(C(=O)N(C)OC)cc(C(C)(C)C)c1
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1cc(C(C)=O)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-tert-Butyl-N-methoxy-5-(2-methoxyethoxy)-N-methylbenzamide (O3.043; 1.35 g) was dissolved in THF (40 ml), methylmagnesium bromide (3.05 ml, 3 M in ether) was added dropwise at 0° C. and then the mixture was stirred at RT for 2 h. Then the mixture was admixed with 1 N hydrochloric acid (50 ml), diluted with water and extracted by shaking three times with EA. Then the combined EA phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified using silica gel (40 g cartridge, n-heptane/EA gradient of 0-30% in 30 min). 1.0 g of the title compound were obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29]OS(C)(=O)=O)=[CH:23][C:8]=1[C:9]([NH:11][CH2:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2)=[O:10]>O1CCCC1.O>[ClH:6].[Cl:6][C:7]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[CH:23][C:8]=1[C:9]([NH:11][CH2:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2)=[O:10]
Reactant: NCCCO
Reactant: CS(=O)(=O)OCCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Solvent: O
Solvent: C1CCOC1
Product: Cl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCNCCCO)ccc1Cl
Temperature: 25 °C

Procedure:
3-Aminopropanol (1 ml) was added to a solution of 2-chloro-5-[3-[(methylsulfonyl)oxy]propyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.270 g, Example 6e) in tetrahydrofuran (30 ml) and the solution heated at reflux for 12 h. On cooling to ambient temperature the reaction mixture was diluted with water and extracted thrice with dichloromethane. The organic extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure. Purification by preparative reverse phase HPLC eluting with a gradient of acetonitrile/0.1% aqueous ammonium acetate (25-95%), gave the title compound as the acetate salt. Treatment with 4M hydrochloric acid in dioxane gave the title compound as the hydrochloride salt (0.070 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][CH:9]([C:11]2[CH:12]=[C:13]([C:28](O)=[O:29])[CH:14]=[C:15]3[C:20]=2[O:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:17][C:16]3=[O:27])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[NH:32]1[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]1>>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][CH:9]([C:11]2[CH:12]=[C:13]([C:28]([N:32]3[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]3)=[O:29])[CH:14]=[C:15]3[C:20]=2[O:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:17][C:16]3=[O:27])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(Nc1cccc(Cl)c1F)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: OC1CCNCC1
Product: CC(Nc1cccc(Cl)c1F)c1cc(C(=O)N2CCC(O)CC2)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 65.7 %

Procedure:
8-(1-(3-chloro-2-fluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (130 mg, 0.29 mmol) was reacted with piperidin-4-ol (35.3 mg, 0.35 mmol) using a procedure similar to the one described in Example 2.00 to give 8-(1-(3-chloro-2-fluorophenylamino)ethyl)-6-(4-hydroxypiperidine-1-carbonyl)-2-morpholino-4H-chromen-4-one (101 mg, 65.5%) as a white solid. Mass Spectrum: M+H+ 530. NMR Spectrum: (DMSOd6) at 323° K: 1.24 (bs, 2H), 1.62 (d, 3H), 1.63 (bs, 2H), 2.99 (bs, 2H), 3.19 (bs partially hidden by H2O, 2H), 3.49-3.63 (m, 4H), 3.65-3.72 (m, 1H), 3.72-3.78 (m, 4H), 4.62 (d, 1H), 5.04-5.13 (m, 1H), 5.56 (s, 1H), 6.28 (d, 1H), 6.33 (dd, 1H), 6.64 (ddd, 1H), 6.82 (ddd, 1H), 7.57 (d, 1H), 7.77 (d, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C:18](=[CH:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[CH3:24].C(N(CC)CC)C.[Br:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.O>O1CCCC1>[Br:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([O:1][CH2:2][C:3](=[O:25])[C@@H:4]2[C@:21]3([CH3:22])[C@H:7]([C@H:8]4[C:18](=[CH:19][CH2:20]3)[C@:16]3([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]3)[CH2:10][CH2:9]4)[CH2:6][C@H:5]2[CH3:24])(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CO
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)COS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
After dissolving 10.0 g (29.4 mmoles) of 21-hydroxy-16α-methylpregna-1,4,9(11)-triene-3,20-dione in 100 ml of tetrahydrofuran, 7.14 ml (51.4 mmoles) of triethylamine, then at 0° C. 13.1 g (51.4 mmoles) of 4-bromobenzenesulfonyl chloride are added to the above solution and the reaction mixture is stirred at room temperature for 4 hours, then dropwise added to 450 ml of water while stirring. The precipitate is filtered off, dried and recrystallized from ether to give the title compound in a yield of 11.0 g (67.07%), m.p.:124°-129° C.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[CH3:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1>>[CH3:16][C:11]1([CH3:17])[C:12]2[NH:13][C:14]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:15]=3)[C:7]=2[C:8](=[O:30])[C:9]2[CH:21]=[CH:20][C:19]([C:35]3[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=3)=[CH:18][C:10]1=2
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: Cn1cc(-c2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)cn1

Procedure:
Under the same conditions as the method for synthesizing Compound B2-22-1, the title compound was prepared from Compound B1 and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][N:10]([CH3:21])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:24](I)[CH3:25]>CS(C)=O>[CH2:24]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][N:10]([CH3:21])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1)[CH3:25]
Reactant: Cn1cc(-c2ccccc2)c(=O)c(-c2cccc(O)c2)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOc1cccc(-c2cn(C)cc(-c3ccccc3)c2=O)c1
Temperature: 25 °C

Procedure:
A 3.2 g. portion of the product of Example 145 was added to a suspension of 0.86 g. of sodium hydride in 50 ml. of dimethylsulfoxide. The mixture was stirred at room temperature, and 3.5 g. of ethyl iodide was added. The mixture was stirred for two and one-half hours more, and extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and then with water, and dried. The dried extract was then filtered and concentrated to dryness under vacuum. The product was 2.2 g. of 3-(3-ethoxyphenyl)-1-methyl-5-phenyl-4(1H)-pyridone, m.p. 133°-135° C.
Reaction SMILES: [NH2:1][C:2]1([CH3:19])[C:14]2[N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[C:11](=[O:18])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.CO[CH:22]1[CH2:26][CH2:25][CH:24](OC)O1>C(O)(=O)C.O>[CH3:19][C:2]1([N:1]2[CH:22]=[CH:26][CH:25]=[CH:24]2)[C:14]2[N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[C:11](=[O:18])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: COC1CCC(OC)O1
Reactant: CC1(N)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Solvent: CC(=O)O
Solvent: O
Product: CC1(n2cccc2)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Temperature: 20 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
To a solution of 1.3 g of 10-amino-10-methyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one in 25 ml of acetic acid is added 0.66 g of 2,5-dimethoxytetrahydrofuran. The mixture is stirred at boiling for 1 hour, cooled to 20° C. and concentrated to dryness under reduced pressure (15 mmHg; 2 kPa) at 60° C. The product obtained is suspended in 100 ml of distilled water and the insoluble product formed is isolated by filtration, washed successively 4 times with 40 ml in total of distilled water, 3 times with 30 ml in total of methanol and 3 times with 30 ml in total of acetone, and then dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 0.82 g of 10-methyl-10-(1-pyrrolyl)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is thus obtained, melting at 320° C. (decomposition) (Analysis, % calculated C: 71.51, H: 4.67, N: 18.53, O: 5.29, % found C: 71.7, H: 4.5, N: 18.3).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:19]=1.[CH3:20]N(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+].IC>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:20])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:19]=1
Reactant: CN(C)C=O
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCC2)CC1(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Product: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Reaction time: 3 h

Procedure:
To a mixture of 5.5 g (0.0191 mole) of 2-chloro-9-cyclobutyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-1), 25 mL of dimethylformamide and 9.4 g (0.0287 mole) of cesium carbonate was added 10.9 g (0.0764 mole) of iodomethane. The mixture was stirred for 3 hours, then 80 mL of water was added and the solid collected by suction filtration to give 4.8 g of 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[CH:16]=C[C:14]([N:17]2[CH2:21][CH2:20][C@H:19]([NH:22][C:23](=[O:30])[O:24][CH2:25][CH2:26]N(C)C)[CH2:18]2)=[CH:13][CH:12]=1)=[O:10].[NH2:31][C@H]1CCN(C2C=CC(C(NC3C=CC=CC=3NC(=O)OC(C)(C)C)=O)=CN=2)C1.[C:60]([OH:66])(C(F)(F)F)=O.Cl.O1CCOCC1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:21][CH2:20][C@H:19]([NH:22][C:23](=[O:30])[O:24][CH2:25][CH2:26][O:66][CH3:60])[CH2:18]2)=[N:31][CH:16]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(N2CC[C@H](N)C2)nc1
Reactant: O=C(O)C(F)(F)F
Reactant: CN(C)CCOC(=O)N[C@H]1CCN(c2ccc(C(=O)Nc3ccccc3N)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: COCCOC(=O)N[C@H]1CCN(c2ccc(C(=O)Nc3ccccc3N)cn2)C1

Procedure:
Following the procedures described above for the synthesis of compound 119 (Scheme 1, Example 1, steps 4 and 5) but replacing compound 117 with the compound 153, and TFA for HCl/dioxane, title compound 154 was obtained as a beige solid. 1H NMR: (DMSO) δ (ppm): 9.42 (s, 1H), 8.72 (d, J=2.3 Hz, 1H), 8.05 (dd, J=8.8, 2.3 Hz, 1H), 7.65 (d, J=6.5 Hz, 1H), 7.13 (d, J=7.8 Hz, 1H), 6.95 (td, J=7.6, 1.4 Hz, 1H), 6.77 (dd, J=8.0, 1.2 Hz, 1H), 6.58 (td, J=7.5, 1.4 Hz, 1H), 6.49 (d, J=8.8 Hz, 1H), 4.87 (s, 2H), 4.17 (q, J=5.7 Hz, 1H), 4.08 (t, J=4.6 Hz, 2H), 3.67 (q, J=5.7 Hz, 1H), 3.57-3.55 (m, 1H), 3.50-3.47 (m, 3H). 3.3 (m, overlap with water, 1H), 3.25 (s, 3H), 2.22-2.14 (m, 1H), 1.96-1.88 (m, 1H). LRMS (ESI): (calc.) 399.2; (obt.) 400.3 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(N(CC)C(C)C)(C)C.[C:20]([O:24][C:25](=[O:33])[NH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21]>O1CCOCC1>[C:20]([O:24][C:25](=[O:33])[NH:26][CH:27]1[CH2:32][CH2:31][N:30]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:29][CH2:28]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
A solution of 1-fluoro-2-nitro-benzene (0.50 mmol, 53 μL), N,N-diisopropylethylamine (0.50 mmol, 87 μL) and Piperidin-4-yl-carbamic acid tert-butyl ester (0.50 mmol, 0.10 g) in 1,4-dioxane (2 mL) was irradiated using microwave for 10 minutes at a temperature of 180° C. The solution was then cooled to room temperature and concentrated in vacuo and the resulting residue was purified using column chromatography on silica gel to provide [1-(2-Nitro-phenyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.12 g, 77% yield). To the solution of this nitro compound in EtOAc (15 mL) was added Pd on carbon (5% Pd, 55 mg). The resulting reaction mixture was stirred under a hydrogen atmosphere at room temperature for about 15 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to provide Intermediate Compound 42A (97 mg, 86% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=O)[NH:10][N:9]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:23])=O>>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([Cl:23])=[N:10][N:9]=2)=[CH:5][CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(Cc2n[nH]c(=O)c3ccccc23)cc1
Product: COc1ccc(Cc2nnc(Cl)c3ccccc23)cc1

Procedure:
To 4-(4-methoxybenzyl)phthalazin-1 (2H)-one (1.18 g, 4.43 mmol) was added phosphorus oxychloride (4.13 ml, 44.3 mmol). A water condenser was attached and the mixture was heated to reflux under a nitrogen atmosphere for 15 hours. The reaction was concentrated in vacuo, diluted with methylene chloride and ice water, then quenched with solid sodium bicarbonate until pH was basic and gas evolution ceased. The layers were separated and the organic layers were dried over sodium sulfate, filtered through a pad of silica gel using EtOAc and concentrated to yield 1-(4-methoxybenzyl)-4-chlorophthalazine as a light orange solid. MS m/z=285 [M+1]+. Calc'd for C16H13ClN2O: 284.75.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([Cl:29])[C:27]=1[OH:28])[NH2:24]>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:24][C:23]4[CH:22]=[C:21]([Cl:20])[C:27]([OH:28])=[C:26]([Cl:29])[CH:25]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Product: Oc1c(Cl)cc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1Cl

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3,5-dichloro-4-hydroxyaniline were reacted to produce N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3,5-dichloro-4-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.50 (bs, 1H), 9.26 (bd, 2H, J=7.5 Hz), 8.06 (d, 1H, J=3.9 Hz), 7.65 (s, 2H), 7.18–7.13 (m, 2H), 6.80 (d, 1H, J=9.0 Hz), 4.20 (s, 4H); LCMS: purity: 100%; MS (m/e): 424(MH+).
Reaction SMILES: C(O[C@H](C)[C@H](NC(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)C(O)=O)C1C=CC=CC=1.N[C@H](C1C=CC(OC[C@H](O)CO)=CC=1)C(N[C@@H]([C@H](C1C=CC=CC=1)C)C(NC1C=CC(I)=CC=1Cl)=O)=O.C(OC(N[C@@H]([C@H](C1C=CC=CC=1)C)C(O)=O)=O)(C)(C)C.[C:90]([O:94][C:95]([NH:97][C@H:98]([C:102]1[CH:107]=[CH:106][C:105]([O:108][CH2:109][C@H:110]2[CH2:114][O:113][C:112]([CH3:116])([CH3:115])[O:111]2)=[CH:104][CH:103]=1)[C:99]([OH:101])=[O:100])=[O:96])([CH3:93])([CH3:92])[CH3:91]>>[C:90]([O:94][C:95]([NH:97][C@H:98]([C:102]1[CH:107]=[CH:106][C:105]([O:108][CH2:109][C@@H:110]2[CH2:114][O:113][C:112]([CH3:116])([CH3:115])[O:111]2)=[CH:104][CH:103]=1)[C:99]([OH:101])=[O:100])=[O:96])([CH3:93])([CH3:91])[CH3:92]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OC[C@H]2COC(C)(C)O2)cc1
Agent: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](N)c1ccc(OC[C@H](O)CO)cc1)C(=O)Nc1ccc(I)cc1Cl
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OC[C@@H]2COC(C)(C)O2)cc1

Procedure:
Prepared by the same method as described in example 3 except that (i) 2-chloro-4-iodoaniline was used in place of 4-bromo-2-chloroaniline in step 1, (ii) (S)-2-tert-butoxycarbonylamino-3-methyl-butyric acid was used in place (2S,3S)-2-tert-butoxycarbonylamino-3-phenyl-butyric acid in step 1, and (iii) (R)-tert-butoxycarbonylamino-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-acetic acid was used in place of (R)-tert-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acid in step 2. (R)-tert-Butoxycarbonylamino-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-acetic acid was prepared and used as described in example 116.