Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH2:26]([N:28]1[CH2:32][CH2:31][C@@H:30]([CH2:33][NH2:34])[CH2:29]1)[CH3:27]>CS(C)=O.CO>[CH2:26]([N:28]1[CH2:32][CH2:31][C@@H:30]([CH2:33][NH:34][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH2:29]1)[CH3:27]
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Reactant: CCN1CC[C@@H](CN)C1
Solvent: CS(C)=O
Solvent: CO
Product: CCN1CC[C@@H](CNc2ccccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OCC2CC32)C1
Temperature: 120 °C

Procedure:
A solution of (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic (Intermediate 67, 0.08 g), and ((S)-1-ethylpyrrolidin-3-yl)methylamine (Intermediate 169, 0.8 g) in DMSO (0.2 mL) was stirred and heated at 120° C. for 24 hours. After cooling, the mixture was diluted with methanol and concentrated under vacuum. The residue was purified by HPLC (C18) to give (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-3-ylmethyl)amino]benzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]-chromene-4-carboxylic acid (0.03 g) as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:9]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[CH:4]=1)#[CH:2].C=O.[CH3:21][NH:22][CH3:23].[CH3:24]S(O)(=O)=O>O1CCOCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:21][N:22]([CH2:24][C:2]#[C:1][C:3]1[C:9]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[CH:4]=1)[CH3:23]
Reactant: CS(=O)(=O)O
Reactant: CNC
Reactant: C#CC1=Cc2ccccc2Sc2ccc(Cl)cc21
Agent: [Cu+2]
Agent: C=O
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CN(C)CC#CC1=Cc2ccccc2Sc2ccc(Cl)cc21
Temperature: 100 °C

Procedure:
A solution of 5.1 g. of 10-ethynyl-8-chloro-dibenzo[b,f]-thiepin in 40 ml. of absolute dioxane is treated with 630 mg. of paraformaldehyde, 4.5 ml. of a 6-M solution of dimethylamine in dioxane and 200 mg. of copper (II) acetate. The mixture is heated at 100° C. in a well-sealed flask for 2 hours. After cooling, the mixture is poured onto ice and then acidified with 3-N methanesulfonic acid. The neutral products are removed by extraction with ether. The aqueous phase is made alkaline with ammonia. By extraction with ether, there is obtained N,N-dimethyl-3-[8-chloro-dibenzo[b,f]thiepin-10-yl]-2-propynylamine, which melts at 118°-120° C. after recrystallization from hexane. The maleate melts at 178°-180° C.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.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.[Br:47][C:48]1[CH:49]=[CH:50][C:51]2[C:57]3[S:58][C:59]([C:61]([N:63]([C:65]4[CH:66]=[C:67]([CH:71]=[CH:72][C:73]=4[Cl:74])[C:68](O)=[O:69])[CH3:64])=[O:62])=[CH:60][C:56]=3[CH2:55][CH2:54][O:53][C:52]=2[CH:75]=1>C1COCC1.O>[Br:47][C:48]1[CH:49]=[CH:50][C:51]2[C:57]3[S:58][C:59]([C:61]([N:63]([C:65]4[CH:66]=[C:67]([CH:71]=[CH:72][C:73]=4[Cl:74])[C:68]([N:4]4[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]4)=[O:69])[CH3:64])=[O:62])=[CH:60][C:56]=3[CH2:55][CH2:54][O:53][C:52]=2[CH:75]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1cc(C(=O)O)ccc1Cl
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: O
Solvent: C1CCOC1
Product: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Cl
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a mixture of tert-butyl piperazine-1-carboxylate (1.7 g, 9.13 mmol), DIPEA (3 mL), HATU (2.78 g, 7.31 mmol) in THF (60 mL) was added 3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoic acid (3.0 g, 6.09 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was stirred overnight, diluted with water, extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo to give tert-butyl 4-(3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoyl)piperazine-1-carboxylate (3.9 g, yield: 97%). LC-MS: (ESI, m/z)=682 [M+Na]+
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[C:10]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[CH3:10][N:3]1[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]1[CH3:1]
Reactant: Cc1nc([N+](=O)[O-])c[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1nc([N+](=O)[O-])cn1C
Temperature: 25 °C
Yield: 45 %

Procedure:
To a mixture of 2-methyl-4-nitro-1H-imidazole (10.0 g, 78.7 mmol) and K2CO3 (21.7 g, 160 mmol) in DMF (80 mL) was added CH3I (13.4 g, 94 mmol) dropwise while stirring at room temperature. The mixture was stirred for 2 h. Water (200 mL) was then added to the mixture. The resulting suspension was filtered, washed with water, and dried in vacuo to afford 337a as a white solid (5.0 g, 45%). MS-ESI: [M+H]+ 142.1.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([CH3:21])[CH2:19]Cl)=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].[OH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CN(C)C=O>[C:7]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([CH3:21])[CH2:19][N:26]2[CH2:27][CH2:28][CH:23]([OH:22])[CH2:24][CH2:25]2)=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(CCl)Cc1ccc(C(C)(C)C)cc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Cc1ccc(C(C)(C)C)cc1)CN1CCC(O)CC1
Temperature: 150 °C
Yield: 72 %

Procedure:
106 g of Na2CO3 are added to a solution of 112 g of 3-(4-tert.-butylphenyl)-2-methyl-propyl chloride and 50 g of 4-hydroxypiperidine in 1 liter of dimethylformamide (DMF). The batch is heated at 150° C. for 15 hours and then concentrated, and the residue is taken up in CH2Cl2. The CH2CL2 phase is washed with water, dried over Na2SO4 and concentrated. Distillation of the crude product gives 103 g of N-[3-(4-tert.-butylphenyl)-2-methyl-propyl]-4-hydroxypiperidine [A] as a pale yellowish oil. Boiling point 175°-178° C./0.4 mbar.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([NH2:18])[N:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([NH:18][C:5](=[O:7])[CH3:6])[N:9]=1
Reactant: Nc1cc2ccccc2cn1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc2ccccc2cn1
Reaction time: 3.5 h
Yield: 100 %

Procedure:
Acetic anhydride (5.92 mL, 62.6 mmol) was added to a suspension of isoquinolin-3-amine (3.01 g, 20.9 mmol) and triethylamine (3.18 mL, 23.0 mmol) in CH2Cl2 (80 mL) at ambient temperature. The mixture was stirred 3.5 hours, then the volatiles were evaporated in vacuo. The residue was chased with toluene and concentrated in vacuo (3×25 mL) to provide the title compound (3.89 g) as a yellow solid. This material, which was found to also contain small quantities of acetic acid, was used without further purification. 1H NMR (300 MHz, DMSO-d6) δ 10.58 (s, 1H), 9.13 (s, 1H), 8.45 (s, 1H), 8.04 (d, J=7.8 Hz, 1H), 7.88 (d, J=8.2 Hz, 1H), 7.69 (ddd, J=8.2, 6.8, 1.2 Hz, 1H), 7.52 (ddd, J=7.9, 6.9, 1.0 Hz, 1H), 2.13 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K]>CN(C)C=O>[O:21]=[C:19]1[C:18]2[C:17](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16](=[O:26])[N:20]1[CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)C(=O)Nc1cccc(CBr)n1
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Nc1cccc(CN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
N-[6-(bromomethyl)-2-pyridinyl]-2,2-dimethylpropaneamide (21-2) (1.9 g) was dissolved in dimethylformamide (20 ml) and to the solution was added potassium phthalimide (1.43 g), followed by stirring at room temperature for 24 hours. The resulting mixture was concentrated under reduced pressure and extrated with water and dichloromethane. An organic layer was concentrated under reduced pressure to yield the compound 21-3 (2.27 g, 96%) as a bright yellow solid.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][S:11][CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[CH:19]([C:23]([Cl:25])=[O:24])[CH2:18][C:17]2=[O:26]>C(N(CC)CC)C>[ClH:25].[CH3:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[CH:19]([C:23]([N:8]1[CH2:9][CH2:10][S:11][CH2:12][CH:7]1[CH2:6][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:24])[CH2:18][C:17]2=[O:26]
Reactant: Cc1ccc2c(c1)C(=O)CC2C(=O)Cl
Reactant: C1CCN(CC2CSCCN2)C1
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)C(=O)CC2C(=O)N1CCSCC1CN1CCCC1
Product: Cl
Yield: 69.2 %

Procedure:
The procedure described in Example 24 was repeated, but using 0.92 g of 3-(pyrrolidin-1-ylmethyl)thiomorpholine, 1.64 ml of triethylamine and 1.66 g of 5-methyl-3-oxoindan-1-carbonyl chloride, to afford 1.35 g of the title compound, melting at 232°-234° C.
Reaction SMILES: C([N:4]1[C:13]2[C:8](=[C:9](OCC3OC3)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH2:5]1)(=O)C.[CH2:19](O)C>Cl.C1C2C(=CC=CC=2)CCC1NCC(O)COC1C=CC=C2C=1CCCN2C(=O)C>[NH2:4][CH:5]1[CH2:6][CH2:7][C:8]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:19]1
Reactant: CC(=O)N1CCCc2c(OCC3CO3)cccc21
Reactant: CCO
Agent: CC(=O)N1CCCc2c(OCC(O)CNC3CCc4ccccc4C3)cccc21
Agent: Cl
Product: NC1CCc2ccccc2C1

Procedure:
Following the procedure of Example 27, but starting from 1-acetyl-5-(2,3-epoxypropoxy)-1,2,3,4-tetrahydroquinoline (2.77 g) and 2-aminotetralin (1.49 g) in ethanol (30 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(1-acetyl-1,2,3,4-tetrahydroquinolin-5-yloxy)propanamine hydrochloride is obtained ((i): R=H, Ar=radical 66, wherein Z is methyl, and the chain is attached to position 2 of the tetralin moiety).
Reaction SMILES: [CH:1](Br)([CH3:3])[CH3:2].[N-:5]=[N+:6]=[N-:7].[Na+].[Br:9][C:10]1[N:11]=[C:12]([C:17]#[CH:18])[C:13]([NH2:16])=[N:14][CH:15]=1>CC(O)(C)C.O.CCOC(C)=O.[Cu]I>[Br:9][C:10]1[N:11]=[C:12]([C:17]2[N:5]=[N:6][N:7]([CH:1]([CH3:3])[CH3:2])[CH:18]=2)[C:13]([NH2:16])=[N:14][CH:15]=1
Reactant: CC(C)Br
Reactant: [N-]=[N+]=[N-]
Reactant: C#Cc1nc(Br)cnc1N
Agent: [Cu]I
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CC(C)n1cc(-c2nc(Br)cnc2N)nn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of isopropyl bromide (2.5 g, 20.3 mmol) and sodium azide (1.3 g, 20.3 mmol) in t-BuOH/water (1:2) (25 mL) was stirred for 2 h at 80° C. Then the reaction mixture was cooled to room temperature, was added 5-bromo-3-ethynyl-pyrazin-2-ylamine (0.40 g, 2.03 mmol) and CuI (catalytic amount) and stirred for 16 h at 80° C. The reaction mixture was cooled to RT, diluted with EtOAc (100 mL) and washed with water (50 mL). The organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure to afford crude product. The crude product was washed with diethyl ether to afford the title compound as a solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[OH:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[O:22][C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])c1cccc2nc(Br)sc12
Reactant: Cc1ccc(O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2nc3cccc([N+](=O)[O-])c3s2)c(C)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 97.5 %

Procedure:
A mixture of 2-bromo-7-nitro-1,3-benzothiazole (200 mg, 0.772 mmol), 2,4-dimethylphenol (0.093 ml, 0.772 mmol) and potassium carbonate (128 mg, 0.772 mmol) in DMF (10 ml) was stirred at 80° C. for 15 h. The mixture was diluted with water and extracted with ethyl acetate (AcOEt). The extract was washed with saturated NaHCO3 solution and brine, dried over Magnesium sulfate and concentrated under vacuum. The residue was purified by chromatography eluting with 10% AcOEt in n-hexane to afford 226 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:9]=[CH:10][C:11]3[C:16](=O)[NH:15][C:14]([CH2:18][O:19][CH3:20])=[N:13][C:12]=3[N:21]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.N1C(C)=CC=CC=1C.O=P(Cl)(Cl)[Cl:32]>C(Cl)(Cl)Cl>[Cl:32][C:16]1[C:11]2[CH:10]=[CH:9][C:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)=[N:21][C:12]=2[N:13]=[C:14]([CH2:18][O:19][CH3:20])[N:15]=1
Reactant: COCc1nc2nc(-c3ncccc3Cl)ccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClC(Cl)Cl
Product: COCc1nc(Cl)c2ccc(-c3ncccc3Cl)nc2n1

Procedure:
Reflux a mixture of 7-(3-chloro-pyridin-2-yl)-2-methoxymethyl-3H-pyrido[2,3-d]pyrimidin-4-one (0.25 g), 2,6-lutidine (0.44 g), and POCl3 (0.51 g) in CHCl3 (5 mL) for 20 hours. Cool the mixture and concentrate under reduced pressure. Partition the residue between EtOAc and saturated NaHCO3 solution. Wash the EtOAc portion with additional NaHCO3 and then dry (Na2SO4) and concentrate under reduced pressure. Filter the brown residue through 2 inches of silica gel (1:1 EtOAc/hexanes eluent) and concentrate under reduced pressure to give 4-chloro-7-(3-chloro-pyridin-2-yl)-2-methoxymethyl-pyrido[2,3-d]pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([OH:9])=[C:4]([CH3:10])[N:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>N1C=CC=CC=1>[C:11]([O:9][C:5]1[C:6](=[O:8])[NH:7][C:2]([NH2:1])=[N:3][C:4]=1[CH3:10])(=[O:13])[CH3:12]
Reactant: Cc1nc(N)[nH]c(=O)c1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)nc(N)[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Amino-5-hydroxy-6-methyl-4-pyrimidone (0.88 g, prepared as described in Hull, J. Chem. Soc., 2033 (1956)), was treated with pyridine (5 ml) and acetic anhydride (0.5 ml) at 0° C. The reaction mixture was stirred at 25° C. for 18 hours. Filtration provided a white solid (0.64 g). Recrystallization (absolute ethanol) afforded a white crystalline solid (m.p.: 273°-276° C.).
Reaction SMILES: FC1C=CC(C[P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])=CC=1.[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26]Br)=[CH:18][CH:17]=1.COP(OC)OC>>[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])=[CH:18][CH:17]=1
Reactant: Clc1ccc(CBr)c2ccccc12
Reactant: COP(=O)(Cc1ccc(F)cc1)OC
Agent: COP(OC)OC
Product: COP(=O)(Cc1ccc(Cl)c2ccccc12)OC

Procedure:
Following the procedure of Compound 11, 4-chloro-1-bromomethylnaphthalene is reacted with trimethylphosphite.
Reaction SMILES: C(OC([N:8]1[C:12]2=[CH:13][N:14]=[C:15]([N:17]3[CH:21]=[N:20][N:19]=[CH:18]3)[CH:16]=[C:11]2[C:10]([CH:22]=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:19]1[N:20]=[CH:21][N:17]([C:15]2[CH:16]=[C:11]3[C:10]([CH:22]=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:9][NH:8][C:12]3=[CH:13][N:14]=2)[CH:18]=1
Reactant: CCOC(=O)C=Cc1cn(C(=O)OC(C)(C)C)c2cnc(-n3cnnc3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C=Cc1c[nH]c2cnc(-n3cnnc3)cc12
Yield: 58.8 %

Procedure:
A solution of ethyl 3-[1-tert-butyloxycarbonyl-5-(1,2,4-triazol-4-yl)pyrrolo[2,3-c]pyridin-3-yl]prop-2-enoate (0.92 g) and trifluoroacetic acid (5 mL) in dry DCM (20 mL) was stirred at ambient temperature under nitrogen for 16 hours. The solvent was evaporated in vacuo and the residue azeotroped with toluene. The residue was chromatographed on silica eluting with 5 to 20% MeOH in DCM to give a cream solid. This was triturated with MeOH and the solid was collected by filtration to afford the title compound (0.4 g, 62%) as a a cream solid. mp 235° C. (dec.). 1H NMR (360 MHz, d6 -DMSO) δ 1.29 (3H, t, J=7.1Hz), 4.21 (2H, q, J=7.1Hz), 6.68 (1H, d, J=16.2Hz), 7.91 (1H, d, J=16.1Hz), 8.33 (1H, s), 8.36 (1H, s), 8.74 (1H, s), 9.35 (2H, s) and 12.44 (1H, br s).
Reaction SMILES: C([O:8][C:9]1[NH:10][N:11]([CH:26]([CH3:28])[CH3:27])[C:12]([C:16]2[CH:25]=[CH:24][C:19]3[O:20][CH2:21][CH2:22][O:23][C:18]=3[CH:17]=2)(C=O)[CH:13]=1)C1C=CC=CC=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([Mg]Br)=[CH:33][CH:32]=1.O.O1CCC[CH2:41]1>>[CH:26]([N:11]1[C:12]([C:16]2[CH:25]=[CH:24][C:19]3[O:20][CH2:21][CH2:22][O:23][C:18]=3[CH:17]=2)=[C:13]([CH2:41][C:34]2[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)[C:9](=[O:8])[NH:10]1)([CH3:27])[CH3:28]
Reactant: C1CCOC1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CC(C)N1NC(OCc2ccccc2)=CC1(C=O)c1ccc2c(c1)OCCO2
Solvent: O
Product: COc1ccc(Cc2c(-c3ccc4c(c3)OCCO4)n(C(C)C)[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-benzyloxy-5-(2,3-dihydrobenzo[1,4]-dioxin-6-yl)-5-formyl-1-isopropyl-1H-pyrazole (0.19 g) in tetrahydrofuran (2 mL) was added a solution of 4-methoxyphenyl-magnesium bromide in tetrahydrofuran (1 mol/L, 0.60 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. A small amount of water was added to the reaction mixture, and the mixture was purified by column chromatography on aminopropylated silica gel (eluent:tetrahydrofuran). The obtained compound was dissolved in ethanol (10 mL). Ten percent (10%) Palladium-carbon powder was added to the solution, and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. Dichloromethane was added to the reaction mixture, and the insoluble material was removed by filtration. The solvent of the filtrate was removed under reduced pressure, and ethanol and hexane were added to the residue. The precipitated material was collected by filtration and dried under reduced pressure to give the title compound (0.056 g).
Reaction SMILES: F[C:2]1[CH:11]=[C:10](F)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:13])[NH:5][CH:6]=[N:7]2.CC(C)([O-])C.[K+].[CH3:20][O:21][CH2:22][CH2:23][OH:24].[CH3:25][O:26][CH2:27][CH2:28][O:29]CCOC>>[NH3:5].[CH3:20][O:21][CH2:22][CH2:23][O:24][C:2]1[CH:11]=[C:10]([O:29][CH2:28][CH2:27][O:26][CH3:25])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:13])[NH:5][CH:6]=[N:7]2
Reactant: O=c1[nH]cnc2cc(F)cc(F)c12
Reactant: COCCO
Reactant: COCCOCCOC
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COCCOc1cc(OCCOC)c2c(=O)[nH]cnc2c1
Product: N
Yield: 99 %

Procedure:
5,7-difluoroquinazolin-4(3H)one (728 mg, 4 mmol) in diglyme (15 ml) and potassium tert-butoxide (4.48 g, 32 mmol) were reacted with 2-methoxyethanol (2.52 ml, 32 mmol) at 110° C. for 1 hour. The mixture was cooled and purified by chromatography on silica gel. Elution with dichloromethane:methanol (96:4) then increased polarity to dichloromethane:methanolic ammonia (95:5) yielded 5,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one (982 mg, 99% yield):
Reaction SMILES: [OH:1][C:2]1[C:15]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:14][C:5]([CH:6]=[N:7][N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[CH:4][C:3]=1[C:20]([CH3:23])([CH3:22])[CH3:21].Cl.O.[H][H]>CO.[C].[Pd]>[OH:1][C:2]1[C:15]([C:16]([CH3:18])([CH3:17])[CH3:19])=[CH:14][C:5]([CH2:6][NH:7][N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[CH:4][C:3]=1[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: [H][H]
Reactant: Cc1cn(N=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cn1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1cn(NCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cn1

Procedure:
6.1 g of 1-(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)-4-methylimidazole are hydrogenated at normal pressure and room temperature in 100 ml of methanol, 21 ml of 1N hydrochloric acid and 30 ml of water in the presence of palladium-carbon. After 500 ml of hydrogen have been taken up, the mixture is filtered. The filtrate is evaporated to a volume of 50 ml. Then, 50 ml of water are added and the mixture is treated with saturated sodium bicarbonate solution up to a neutral reaction (pH=7). The separated crystals are removed by filtration, and taken up with methylene chloride. The methylene chloride solution is washed once with water, dried and evaporated. The residue is triturated with cold ether. Thereafter the solid is removed by filtration, washed with ether and n-hexane and dried at 60° in a vacuum. There is obtained 1-(4-hydroxy-3,5-di-tert.-butylbenzylamino)-4-methylimidazole of m.p. 150°-151°.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15](I)[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.[Cu][C:28]#[N:29]>O1CCCC1.C(OCC)(=O)C.[Cu]I>[Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([C:28]#[N:29])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: Cc1cc(I)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Reactant: N#C[Cu]
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12

Procedure:
To a solution of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-iodo-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the benzoxazinone product of Step E) (600 mg, 1.1 mmol) in tetrahydrofuran (15 mL) was added copper(I) iodide (126 mg, 0.66 mmol), tetrakis(triphenyphosphine)palladium(0) (382 mg, 0.33 mmol) and copper(I) cyanide (800 mg, 8.8 mmol) sequentially at room temperature. The reaction mixture was then heated at reflux overnight. The reaction turned black in color, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The reaction mixture was diluted with ethyl acetate (20 mL) and filtered through Celite®, followed by washing three times with 10% sodium bicarbonate solution and once with brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure to afford 440 mg of the title compound as a crude yellow solid.
Reaction SMILES: C(OC(=O)[C@@H]([N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=[O:13])C)C.[CH2:15]1[CH2:19][O:18]C[CH2:16]1.[OH-:20].[Na+]>O>[O:13]=[C:8]1[C:9]([C@H:15]([CH3:16])[C:19]([OH:18])=[O:20])=[CH:10][CH:11]=[CH:12][NH:7]1
Reactant: C1CCOC1
Reactant: CCOC(=O)[C@H](C)n1ccccc1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: C[C@H](C(=O)O)c1ccc[nH]c1=O
Reaction time: 1 h
Yield: 27 %

Procedure:
A stirred mixture of (S)-2-(2-Oxo-2H-pyrid-1-yl)-propionic acid ethyl ester (364 mg, 1.87 mmol), THF (2 ml), water (1 ml) and sodium hydroxide (90 mg, 2.24 mmol) was kept at room temperature for 1 h, then concentrated under reduced pressure. The residue was dissolved in ether and the resulting solution washed with water. The organic layer was discarded and the aqeous layer was acidified with concentrated HCl then extracted several times with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was triturated with ether to afford the title compound as a colorless solid (84 mg, 27%): [α]31D=−50° (c=0.2, CH3OH) 1H NMR (400 MHz, DMSO) δ 1.5 3H, d), 5.1 1H, q), 6.2 1H, t), 6.4 1H, d), 7.4 1H, m), 7.6 1H, d).
Reaction SMILES: NC1N=C(OCCCC)N=C2C=1N=C(OC)N2CCCC1CCCCN1C(OCC1C=CC=CC=1)=O.FC(F)(F)C(O)=O.[CH3:44][C@H:45]([O:49][C:50]1[N:58]=[C:57]2[C:53]([N:54]=[C:55]([O:59][CH3:60])[NH:56]2)=[C:52]([NH2:61])[N:51]=1)[CH2:46][CH2:47][CH3:48].Br[CH2:63][CH2:64][CH2:65][CH2:66][CH:67]1[CH2:72][CH2:71][N:70]([C:73]([O:75][CH2:76][C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)=[O:74])[CH2:69][CH2:68]1>>[NH2:61][C:52]1[N:51]=[C:50]([O:49][C@@H:45]([CH3:44])[CH2:46][CH2:47][CH3:48])[N:58]=[C:57]2[C:53]=1[N:54]=[C:55]([O:59][CH3:60])[N:56]2[CH2:63][CH2:64][CH2:65][CH2:66][CH:67]1[CH2:68][CH2:69][N:70]([C:73]([O:75][CH2:76][C:77]2[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=2)=[O:74])[CH2:71][CH2:72]1
Reactant: O=C(OCc1ccccc1)N1CCC(CCCCBr)CC1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)[nH]c2n1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine trifluoroacetate salt and phenylmethyl 4-(4-bromobutyl)-1-piperidinecarboxylate.