Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29]([Br:32])[C:28](=[O:33])[N:27]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][C:9]1([CH3:40])[CH3:39])=O)(C)(C)C.[Cl:41]CCl>Cl>[ClH:41].[Br:32][C:29]1[C:28](=[O:33])[N:27]([CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:25]2[N:26]=[C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:12][CH2:13][NH:8][C:9]([CH3:40])([CH3:39])[CH2:10]4)=[CH:15][N:16]=3)[N:22]=[CH:23][C:24]=2[C:30]=1[CH3:31]
Reactant: ClCCl
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)C(C)(C)C4)cn3)ncc12
Agent: Cl
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCNC(C)(C)C4)cn3)ncc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
4-[6-(6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.051 g, 0.083 mmol) was dissolved in dichloromethane (3 mL) to which 2 N HCl (2 mL) was added and the resulting mixture was stirred at room temperature for 2 hours. This mixture was concentrated and allowed to sit for 10 days, it was then dissolved in 2 N HCl (2 mL) and stirred at room temperature for 5 hours. The solvent was removed to give 6-bromo-8-cyclopentyl-2-[5-(3,3-dimethyl-piperazin-1-yl)-pyridin-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride salt as a yellow solid (0.035 g, 71.4%). 1H NMR δ (400 MHz, DMSO-d6) 9.32 (s, 2H), 8.98 (s, 1H), 8.04 (d, J=2.7 Hz, 1H), 7.83 (d, J=9.3 Hz, 1H), 7.26 (m, 1H), 5.89 (m, 2H), 3.34 (m, 2H), 3.23 (m, 4H), 2.58 (s, 3H), 2.14 (m, 2H), 1.91 (m, 2H), 1.77 (m, 2H), 1.57 (m, 2H), 1.38 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:13])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[C:4]([CH3:14])[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:56][O:57][C:58](=[O:71])[CH2:59][CH2:60][NH:61][C:62](=[O:70])[C:63]1[CH:68]=[CH:67][C:66](O)=[CH:65][CH:64]=1>C1(C)C=CC=CC=1>[CH3:56][O:57][C:58](=[O:71])[CH2:59][CH2:60][NH:61][C:62](=[O:70])[C:63]1[CH:68]=[CH:67][C:66]([O:13][CH:8]([C:6]2[CH:5]=[C:4]([CH3:14])[C:3]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=3)=[C:2]([CH3:1])[CH:7]=2)[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:65][CH:64]=1
Reactant: COC(=O)CCNC(=O)c1ccc(O)cc1
Reactant: Cc1cc(C(O)CC(C)C)cc(C)c1-c1ccc(C(F)(F)F)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)CCNC(=O)c1ccc(OC(CC(C)C)c2cc(C)c(-c3ccc(C(F)(F)F)cc3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yl)-3-methyl-butan-1-ol (270 mg, 0.8 mmol) in toluene (8 mL) is added 1,1′-(azodicarbonyl) dipiperidine (ADDP, 304 mg, 1.21 mmol) at 0° C., followed by the addition of tributylphosphine (0.3 mL, 12.1 mmol) and 3-(4-hydroxy-benzoylamino)-propionic acid methyl ester (215 mg, 0.96 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving 3-{4-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yl)-3-methyl-butoxy]-benzoylamino}-propionic acid methyl ester. The ester product is taken into methanol (2 mL), treated with sodium hydroxide (5N aqueous, 1 mL) for 5 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (1.1 mL), extracted with ethyl acetate. The organic layers are dried and concentrated to afford 51 mg of the titled compound. MS (ES): 528.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:22][OH:23])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[S:14][CH:15]=1.O[C:25]1[C:29]([CH:30]=[O:31])=[CH:28][N:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:26]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([N:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[S:14][CH:15]=1)[CH2:22][O:23][C:25]1[C:29]([CH:30]=[O:31])=[CH:28][N:27]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:26]=1
Reactant: COc1cc(CO)ccc1OCc1csc(N2CCCCC2)n1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1csc(N2CCCCC2)n1
Reaction time: 15 h
Yield: 66.3 %

Procedure:
To a mixture of {3-methoxy-4-[(2-piperidin-1-yl-1,3-thiazol-4-yl)methoxy]phenyl}methanol (1.15 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.70 g), tributylphosphine (1.03 g) and tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.29 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 3-({3-methoxy-4-[(2-piperidin-1-yl-1,3-thiazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde as crystals (1.15 g, yield 67%) from a fraction eluted with ethyl acetate-hexane (2:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 123-124° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1>C(O)CCC.O>[CH2:11]([O:12][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1)[CH2:16][CH2:15][CH3:14]
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Solvent: CCCCO
Solvent: O
Product: CCCCOc1nc(N)c2ncn(C3CCCCO3)c2n1

Procedure:
The product from step (i) (40 g) was dissolved in 19% (w/w)-sodium butoxide in butanol (250 ml). The reaction mixture was stirred under reflux for 6 hours. The resultant suspension was cooled to room temperature, diluted with water and extracted with diethyl ether. The combined organic phase was washed with water, dried and concentrated in vacuo. The subtitle compound was crystallised from diethyl ether/isohexane (1/1, 300 ml) and obtained by filtration. Yield 19 g.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)[NH2:17].Cl.C(=O)(O)[O-].[Na+]>O.C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([NH:17][C:16]2[CH:18]=[CH:19][C:20]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[NH:28][CH:29]=[CH:30][C:23]=34)=[C:14]([F:13])[CH:15]=2)[N:3]=1
Reactant: COC(=O)c1cc(Cl)nc(N)n1
Reactant: Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)nc(N)n1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
0.209 g (1.12 mmol) of methyl 2-amino-6-chloropyrimidine-4-carboxylate (prepared according to G. Doyle Daves, Fred Baiocchi, Roland K. Robins, and C. C. Cheng, J. Org. Chem., 26 (1961), 2755-2763) and 0.4 g (1.12 mmol) of [3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]amine (example XIX) are suspended in 5 ml of water and 5 ml of ethanol. 0.11 ml (1.34 mmol) of 37% strength hydrochloric acid is added. The mixture is stirred at 100° C. for 18 hours. After cooling, the mixture is neutralized using an aqueous saturated sodium bicarbonate solution. The resulting precipitate is filtered off with suction and dried. This gives 0.46 g of product (68% of theory).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13]2.[Cl:19][C:20]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24]([Cl:31])[C:21]=1[CH2:22]Br.O>CN(C=O)C>[Cl:19][C:20]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24]([Cl:31])[C:21]=1[CH2:22][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13]2
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: O=[N+]([O-])c1ccc(Cl)c(CBr)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc([N+](=O)[O-])c3Cl)c2n1
Reaction time: 0.5 h

Procedure:
Cs2CO3 (10.8 g, 33.3 mmol) was added at room temperature to 8-hydroxy-2-methylquinoline (5 g, 33.3 mmol) in DMF (65 ml). After 30 min, 2,6-dichloro-3-nitrobenzyl bromide (13 g, 45.6 mmol) was added. After 18 h, H2O was added and the precipitate was filtered off with suction and washed with EA (50 ml), the title compound being obtained as an amorphous substance.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:15]=3[CH:16]=2)[CH2:8][CH2:7]1)=O)C.[OH-].[K+]>C(O)CO.C1(C)C=CC=CC=1>[F:21][C:18]1[CH:19]=[CH:20][C:14]2[O:13][C:12]([CH:9]3[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]3)=[CH:16][C:15]=2[CH:17]=1
Reactant: CCOC(=O)N1CCC(c2cc3cc(F)ccc3o2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: Cc1ccccc1
Product: Fc1ccc2oc(C3CCNCC3)cc2c1

Procedure:
5.9 g (about 0.02 mole) of 4-(5-fluoro-2-benzofuranyl)-1-piperidinecarboxylic acid ethyl ester is dissolved in 65 ml of ethylene glycol. After the addition of 19.4 g of 86% potassium hydroxide, the cloudy solution formed is heated, with vigorous stirring, for 18 hours at 160°. The reaction solution is thereupon cooled to 100°, diluted with 65 ml of toluene and then cooled to 20°. The organic phases are firstly extracted twice with one liter of water each time, then four times with 200 ml of a 10% solution of methanesulphonic acid in water. The methanesulphonic acid solution is thereupon brought to the pH-value of 12 by the addition of 30% sodium hydroxide solution, and is subsequently extracted with one liter of chloroform. The chloroform solution is dried with sodium sulphate, filtered and concentrated by evaporation to thus obtain crude 4-(5-fluoro-2-benzofuranyl)-piperidine. The base is distilled by molecular distillation in high vacuum. The fraction distilling at 190°-200° and 0.05 Torr is 4-(5-fluoro-2-benzofuranyl)-piperidine. The hydrochloride is prepared with hydrogen chloride in ethyl acetate and recrystallised from ethyl acetate, whereupon it melts at 235°-237°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(-c2ccncn2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cccc(-c2ccncn2)c1
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a suspension of (57) (6.3 g, 31 mmol) in a mixture of MeOH (60 ml) and THF (30 ml) was added 5% palladium on activated carbon (300 mg) and the mixture was hydrogenated at ambient pressure for 1 hr. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column-chromatography on silica gel using a mixture of hexane and ethylacetate (3:1) as the eluent to give (58) (5.1 g, 96%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].C(O)(=O)C.[Br:17]Br>>[NH2:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([Br:17])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: BrBr
Reactant: CNC(=O)c1cccc(F)c1N
Solvent: CC(=O)O
Product: CNC(=O)c1cc(Br)cc(F)c1N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-Amino-3-fluoro-N-methyl-benzamide (10.0 g, 59.5 mmol) was dissolved in acetic acid (100 mL, 176 mmol) and bromine (3.22 mL, 62.4 mmol) was added. The reaction was stirred at room temperature for 20 minutes and the precipitate was then collected by filtration and washed with ethyl ether. The white solid was dried overnight under high vacuum at 50° C. to obtain 2-amino-5-bromo-3-fluoro-N-methyl-benzamide; hydrobromide as a white solid (16.8 g, 86%). LCMS (m/e) 216 (M-NHCH3); 1H-NMR (d6-DMSO, 400 MHz) δ 8.49-8.38 (m, 1H), 7.83-7.46 (m, 3H), 7.54 (s, 1H), 7.43 (d, 1H, J=10.89 Hz), 2.72 (d, 3H, J=4.2 Hz); 19F-NMR (d6-DMSO, 400 MHz) δ 131.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[Br:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:13])([CH3:14])[C:6]=3[CH:15]=2)=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: CN1C(=O)OC(C)(C)c2cc(N)ccc21
Product: CN1C(=O)OC(C)(C)c2cc(Nc3ccc(Br)cc3)ccc21

Procedure:
Prepared from 6-amino-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 4-bromophenyl boronic acid according to the coupling procedure described in example 1. MS (ESI) m/z 361/363 ([M+H]+); MS (ESI) m/z 359/361 ([M−H]−); Anal. calcd for C17H17BrN2O2: C, 56.52; H, 4.74; N, 7.75. Found: C, 56.98; H, 4.34; N, 7.30.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH:22]=[N:23][OH:24].B.N1C=CC=CC=1.Cl>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][NH:23][OH:24]
Reactant: CSc1ccc(/C=C2/C(C)=C(CC=NO)c3cc(F)ccc32)cc1
Agent: B
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CSc1ccc(/C=C2/C(C)=C(CCNO)c3cc(F)ccc32)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of the oxime from Step 3 (2.0 g, 5.9 mmol) in ethanol (35 mL) at 0° C. there was added pyridine-borane (1.1 g, 11.8 mmol) and 12 N aqueous HCl (1.48 mL, 17.75 mmol). The mixture was stirred at 0° C. for 1 hour, then warmed to room temperature. Most of the ethanol was evaporated, the residue was diluted with water and ethyl acetate (the product as hydrochloride salt remains in the organic phase) and was basified with 1N aqueous NaOH. The product obtained from the organic phase was triturated with hexane and was filtered to afford the title compound as a yellow solid, mp: 126° C. dec.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[C:8](OCC)(=[O:11])[C:9]#[CH:10].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[C:2]([N:6]1[CH:10]=[CH:9][C:8]([OH:11])=[N:7]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)NN
Reactant: C#CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)(C)n1ccc(O)n1
Temperature: 35 °C
Reaction time: 8 h
Yield: 1.1 %

Procedure:
t-Butylhydrazine hydrochloride (4.5 g, 35.7 mmol) was suspended in t-butanol (35 ml) at room temperature in a dry nitrogen atmosphere. The mixture was warmed to 35° C., ethyl propiolate (3.85 g, 39.3 mmol) dropwise added and, after ice cooling, potassium t-butoxide (13.8 g, 107 mmol) was slowly added in small portions. The resulting mixture was stirred overnight at room temperature. The solvent was evaporated in vacuo, water added to the residue and extracted with dichloromethane. The aqueous phase was acidified by addition of acetic acid, evaporated to dryness in vacuo and the residue was extracted several times with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and evaporated yielding 53 mg of 1-tert-butyl-1H-pyrazol-3-ol as a beige colour solid.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH:4]([OH:14])[CH2:5][N:6]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[N:7]1.[H][H]>[Pd].C(O)C>[NH2:11][C:9]1[CH:8]=[N:7][N:6]([CH2:5][CH:4]([OH:14])[CH2:3][N:2]([CH3:1])[CH3:15])[CH:10]=1
Reactant: CN(C)CC(O)Cn1cc([N+](=O)[O-])cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN(C)CC(O)Cn1cc(N)cn1
Yield: 92 %

Procedure:
1-(dimethylamino)-3-(4-nitro-1H-pyrazol-1-yl)propan-2-ol (253 mg, 1.18 mmol) and palladium on carbon (10%, 25 mg) were stirred in ethanol (5 mL) under a balloon of hydrogen for 24 h. The palladium was removed by filtration through celite and the solution was concentrated to afford 1-(4-amino-1H-pyrazol-1-yl)-3-(dimethylamino)propan-2-ol as a brown oil (200 mg), which was used crude in the following reaction.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1.C(OCC)(=O)C>[C:1]1([S:7]([N:10]2[CH2:12][CH:11]([C:13]3[CH:14]=[CH:15][C:16]([Br:19])=[CH:17][CH:18]=3)[N:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:29]2=[O:30])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)N1CC1c1ccc(Br)cc1
Reactant: O=C=Nc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1N(c2ccccc2)C(c2ccc(Br)cc2)CN1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 72 %

Procedure:
To a stirred solution of 1-benzenesulfonyl-2-(4-bromo-phenyl)-aziridine (1.00 g) in tetrahydrofuran (16.5 mL) under argon were added sodium iodide (0.487 g) and phenylisocyanate (0.539 g). The mixture was stirred for 5 days at room temperature. The mixture was diluted with ethyl acetate (50 mL) and washed with water. The org. phase was dried (MgSO4), filtered and concentrated. The product was purified using column chromatography (SiO2, cyclohexane/ethyl acetate 1:0=>0:1) to give 1-benzenesulfonyl-4-(4-bromo-phenyl)-3-phenyl-imidazolidin-2-one (0.974 g) as a colorless solid. MS: 458.9 ([M+H]+)
Reaction SMILES: ClC1C=CC=[C:4]([C:8]([O:10]O)=[O:9])C=1.[CH2:12]([NH:19][CH2:20][CH2:21][C:22]1[CH:37]=[CH:36][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30](C(=O)C)=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl.ClCCl>[CH2:12]([NH:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:10][C:8](=[O:9])[CH3:4])=[CH:31][CH:32]=2)=[CH:36][CH:37]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)c1ccc(Oc2ccc(CCNCc3ccccc3)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1ccc(Oc2ccc(CCNCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
Metachloroperbenzoic acid (0.23 g) was added to a solution of 1-{4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl}-ethanone (0.36 g) in chloroform (25 mL) while stirring at room temperature. Stirring was continued overnight then the reaction was diluted with dichloromethane, washed with saturated aqueous sodium thiosulfate, dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator. The residue was diluted with methanol (5 mL) and saturated aqueous sodium bicarbonate (5 mL) then stirred overnight at room temperature. The methanol was removed on a rotary evaporator and the pH of the residue was adjusted to 7-8 then extracted with dichloromethane (3×30 mL). The combined dichloromethane extracts were dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator to yield 0.4 g of crude product, which was purified by flash column chromatography on silica gel eluting with ethanol in dichloromethane to yield Acetic acid 4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl ester (117 mg), 1H NMR (CDCl3, 300.00 MHz): 8.01-7.93 (m, 2H), 7.42-7.21 (m, 7H), 7.06-6.97 (m, 4H), 3.87 (s, 2H), 3.02-2.94 (m, 4H), 2.61 (s, 3H); m/z=361.85(M+1).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C([O:10][CH2:11][CH:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]1)(=O)C>CO>[CH3:17][C:14]1([CH3:18])[O:13][CH:12]([CH2:11][OH:10])[CH2:16][O:15]1
Reactant: CC(=O)OCC1COC(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)OCC(CO)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
Then sodium carbonate (40.63 g, 0.294 mol) was added to a mixture of 4-acetoxymethyl-2,2-dimethyl-1,3-dioxolane (34.18 g, 0.196 mol) and methanol (200 ml) and the resulting mixture was stirred for 8 hours at 25° C. After completion of the reaction the salt was filtered off and the filtrate was condensed in vacuo and water was added to the residue and extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and condensed in vacuo. The crude product was distilled to give 23.12 g of 2,2-dimethyl-1,3-dioxolane-4-methanol (yield 89%, b.p. 72° C. at 8 mmHg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:5][NH:6][NH2:7].C([O:14][C:15](=O)[CH:16]([CH:18]=O)[CH3:17])C>C(O)C>[CH3:18][C:16]1[C:15](=[O:14])[N:6]([CH2:5][C:4]2[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=2)[NH:7][CH:17]=1
Reactant: NNCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C(C)C=O
Solvent: CCO
Product: Cc1c[nH]n(Cc2ccc(Cl)c(Cl)c2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.9 g of 3,4-dichlorobenzylhydrazine were added dropwise to a solution of 7.5 g of α-formylpropionic acid ethyl ester in 50 ml of ethanol. After stirring overnight at room temperature, the solvent was distilled off in vacuo and the solid residue was recrystallized from ethanol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:19][CH:20]1[CH2:22][O:21]1>CN(C=O)C>[O:21]1[CH2:22][CH:20]1[CH2:19][O:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: BrCC1CO1
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(OCC2CO2)c1
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (3-hydroxyphenyl)carbamate (1 g, 4.79 mmol) in DMF (15 mL) was added NaH (0.126 g, 5.26 mmol) at 0° C. After stirring for 30 min, 2-(bromomethyl)oxirane (0.716 g, 5.26 mmol) was added and the mixture stirred at 0° C. for 1 h before quenching with the addition of MeOH. After evaporation of this mixture, the resulting residue was dissolved in ethyl acetate and washed with water, dried and with sodium sulfate and concentrated with the resulting crude product used for next step without further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][N:11]([C:13]3[N:18]=[C:17]([C:19]([OH:21])=O)[CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9][C:7]=2[N:8]=1.[CH:22]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)([CH3:24])[CH3:23].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:22]([C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:19]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([N:11]3[CH2:10][CH2:9][C:7]4[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[CH2:12]3)[N:18]=2)=[O:21])=[CH:27][CH:26]=1)([CH3:24])[CH3:23]
Reactant: CSc1ncc2c(n1)CCN(c1cccc(C(=O)O)n1)C2
Reactant: CC(C)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSc1ncc2c(n1)CCN(c1cccc(C(=O)Nc3ccc(C(C)C)cc3)n1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-[2-(Methylthio)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-yl]pyridine-2-carboxylic acid (600 mg, 1.98 mmol), 4-isopropylaniline (0.28 ml, 1.98 mmol) and DIEA (1.64 ml, 9.90 mmol) in DMF (10 ml) was treated with HATU (828 mg, 2.18 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water, dried (MgSO4), filtered and concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, 1:1 hexanes:EtOAc) gave the title compound as an oil which crystallized on standing (804 mg, 97%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:19][C:20](=[O:22])[CH3:21])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9](N2CCOCC2)[N:8]=1.Cl.[CH:24]1(C(N)=N)[CH2:26][CH2:25]1>>[CH:24]1([C:9]2[N:8]=[C:7]([C:6]3[S:5][C:4]([NH:19][C:20](=[O:22])[CH3:21])=[N:3][C:2]=3[CH3:1])[CH:12]=[CH:11][N:10]=2)[CH2:26][CH2:25]1
Reactant: N=C(N)C1CC1
Reactant: CC(=O)Nc1nc(C)c(-c2ccnc(N3CCOCC3)n2)s1
Agent: Cl
Product: CC(=O)Nc1nc(C)c(-c2ccnc(C3CC3)n2)s1

Procedure:
The titled compound is prepared by an analogous procedure to N-[4-Methyl-5-(2-morpholin-4-yl-pyrimidin-4-yl)-thiazol-2-yl]-acetamide (25e) by replacing morpholinoformamidine hydrobromide (part 25c) with cyclopropanecarboxamidine hydrochloride.