Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([Cl:12])[CH:3]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1N2CCN(CC2)C1>[Cl:12][C:4]1[CH:3]=[C:2]([CH:15]=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]=[CH:6][C:5]=1[C:8]([F:11])([F:10])[F:9]
Reactant: C=CC(=O)OCC
Reactant: FC(F)(F)c1ccc(Br)cc1Cl
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(C(F)(F)F)c(Cl)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
DABCO (86.4 mg, 0.7 mmol), Pd(OAc)2 (86.5 mg, 0.38 mmol), 4-bromo-2-chloro-1-(trifluoromethyl)benzene (5.0 g, 19.2 mmol) and ethyl acrylate (2.86 g, 28.9 mmol) were added to a stirred solution of K2CO3 (2.6 g, 19.27 mmol) in DMF degassed previously for 20 minutes. The resulting mixture was stirred for 1 hour at 110° C. The reaction was monitored by TLC (5% ethyl acetate in hexane). Purification by column chromatography on silica gel (5% ethyl acetate in hexane) afforded 5.0 g of the product (94.3% yield).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[NH:13]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CS(C)=O>[N:13]1([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: C1CNCCNC1
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCCNCC2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 93.6 %

Procedure:
Ethyl 4-fluorobenzoate (11.01 mL, 75 mmol) and 1,4-diazepane (30.0 g, 300.00 mmol) in DMSO (150 mL) warmed to 100° C. under nitrogen. The resulting solution was stirred at 100° C. for 24 h. The reaction mixture was cooled and evaporated to dryness. The reaction mixture was quenched with 2M NaOH (150 mL), extracted with EtOAc (3×75 mL), the organic layer was washed with saturated brine (100 ml), dried over MgSO4, filtered and evaporated to afford ethyl 4-(1,4-diazepan-1-yl)benzoate (17.43 g, 94%) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1([C:12]#[N:13])[CH2:7][C:6](O)=[C:5]([F:9])[C:4](=[O:10])[N:3]1[CH3:11].P(Cl)(Cl)([Cl:16])=O>C(#N)C>[NH2:1][C:2]1([C:12]#[N:13])[CH2:7][C:6]([Cl:16])=[C:5]([F:9])[C:4](=[O:10])[N:3]1[CH3:11]
Reactant: CN1C(=O)C(F)=C(O)CC1(N)C#N
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CN1C(=O)C(F)=C(Cl)CC1(N)C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine 2-amino-5-fluoro-4-hydroxy-1-methyl-6-oxo-1,6-dihydropyridine-carbonitrile (30.0 g, 0.164 mol) and anhydrous acetonitrile (150 mL). Slowly add phosphorous oxychloride (37 mL). After addition is complete heat to reflux. After 3 hours, cool to ambient temperature and then in an ice-bath. Add another portion of acetonitrile (150 mL). Slowly add to ice-water (300 mL, 10 volumes). Heat to about 50° C. After 5 hours, cool in an ice bath to give a solid, filter, rinse the solid with water, and dry in vacuo to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ7.73 (s, 2H). 3.33 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ153.3 (d, J=32.9 Hz), 139.2, 136.9, 128.5 (d, J=16.9 Hz), 115.3 (d, J=2.2 Hz), 68.1, 29.7 (d, J=1.4 Hz); 19F NMR (376 MHz, DMSO-d6) δ−152.0; MS (M+H)+m/z calcd 202.0. found 202.0. Combine the title compound (4.4 g) in 40 mL of dimethylacetamide (40 mL) and heat to 38° C. Add activated carbon (4.4 g). After 30 minutes filter through Celite®, rinse with dimethylacetamide, and add water to the filtrate, then cool in an ice bath to give a solid. Collect the solid by filtration, rinse with water (20 mL), and dry in vacuo at give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=O.Cl.[NH2:13]O.C([O-])=O.[Na+]>C(O)=O>[Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:13]
Reactant: O=Cc1c(F)cc(O)cc1Cl
Reactant: NO
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Product: N#Cc1c(F)cc(O)cc1Cl
Temperature: 105 °C
Reaction time: 3.5 h
Yield: 55.9 %

Procedure:
A solution of 2-chloro-6-fluoro-4-hydroxybenzaldehyde (WO 2008141249, 90 mg, 0.344 mmol) in formic acid (1 mL) was treated with hydroxylamine hydrochloride (23.9 mg, 0.344 mmol) and sodium formate (23.4 mg, 0.344 mmol) and stirred under nitrogen for 3.5 hours at 105° C. The mixture was concentrated in vacuo and the residue treated with saturated aqueous sodium bicarbonate solution (10 mL). The aqueous solution was extracted with ethyl acetate (2×10 mL), dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 30-50% EtOAc in heptanes to afford the title compound as a beige solid (33 mg, 56%).
Reaction SMILES: C([O:3][C:4](=[O:30])[C@H:5]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][N:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)[N:6]([C:8](=[O:17])[C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[CH:10]=1)[CH3:7])C.O.[OH-].[Li+].O>CO.O1CCCC1>[CH3:15][C:13]1[CH:14]=[C:9]([CH:10]=[C:11]([CH3:16])[CH:12]=1)[C:8]([N:6]([CH3:7])[C@H:5]([C:4]([OH:30])=[O:3])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][N:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)=[O:17]
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2ccno2)cc1)N(C)C(=O)c1cc(C)cc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C)cc(C(=O)N(C)[C@@H](Cc2ccc(-c3ccno3)cc2)C(=O)O)c1

Procedure:
A solution of N-(3,5-dimethylbenzoyl)-3-[4-(5-isoxazolyl)-phenyl]-alanine ethyl ester (3.8 g) and methyliodide (1.8 ml) in dry N,N-dimethylformamide (40 ml) is cooled in an ice bath and sodium hydride (60% in oil, 390 mg) is added in portions. The mixture is allowed to warm to room temperature during 5 hours, then poured into water, extracted with ethyl acetate, the organic phase washed with water, and with brine, dried and evaporated. Flash chromatography of the residue on silica gel (hexanelethyl acetate 3:1) gives pure N-(3,5-di methylbenzoyl)-N-methyl-3-[4-5-isoxazolyl)-phenyl]-alanine ethyl ester. N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-isoxazolyl)-phenyl]-alanine ethyl ester (44 mg) is treated with lithium hydroxide monohydrate (5 mg) in methanol (0.5 ml), tetrahydrofurane (0.25 ml), and water (0.25 ml) for 3 hours at room temperature. The mixture is then partitioned between water and ether, the water phase acidified with 1N hydrochloric acid, and subsequently extracted with ethyl acetate. The ethyl acetate phase is washed with brine, dried, and evaporated to give N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-isoxazolyl)-phenyl]-alanine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][O:12][C:11](=[O:14])[N:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[N:9]=2)=[CH:4][CH:3]=1>CCO.C(O)(=O)C.[Fe]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:10]2[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:13][O:12][C:11]2=[O:14])=[CH:17][CH:18]=1
Reactant: O=C1OCC(c2ccc(Cl)cc2)=NN1Cc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccc(CN2N=C(c3ccc(Cl)cc3)COC2=O)cc1

Procedure:
A suspension of the compound obtained in Step D (42.02 mmoles) in a mixture of EtOH (350 ml) and acetic acid (26 ml) is heated at reflux for 5 minutes. Powdered iron (309 mmoles) and FeCl3.6H2O (2.1 mmoles) are added to the resulting solution. The reaction mixture is stirred at reflux overnight. After evaporation, water (250 ml) is added to the residue and then sonicated for 2 minutes. The mixture is made alkaline (pH 12) using aqueous 2M sodium hydroxide solution, then diluted with AcOEt (500 ml) and then filtered over Celite. The phases are separated and the aqueous phase is extracted with AcOEt. The organic phases are combined. The organic phase obtained is washed with water and then with saturated NaCl solution, dried over sodium sulphate, filtered and evaporated to dryness. The residue is triturated in ethyl ether, filtered and dried in vacuo to yield the title product in the form of a white powder, which is used directly in the next Step.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[OH:19].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].O>CN(C)C=O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCOC(=O)CCCCCCBr
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCCOc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Temperature: -70 °C

Procedure:
6,7-Dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-one (12 g., 0.04 mole) is dissolved in dimethylformamide (30 ml.), and potassium carbonate (5.5 g., 0.04 mole) is added and the mixture stirred and heated on a steam bath for 30 minutes. Ethyl 7-bromoheptanoate is added dropwise over 10 minutes with stirring and heating on a steam bath for two hours. The mixture is poured into a mixture of ice and water (300 g., total) and then extracted with ether. The ether extract is dried over Na2SO4, filtered and the ether removed at reduced pressure. The residue is dissolved in petroleum ether and cooled to -70 °C. to obtain ethyl 7-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]heptanoate, 17.7 g., m.p. 47°-50 °C.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:9][C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[N:33].C(=O)([O-])[O-].[K+].[K+]>>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[N:33])[C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCCCCCCBr
Reactant: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#CCCCCCCn1c(-c2ccccc2)c(-c2ccccc2)n(-c2ccccc2)c1=O

Procedure:
1,4,5-TriphenylimidazoI-2-one was treated with 7-bromo-heptanonitrile and potassium carbonate in bumone to give after chromatographic work-up 7-(3,4,5-triphenyl-2-oxo-2,3-dihydroimidazol-1-yl)heptanonitrile, m.p. 100°-101° C., Found: C, 79.7; H, 6.6; N, 9.8%; C28H27N3O requires: C, 79.9; H, 6.4; N, 10.0%; and 7-(1,4,5-triphenylimidazol-2-yloxy)heptanonitrile, m.p..93°-94° C., Found: C, 79.5; H, 6.6; N, 9.7%; C28H27N3O requires: C, 79.9; H, 6.4; N, 10.0%.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.CO[CH:17](OC)[CH2:18][CH:19](OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[N:1]1[C:2]2=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]2[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1c(N)[nH]c2ccccc12
Reactant: COC(CC(OC)OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: COC(=O)c1c2ccccc2n2cccnc12

Procedure:
A stirred solution of methyl 2-aminoindole-3-carboxylate (I. Forbes et al, J. Chem. Soc. Perkin I, 1992, 275) (0.5 g, 0.0026 mole) in xylene (10 ml) was treated with 1,1,3,3-tetramethoxypropane (0.43 g, 0.0026 mole) and a few crystals of 4-toluenesulphonic acid and heated under reflux for 2.5 h. The mixture was concentrated in vacuo and the residue dissolved in chloroform (25 ml), washed with water (2×10 ml), dried (MgSO4) and concentrated in vacuo to leave a dark orange solid. This was purified by chromatography on silica gel eluting with ethyl acetate to afford the title compound (D19) as an orange solid (0.23 g, 35%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH:10]=[CH:9]2.[NH2:17][CH2:18][CH:19]([OH:21])[CH3:20]>CC(O)C>[OH:21][CH:19]([CH3:20])[CH2:18][NH:17][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH:10]=[CH:9]2
Reactant: CC(O)CN
Reactant: O=c1ccc2cc(OCCCCl)ccc2[nH]1
Solvent: CC(C)O
Product: CC(O)CNCCCOc1ccc2[nH]c(=O)ccc2c1

Procedure:
6-(3-Chloropropoxy)carbostyril (5 g) and 1-amino-2-propanol (24 ml) are dissolved in 2-propanol (100 ml), and the mixture is refluxed for 4 hours. After the reaction mixture is allowed to cool, the precipitated crystals are collected by filtration, washed with ethanol, and dried to give 6-[3-(2-hydroxypropyl)aminopropoxy]carbostyril (3.1 g) as a white powder.
Reaction SMILES: O[C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1>CS(C)=O>[C:8]([OH:10])(=[O:9])[CH:7]=[CH:6][C:5]1[CH:4]=[CH:3][CH:2]=[CH:12][CH:11]=1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Solvent: CS(C)=O
Product: O=C(O)C=Cc1ccccc1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
2.8 g of p-hydroxy cinnamic acid was dissolved in 3 ml of DMSO, and 10 mg of sodium hydride of which the oil was washed by hexane was added. The mixture was stirred and heated to 90° C. under a flow of N2 gas. 5.0 g of glycidol was added gradually, heating and agitation were carried out for 1.5 hours, neutralized by adding hydrochloric acid and then the adduct of cinnamic acid and glycerin was obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]3[C:18]=2[CH2:17][N:16](C)[C:15]3=[O:20])[CH:7]=[N:6]1.NC1C(C(NC)=O)=C([Cl:61])C(C2C=NN(CCCO)C=2)=CC=1>>[Cl:61][C:18]1[C:14]([C:15](=[O:20])[NH:16][CH3:17])=[C:13]([NH:21][C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]3[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=3[O:48][CH3:49])[N:23]=2)[CH:12]=[CH:11][C:10]=1[C:8]1[CH:7]=[N:6][N:5]([CH2:4][CH2:3][CH2:2][OH:1])[CH:9]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CNC(=O)c1c(N)ccc(-c2cnn(CCCO)c2)c1Cl
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c(Cl)c3C(=O)NC)n2)c(OC)c1)OCC
Yield: 3 %

Procedure:
Prepared analogously to Compound 1B replacing Compound 1C with 6-amino-2-chloro-3-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-N-methylbenzamide (Compound 28C, 274 mg, 887 μmol) to afford 21 mg of the title compound (3%). 1H NMR (400 MHz, CD3OD) δ=8.31 (s, 1H), 8.17 (s, 1H), 7.93 (s, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 6.94 (t, J=2.0 Hz, 1H), 6.66 (d, J=7.8 Hz, 1H), 4.34 (t, J=6.8 Hz, 2H), 3.95-4.05 (m, 4H), 3.89 (s, 3H), 3.59 (t, J=6.2 Hz, 2H), 3.20 (s, 1H), 3.14 (s, 1H), 2.86 (s, 3H), 2.11 (quin, J=6.6 Hz, 2H), 1.22 (t, J=7.1 Hz, 6H). MS (ESI): m/z=726.19 [M+H]+. UPLC: tR=1.32 min (UPLC-TOF: polar—3 min).
Reaction SMILES: C(N[C:4]([NH:9][CH2:10][C:11]#C)=[N:5][CH2:6][CH2:7]S)#N.[C:13]([NH:15][C:16]([NH:21][C:22]([CH3:26])([C:24]#[CH:25])[CH3:23])=[N:17][CH2:18][CH2:19][SH:20])#[N:14]>>[C:13]([NH:15][C:16]([NH:17][CH2:18][CH2:19][S:20][CH2:11][C:10]1[NH:9][CH:4]=[N:5][C:6]=1[CH3:7])=[N:21][C:22]([CH3:26])([C:24]#[CH:25])[CH3:23])#[N:14]
Reactant: C#CCNC(=NCCS)NC#N
Reactant: C#CC(C)(C)NC(=NCCS)NC#N
Product: C#CC(C)(C)N=C(NC#N)NCCSCc1[nH]cnc1C

Procedure:
The general procedure of Example 1C is repeated except that the N-cyano-N'-propargyl-N"-(2-mercaptoethyl)guanidine utilized therein is replaced by an equimolar amount of N-cyano-N'-(2-methyl-3-butyn-2-yl)-N"-(2-mercaptoethyl)guanidine, and the title product is thereby produced.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)[CH3:2].[C:11](Cl)(=[O:14])[CH2:12][CH3:13]>>[CH2:1]([N:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)[C:11](=[O:14])[CH2:12][CH3:13])[CH3:2]
Reactant: CCNc1cccc(C)c1
Reactant: CCC(=O)Cl
Product: CCC(=O)N(CC)c1cccc(C)c1

Procedure:
N-Ethyl-N-(3-methylphenyl)propionamide was prepared on a laboratory scale by acylation of N-ethyl-m-toluidine with propionyl chloride. The reaction was carried out in a 5 litre 3 necked round bottomed flask equipped with a mechanical stirrer, a thermometer (0°-250° C.), an addition vessel and a condenser.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][Si](C(C)(C)C)(C)C)=[CH:9][N:8]=1.[C:22]([N:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].[NH4+].[Cl-].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[SiH3]O[SiH3]>C1COCC1>[OH:35][C:32]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][N:8]=2)[CH2:31][CH2:30][N:29]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(CO)cn2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43.5 %

Procedure:
A solution of BuLi (9.94 mmol) in hexanes (1.6 M, 6.2 ml) was added dropwise over 3 min to a stirred solution of 2-bromo-5-(tert-butyldimethylsilyloxymethyl)pyridine (2.0 g, 6.63 mmol) in THF (40 ml) at −78° C. under N2. The resulting solution was then stirred at −78° C. for 30 min and a solution of N-Boc-4-piperidone (1.95 g, 9.93 mmol) in THF (20 ml) was added. The reaction was allowed to warm to room temperature and stirred for a further 15 min. NH4Cl solution (40 ml) was added and the organics were extracted with EtOAc (3×50 ml). The combined organics were washed with brine (50 ml) and then concentrated under reduced pressure. A solution of tetrabutylammonium fluoride(6.63 mmol) in THF (1.0 M, 6.63 ml) was added to a stirred solution of the crude silyl ether in THF (100 ml) at room temperature under N2 and the reaction mixture was stirred for 1 h. NH4Cl solution (40 ml) was added and the organic were extracted with EtOAc (3×50 ml), then washed with brine (50 ml), dried and concentrated under reduced. The mixture was purified by column chromatography on silica using 100% EtOAc as eluent to yield the desired hydroxymethylpyridine (0.89 g, 44%). 1H NMR (360 MHz, CDCl3) δ 8.48 (1H, s), 7.74 (1H, d, J=8.1 Hz), 7.32 (1H, d, J=8.1 Hz), 4.72 (1H, broad s), 4.10 (2H, s), 4.10-4.00 (2H, m), 3.30-3.20 92H, m), 1.89 (2H, td, J=8.1, 4.9 Hz), 1.56 92H, d, J=8.1 Hz), 1.47 (9H, s). m/z (ES+) 423 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[Cl:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[Cl:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27]([NH:16][C:13]1[CH:14]=[CH:15][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:2](=[O:6])[CH3:1])[N:12]=1)=[O:28]
Reactant: O=C(O)/C=C/c1ccc(F)cc1Cl
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Product: CC(=O)CCCCn1ccc(NC(=O)/C=C/c2ccc(F)cc2Cl)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and (E)-3-(2-chloro-4-fluoro-phenyl)-acrylic acid.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH:13]([CH:16]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH3:17])[CH2:12]1)=O)C1C=CC=CC=1>[Pd].C(O)C>[C:22]([O:21][C:19]([NH:18][CH:16]([CH:13]1[CH2:14][CH2:15][NH:11][CH2:12]1)[CH3:17])=[O:20])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(NC(=O)OC(C)(C)C)C1CCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(NC(=O)OC(C)(C)C)C1CCNC1
Reaction time: 3 h
Yield: 99.1 %

Procedure:
640 mg of 1-benzyloxycarbonyl-3-(1-tert-butoxycarbonylaminoethyl)pyrrolidine isomer (P-2A) and 300 mg of 5% Pd-C (50% wet) were added to 20 ml of ethanol and catalytic reduction was carried out at room temperature under 3 atm. for 3 h. Then, the catalyst was filtered off and ethanol was distilled off to obtain 390 mg of the desired compound (P-3A) in the form of a colorless, viscous oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:31][CH2:32][CH:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[C:17]4[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.Cl>CO>[CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:31][CH2:32][CH:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[C:17]4[CH2:23][NH:22][CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(NCC4CCOCC4)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Agent: Cl
Solvent: CO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(NCC4CCOCC4)n2)CNCC3)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-((tetrahydro-2H-pyran-4-yl)methylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (62 mg, 0.12 mmol) was dissolved in methanol (3 mL). Hydrochloric acid (3.63 μL, 0.12 mmol) was added and the reaction mixture was stirred at 80° C. for 1 h. The solvent was evaporated under reduced pressure and the crude N2-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-N4-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (49.0 mg, 98%) was used as such in the subsequent step. MS (ES+) m/z 420.3 (M+H)+
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CC(C)([O-])C.[K+].[CH:18]1([CH:23]=O)[CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1>[CH:18]1([CH:23]=[CH:3][C:1]#[N:2])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=CC1CCCC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC=CC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
A solution of diethyl cyanomethylphosphonate (7, 742.5 g, 4.2 mol, 1.1 equiv) in dry THF (5.75 L) was stirred under nitrogen on an ice-water-methanol bath and a solution of 1 M potassium tert-butoxide in THF (4 L, 4.0 mol, 1.05 equiv) was added at such a rate as to keep the temperature below 0° C. After addition of 1 M potassium tert-butoxide in THF was complete, the stirring was continued on the cold bath for 1 h and a solution of cyclopentanecarbaldehyde (6, 374 g, 3.81 mol) in dry THF (290 mL) was added at such a rate as to maintain the temperature below 0° C. The cold bath was removed, and the reaction mixture was gradually warmed to room temperature and stirred at room temperature for overnight. When the reaction was deemed complete, the reaction mixture was partitioned between methyl tert-butyl ether (MTBE, 14 L), water (10 L) and brine (6 L). The two layers were separated, and the combined organic phase was washed with brine (6 L). The aqueous phase was extracted with MTBE (10 L) and washed with brine (6 L). The combined organic extracts were concentrated under reduced pressure and the residue was distilled (65-78° C./6 torr) to afford 3-cyclopentylacrylonitrile (8, 437.8 g, 461.7 g theoretical, 94.8% yield) as a colorless oil, which was found to be a mixture of E- and Z-isomer. For 8: 1H NMR (DMSO-d6, 400 MHz, for Z-isomer) δ ppm 6.58 (t, 1H, J=10.6 Hz), 5.55 (dd, 1H, J=10.8, 0.59 Hz), 2.85 (m, 1H), 1.90-1.46 (m, 6H), 1.34 (m, 2H) and (for E-isomer) δ ppm 6.83 (q, 1H, J=8.3 Hz), 5.66 (dd, 1H, J=16.5, 1.4 Hz), 2.60 (m, 1H), 1.90-1.46 (m, 6H), 1.34 (m, 2H); 13C NMR (DMSO-d6, 100 MHz, for Z-isomer) δ ppm 159.8, 116.6, 97.7, 42.3, 32.3, 25.1 and (for E-isomer) δ ppm 160.4, 118.1, 97.9, 43.2, 31.5, 24.8; C8H11N (MW, 121.18), GCMS (EI) m/e 120 (M+−H).