Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:28]=[C:27]([CH2:29][CH3:30])[S:26][C:17]=2[N:18]=[C:19]([C:21]2[O:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[O:25]1[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[CH:28]=[C:27]([CH2:29][CH3:30])[S:26][C:17]=3[N:18]=2)=[CH:22][CH:23]=[N:24]1
Reactant: CCc1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCCc1ccc2c(c1)OCCO2
Product: CCc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(isoxazol-5-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]([C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH:20]=[CH:21][C:22]=1F>>[C:24]([C:19]1[CH:20]=[CH:21][C:22]([O:1][C:2]2[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=2)=[C:17]([Cl:16])[CH:18]=1)(=[O:25])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Reactant: O=C(c1ccccc1)c1ccc(F)c(Cl)c1
Product: O=C(O)Cc1cc(Oc2ccc(C(=O)c3ccccc3)cc2Cl)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 25 step (iv) and the product from step (i).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:41](=[N:43]O)[NH2:42])=[CH:37][CH:36]=1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]2[O:18][N:43]=[C:41]([C:38]3[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=3)[N:42]=2)[N:8]([C:6]([C:31]2[CH:30]=[CH:29][C:28]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:33][CH:32]=2)=[O:7])[CH2:12]1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NC(=NO)c1ccc(F)cc1
Product: CON=C1C[C@@H](c2nc(-c3ccc(F)cc3)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 59, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylic acid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, and 4-fluoro-N′-hydroxybenzenecarboximidamide, the title compound was obtained in 79% purity by HPLC. MS(ESI+): m/z=457.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=1[S:41](Cl)(=[O:43])=[O:42]>>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=1[S:41]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)(=[O:23])=[O:24])(=[O:42])=[O:43]
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Product: COc1ccc(OC)c(S(=O)(=O)Nc2ccc(N3CCNCC3)cc2NS(=O)(=O)c2ccccc2)c1

Procedure:
2,5-Dimethoxy-N-[2-[(phenylsulfonyl)amino]4-(1-piperazinyl)phenyl]benzenesulfonamide was synthesized from of N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 2,5-dimethoxybenzenesulfonylchloride (57 mg, 0.239 mmol) according to general method 3 to give 60 mg of a purple solid. MS (posES-FIA) m/z=Found: 533.1; Calcd: 533.14; 1H-NMR δ 7.68-7.48 (m, 5H), 7.16-7.05 (m, 4H), 6.69 (dd, 1H), 6.42 (d, 1H), 4.03 (s, 3H), 3.69 (s, 3H), 3.26-3.10 (m, 8H).
Reaction SMILES: OC[CH2:3][C:4]1[C:9](=O)[N:8]2[N:11]=[CH:12][CH:13]=[C:7]2[NH:6][C:5]=1[CH3:14].C(N(CC)CC)C.P(Cl)(Cl)([Cl:24])=O.[CH:27]([Cl:30])(Cl)Cl>>[Cl:24][C:9]1[N:8]2[N:11]=[CH:12][CH:13]=[C:7]2[N:6]=[C:5]([CH3:14])[C:4]=1[CH2:3][CH2:27][Cl:30]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1[nH]c2ccnn2c(=O)c1CCO
Reactant: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc2ccnn2c(Cl)c1CCCl
Temperature: 100 °C
Yield: 59.8 %

Procedure:
To 5.30 g (27.46 mmol) of 6-(2-hydroxyethyl)-5-methylpyrazolo[1,5-a]pyrimidin-7(4H)-one were added 8.5 ml (d=0.726, 61.10 mmol) of triethylamine. While cooling with ice water and stirring under a nitrogen atmosphere, 8.5 ml (d=1.645, 91.19 mmol) of phosphorus oxychloride were added dropwise to the mixture over 2 minutes. The resultant mixture was then stirred for 1 hour in an oil bath heated to 100° C. Thereafter, the reaction mixture was cooled with ice water and dissolved in 100 ml of chloroform, and the solution was poured into 500 ml of ice water. After full shake of the resultant mixture, the chloroform layer was separated, and the water layer was further extracted with chloroform (100 ml×2), and the chloroform layers were put together. After the whole chloroform layer was dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was subjected to column chromatography on silica gel (chloroform) to obtain 3.7 g (yield: 59.8%) of the intended product.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)[CH3:3].C(Cl)(=O)C(Cl)=O.[CH2:19]([N:21]1[C:29]2[CH:28]=[C:27]([NH2:30])[N:26]=[CH:25][C:24]=2[C:23]([CH3:31])=[CH:22]1)[CH3:20]>C1(C)C=CC=CC=1.ClCCl>[CH2:19]([N:21]1[C:29]2[CH:28]=[C:27]([NH:30][C:8](=[O:10])[C:7]3[CH:6]=[CH:5][C:4]([C:2]([CH3:3])=[CH2:1])=[CH:12][CH:11]=3)[N:26]=[CH:25][C:24]=2[C:23]([CH3:31])=[CH:22]1)[CH3:20]
Reactant: CCn1cc(C)c2cnc(N)cc21
Reactant: C=C(C)c1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=C(C)c1ccc(C(=O)Nc2cc3c(cn2)c(C)cn3CC)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
In a 50 ml round bottom flask, 4-(prop-1-en-2-yl)benzoic acid (1.0 g, 6.3 mmol) was dissolved in 15 ml toluene and 2.0 M oxalyl dichloride (6.3 ml, 13 mmol) in dichloromethane was added slowly. Stirring continued for 3 hours, and then volatiles were evaporated from the reaction mixture. To the residue was added 5 ml toluene and the mixture was concentrated in vacuo to azeotropically remove residual water. The residue was then dissolved in DMA (10 ml) and 1-ethyl-3-methyl-1H-pyrrolo[3,2-c]pyridin-6-amine (1Q, 550 mg, 3.14 mmol) was added. Stirring continued at 50° C. overnight. The mixture was then poured into ice water. The precipitate was collected and dried to obtain the product N-(1-ethyl-3-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(prop-1-en-2-yl)benzamide (6B, 820 mg, 82%). This was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:3]2[S:18][C:17]([NH2:19])=[N:16][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=1.[NH2:20][C@H:21]([CH2:24][CH3:25])[CH2:22][OH:23].CN1CCCC1=O.C(N(CC)C(C)C)(C)C>O>[NH2:19][C:17]1[S:18][C:3]2[C:2]([NH:20][C@H:21]([CH2:24][CH3:25])[CH2:22][OH:23])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:5][C:4]=2[N:16]=1
Reactant: CC[C@@H](N)CO
Reactant: Nc1nc2nc(SCc3ccccc3)nc(Cl)c2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: CC[C@H](CO)Nc1nc(SCc2ccccc2)nc2nc(N)sc12

Procedure:
To a mixture of the product of example 1 step c) (2.5 g) and (R)-(−)-2-amino-1-butanol (5 g) in a solvent of N-methylpyrrolidinone (10 ml) was added N,N-diisopropylethylamine (5 ml) and the resultant mixture heated at 100° C. for 10 hours. The mixture was poured into water and the product collected by filtration to give the subtitle compound (2.5 g)
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH2:22])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:1]([C:8]1[C:9]([NH:22][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ncc(-c3ccc(OC)cc3)nc2Cc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 17 h
Yield: 80.8 %

Procedure:
To a solution of 3-benzyl-5-(4-methoxyphenyl)pyrazin-2-amine (12) (synthesized by the process of M. Adamczyk, et al., Org. Prep. Proced. Int., 33, 477-485 (2001)) (500 mg, 1.72 mmol) in pyridine (5 mL) were successively added 4-(dimethylamino)pyridine (21.0 mg, 172 μmol) and 4-methoxybenzoyl chloride (17) (587 mg, 3.44 mmol) at room temperature, and the mixture was heated with stirring at 50° C. for 17 hours. After cooling to room temperature, to the mixture was added water and the product was extracted with dichloromethane (×3). The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residual pyridine was azeotropically removed with toluene (×3). The residue was purified by column chromatography (silica gel 50g, dichloromethane/ethyl acetate=9/1). The residue was further recrystallized from ethyl acetate to give Compound 11x (592 mg, 1.39 mmol, 80.8%) as a colorless solid. Rf=0.63 (dichloromethane/ethyl acetate=9/1); 1H NMR (400 MHz, DMSO-d6) δ 3.83 (s, 3H), 3.85 (s, 3H), 4.17 (s, 2H), 7.04-7.11 (m, 4H), 7.14-7.26 (m, 5H), 7.93-7.98 (AA′BB′, 2H), 8.05-8.11 (AA′BB′, 2H), 8.96 (s, 1H), 10.63 (s, 1H); 13C NMR (67.8 MHz, DMSO+CDCl3) δ 40.3, 54.7, 54.8, 112.9 (2C), 113.7 (2C), 125.4, 125.7, 127.4 (2C), 127.7 (2C), 128.0, 128.5 (2C), 129.4 (2C), 136.2, 137.6, 143.6, 148.2, 150.4, 160.1, 162.0, 165.5; IR (KBr, cm−1) 700, 743, 843, 1030, 1159, 1177, 1258, 1290, 1452, 1485, 1514, 1535, 1580, 1609, 1643, 3242; Anal. Calcd. For C26H23N3O3: C, 73.39; H, 5.45; N, 9.88. Found: C, 73.48; H, 5.40; N, 9.94.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:31][CH:30]3[CH:26]([CH2:27][NH:28][CH2:29]3)[CH2:25]2)[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:20])[CH3:19])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].Cl[C:33]1[N:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36].CC[N:44]([CH:48]([CH3:50])C)[CH:45](C)C.N1CCC1>C(Cl)Cl.C1COCC1>[N:44]1([C:33]2[C:34]([C:35]([N:28]3[CH2:29][CH:30]4[CH2:31][N:24]([CH2:23][CH2:22][CH2:21][N:9]([C:4]5[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([Cl:1])[CH:3]=5)[C:10]([CH:12]5[CH2:17][CH2:16][N:15]([C:18](=[O:20])[CH3:19])[CH2:14][CH2:13]5)=[O:11])[CH2:25][CH:26]4[CH2:27]3)=[O:36])=[CH:38][CH:39]=[CH:40][N:41]=2)[CH2:45][CH2:50][CH2:48]1
Reactant: CC(=O)N1CCC(C(=O)N(CCCN2CC3CNCC3C2)c2ccc(C)c(Cl)c2)CC1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)c1cccnc1Cl
Agent: C1CNC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)N1CCC(C(=O)N(CCCN2CC3CN(C(=O)c4cccnc4N4CCC4)CC3C2)c2ccc(C)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 42b (0.063 g, 0.138 mmol) and 2-chloronicotinoyl chloride (73, 0.027 g, 0.15 mmol) in DCM (3 mL) at RT was added DIPEA (0.05 mL, 0.27 mmol). The mixture was stirred overnight at RT and the solvent was evaporated. The residue as obtained contained 74a and was treated with a solution of azetidine (0.1 mL, excess) in THF (2 mL). The reaction mixture was heated at 80° C. with stirring for 4 h. The reaction mixture was cooled to RT and the solvents evaporated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with MeOH (containing 10% NH4OH)/DCM (0 to 4% MeOH/NH4OH). The recovered material was dissolved in DCM and cyclohexane was added which resulted in the separation of an oil. The solvents were decanted and product dried in vacuo to afford 0.045 g of II-356: mp 72.9-74° C.; Anal. calcd. for C33H43ClN6O3 (containing 0.5 mol of C6H12 and 0.5 mol of H2O): C, 65.69; H, 7.66; N, 12.77. Found: C, 65.99; H, 7.47; N, 12.61; ms (ES+) m/z 607 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13].CCN(C(C)C)C(C)C.[CH2:26]([CH2:28][NH2:29])[OH:27]>CCCCO>[F:9][C:10]1[CH:11]=[C:12]([NH:13][C:6]2[N:7]=[CH:2][N:3]=[C:4]([NH:29][CH2:28][CH2:26][OH:27])[CH:5]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cccc(F)c1
Reactant: NCCO
Reactant: Clc1ccnc(Cl)n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: OCCNc1cc(Nc2cccc(F)c2)ncn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
100 mg of 2,6-dichloropyrimidine, 82 mg of m-fluoroaniline and 103 mg of DIPEA in 1 mL of n-BuOH were charged into a microwave vial and the vial obtained was kept in a heating block at 120° C. for 4 hours. The reaction was monitored by TLC and was completed in 4 h. The mixture obtained was cooled to r.t., 61 mg ethanolamine and 139 mg of DIPEA were added and the mixture obtained was heated under microwave irradiation for an hour at 200° C. The reaction was finished and crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc: MeOH 20:1. 2-(6-(3-Fluorophenylamino)pyrimidin-4-ylamino)ethan-1-ol in the form of a colorless solid was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][NH2:14])[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].C(N(CC)CC)C.[CH2:22]([O:24][C:25](Cl)=[O:26])[CH3:23].C([O-])(O)=O.[Na+]>ClCCl>[CH2:22]([O:24][C:25](=[O:26])[NH:14][CH2:13][CH2:12][C:4]1[CH:5]=[C:6]([O:10][CH3:11])[C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=1)[CH3:23]
Reactant: CCOC(=O)Cl
Reactant: COc1cc(CCN)cc(F)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCCc1cc(F)c(OC)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(3-fluoro-4,5-dimethoxy-phenyl)-ethylamine (576 mg) and triethylamine (0.8 ml) in dichloromethane (20 ml) was added dropwise at 0° C. ethylchloroformate (300 μl). The mixture was stirred for 1 h, poured into ice water, neutralized with NaHCO3 and extracted with dichloromethane. The organic layers were separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was passed through a short silica column (heptane/ethyl acetate as eluent).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]([Cl:13])([Cl:12])[Cl:11])[OH:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]([Cl:11])([Cl:12])[Cl:13])[OH:9])=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(C(O)C(Cl)(Cl)Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(O)C(Cl)(Cl)Cl)cc1
Yield: 98.5 %

Procedure:
A 0.1 mole quantity of p-hydroxyphenyl trichloromethyl carbinol was dissolved in 0.3 mole of pyridine. To the solution was dropwise added 0.22 mole of acetic acid anhydride with stirring. The resulting mixture was agitated for 2 hours. After completion of the reaction, the pyridine was distilled off at reduced pressure and the residue was washed with 50 ml of water. The crystals were filtered off to obtain ester of p-acetoxyphenyl trichloromethyl carbinol and acetic acid. Yield 98.5%, m.p. 152.5°-153° C.
Reaction SMILES: [Na].[CH3:2][O:3][CH2:4][CH2:5][OH:6].F[C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:18])[NH:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1.Cl>O>[CH3:2][O:3][CH2:4][CH2:5][O:6][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:18])[NH:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1
Reactant: COCCO
Reactant: O=c1[nH]cnc2cc(F)ccc12
Agent: Cl
Agent: [Na]
Solvent: O
Product: COCCOc1ccc2c(=O)[nH]cnc2c1
Yield: 58 %

Procedure:
Sodium (400 mg, 17 mmol) was added carefully to 2-methoxyethanol (10 ml) and the mixture heated at reflux for 30 minutes. 7-Fluoro-3,4-dihydroquinazolin-4-one (750 mg, 4.57 mmol) was added to the resulting solution and the mixture heated at reflux for 15 hours. The mixture was cooled and poured into water (250 ml). The mixture was acidified to pH4 with concentrated hydrochloric acid. The resulting solid product was collected by filtration, washed with water and then with ether, and dried under vacuum to give 7-(2-methoxyethoxy) 3,4-dihydroquinazolin-4-one (580 mg, 58%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([C:32]1[N:33]=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.N1CCC[C@@H]1C#N>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH2:24][C@@H:23]2[C:32]#[N:33])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Agent: N#C[C@H]1CCCN1
Product: CC(C)(C)c1nc(N2CCC[C@@H]2C#N)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (R)-pyrrolidine-2-carbonitrile hydrochloride and isolated as light-yellow solid (9.7 mg, 52%). MS(m/e): 396.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=O)[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:10]2)=[CH:4][CH:3]=1.O1CCOCC1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[S:40])[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:10]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1nn(Cc2ccc(Cl)nc2)c2ncccc2c1=O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1nn(Cc2ccc(Cl)nc2)c2ncccc2c1=S
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
Ethyl 1-[(6-chloropyridin-3-yl)methyl]-4-oxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxylate (490 mg, 1.42 mmol) was suspended in toluene (5 mL) and dioxane (5 mL) and placed into a preheated oil bath at 110° C. The mixture was treated with Lawesson's Reagent (316 mg, 0.782 mmol, 0.55 equiv) portionwise over 45 minutes and stirred for an addition 30 minutes at 110° C. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 50:50; hexanes:ethyl acetate), providing the titled compound as a brown foam.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[C:26]4[CH:25]=[C:24]([O:27][C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35](=[O:37])[CH3:36])[CH:29]=5)[N:23]=[CH:22][C:21]=4[N:20]=[C:19]3[CH2:38][C:39]#[N:40])=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.[N:41]([O-:43])=O.[Na+].CC[N:47](CC)CC>CO.Cl.O1CCOCC1>[NH2:47][C:39]1[C:38]([C:19]2[N:18]([C:12]3[CH:11]=[C:10]4[C:15]([CH2:16][CH2:17][NH:8][CH2:9]4)=[CH:14][CH:13]=3)[C:26]3[CH:25]=[C:24]([O:27][C:28]4[CH:29]=[C:30]([NH:34][C:35](=[O:37])[CH3:36])[CH:31]=[CH:32][CH:33]=4)[N:23]=[CH:22][C:21]=3[N:20]=2)=[N:41][O:43][N:40]=1
Reactant: CC(=O)Nc1cccc(Oc2cc3c(cn2)nc(CC#N)n3-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3)c1
Reactant: O=N[O-]
Reactant: CCN(CC)CC
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(Oc2cc3c(cn2)nc(-c2nonc2N)n3-c2ccc3c(c2)CNCC3)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
The product from Step 4 (0.250 g, 0.46 mmol) was dissolved in MeOH (5 mL) and 2N HCl (3 mL). To the solution was added NaNO2 (0.065 g, 0.92 mmol), and the mixture was allowed to stir at rt for 30 min. The reaction mixture was concentrated, then dissolved in THF (3 mL). Triethylamine (0.25 mL), and NH2OH (50% aqueous solution, 0.07 mL) were added and the mixture was heated in a sealed tube to 90° C. for 1 hour. The reaction mixture was then cooled, poured into EtOAc and washed with H2O. The organic layer was dried over MgSO4, filtered, then concentrated in-vacuo to give a dark oil. The oil was dissolved in dioxane (3 mL) and Et3N (0.5 mL) and the reaction mixture was heated in a sealed tube to 150° C. for 1 hour. The mixture was then cooled, and concentrated in-vacuo. The crude oil was dissolved in dichloromethane (2 mL) and to the solution was added 4N HCl in dioxane and the resulting solution was allowed to stir at rt for 30 min. The mixture was then concentrated in-vacuo, and the oil was dissolved in a minimal amount of MeOH then poured into Et2O to afford the title compound as a tan solid (40 mg, 18%). MS (ES+) m/e 484 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[CH:7]1([C:10]2[C:11]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([C:27]4[CH:28]=[N:29][C:30](F)=[CH:31][C:32]=4[CH3:33])=[O:26])[CH2:21][CH2:20]3)=[N:12][CH:13]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[CH:15]=2)[CH2:9][CH2:8]1>>[CH:7]1([C:10]2[C:11]([N:19]3[CH2:20][CH2:21][N:22]([C:25]([C:27]4[C:32]([CH3:33])=[CH:31][C:30]([N:1]5[CH2:5][CH2:4][CH2:3][C:2]5=[O:6])=[N:29][CH:28]=4)=[O:26])[CH2:23][CH2:24]3)=[N:12][CH:13]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[CH:15]=2)[CH2:8][CH2:9]1
Reactant: O=C1CCCN1
Reactant: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: Cc1cc(N2CCCC2=O)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1

Procedure:
Using pyrrolidin-2-one (326 μL) and [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (400 mg) described in Preparation Example 174 and by the reaction and treatment in the same manner as in Example 323, the title compound (187 mg) was obtained.
Reaction SMILES: N(CCO)CCO.CCOCC.[CH3:13][CH:14]([C:18]([CH3:20])=[O:19])[C:15]([OH:17])=[O:16].[N+]([O-])([O-])=O.[Ag+:25]>O>[CH3:13][CH:14]([C:18]([CH3:20])=[O:19])[C:15]([O-:17])=[O:16].[Ag+:25]
Reactant: CC(=O)C(C)C(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCOCC
Solvent: O
Solvent: OCCNCCO
Product: CC(=O)C(C)C(=O)[O-]

Procedure:
Diethanolamine (4.4 g) was dissolved in water (5 mL), and this solution was added to the ether solution of α-methylacetoacetic acid while cooling with ice. A solution of silver nitrate (6.8 g) dissolved in water (8 mL) was then added dropwise. The white precipitate that precipitated was filtered off, washed with ice water and then isopropanol, and then dried, yielding silver α-methylacetoacetate as a white precipitate (yield 4.78 g).