Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[O:37][CH3:38]>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=4[O:37][CH3:38])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Yield: 80.8 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1H-indazole (3.5 g, 16 mmol), K2CO3 (2.2 g), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (3.8 g, 16 mmol) acetonitrile (90 ml) was refluxed for 16 hours. The reaction was poured into water and the resulting white solid, which precipitation from solution, was collected to afford 5.5 g of the desired product. The compound was recrystallized from dimethylformamide (twice) to afford 3.0 g (44%) of 1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]propoxy]methoxyphenyl]ethanone as a white solid, m.p.=202°-204° C.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[N:10][CH:11]=[N:12][C:7]=2[C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:3]1.[C:23]([NH:30][C@H:31]([C:39](O)=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.C(N(CC)CC)C>[C:26]([O:25][C:23]([NH:30][C@@H:31]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:39]([NH:1][CH:2]1[C:8]2[CH:9]=[N:10][CH:11]=[N:12][C:7]=2[C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[C:4]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:3]1)=[O:40])=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: NC1N=C(c2ccccc2)c2ccccc2-c2ncncc21
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NC1N=C(c2ccccc2)c2ccccc2-c2ncncc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Crude 5(R,S)-amino-7-phenyl-5H-pyrimido[5,4-d][2]benzazepine (1.37 g), Boc-L-phenylalanine (1.37 g, 5.17 mmole), 1-hydroxybenzotriazole (HBT) (0.70 g, 5.17 mmole), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) (0.99 g, 5.17 mmole) are combined in DMF (30 ml) and stirred at room temperature. The pH of the mixture is adjusted to 9.5 with triethylamine. After about 1/2 hour, the DMF is removed in vacuo and the residue is partitioned between methylene chloride and 10% citric acid solution. The layers are separated and the organic phase is washed with saturated NaHCO3 solution, water and brine, then dried over Na2SO4, filtered, and evaporated to dryness in vacuo. The residue is chromatographed on silica gel and the combined product fractions evaporated to dryness in vacuo to give the title compound as a mixture of diastereomers.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[OH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: OCCCCCCCCCCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCCCCCCCCCCO)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 58 %

Procedure:
50.0 g (409 mmol) of 4-hydroxybenzaldehyde and 123.0 g (490 mmol) of 11-bromoundecan-1-ol are dissolved in 400 mL of N,N-dimethylformamide. 113.0 g (819 mmol) of potassium carbonate and 7.0 g (42 mmol) of potassium iodide are added and the suspension is heated to 80° C. After 48 h, the excess of potassium carbonate is filtered off and the resulting filtrate is poured to icy water. The aqueous layer is extracted twice with ethyl acetate. Combined organic layers are washed with brine, concentrated to minimum volume and precipitated in cold heptane. The precipitate is filtered off and washed with cold heptanes. 69.4 g of 4-[(11-hydroxyundecyl)oxy]benzaldehyde are obtained as a white solid (57% yield). This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: C(OCCCCCCCCC(O)=O)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[OH-].[Na+].C[O:35][C:36](=[O:68])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][O:48][C:49]([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C1COCC1>[C:49]([O:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][C:36]([OH:68])=[O:35])([C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: COC(=O)CCCCCCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)CCCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCCCCCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 48 h
Yield: 84.1 %

Procedure:
The synthesis and purification procedures of 16b were followed. Aqueous 0.5 M NaOH (4.6 mL, 2.3 mmol), 15c (548 mg, 1.2 mmol), and THF (9.3 mL) were used and the reaction duration was shortened to 2 days. After purification, 463 mg (87%) of 16c was obtained as a colorless oil. 1H-NMR (400 MHz, CDCl3, δH ppm): 7.43 (6H, m, p-Ar), 7.28 (6H, m, m-Ar), 7.21 (3H, m, o-Ar), 3.02 (2H, t, 3JH—H=6.7 Hz, HO—CH2), 2.34 (2H, t, 3JH—H=7.5 Hz, CH2CO2), 1.55-1.67 (4H, m, 2CH2), 1.19-1.39 (14H, m, 7CH2). 13C-NMR (100 MHz, CDCl3, δH ppm): 180.02, 144.53, 128.69, 127.64, 126.75, 86.25, 63.66, 34.02, 30.04, 29.52, 29.50, 29.48, 29.39, 29.22, 29.05, 26.25, 24.66. HRMS (EI): m/z calcd 458.2821 (C31H38O3), found 458.2814 [M]+.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].Br.Br.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[NH:25][CH:26]2[CH2:27][CH2:28][N:29]([CH2:2][C:3](=[O:5])[CH3:4])[CH2:30][CH2:31]2)=[CH:11][CH:10]=1
Reactant: CC(=O)CCl
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)CN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 50 °C
Yield: 39.5 %

Procedure:
A mixture of 9.25 parts of 1-chloro-2-propanone, 48.6 parts of 1-(4-fluorophenylmethyl)-N-(4-piperidinyl)-1H-benzimidazol-2-amine dihydrobromide, 32 parts of sodium carbonate and 135 parts of N,N-dimethylformamide was stirred and heated overnight at 50° C. The reaction mixture was poured onto water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from 4-methyl-2-pentanone, yielding 15 parts (39.5%) of 1-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-2-propanone (intermediate 130).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:39])[CH:8]1[CH2:11][N:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH3:36])[CH:28]=4)[C:24]([CH3:37])=[CH:23][N:22]=3)=[CH:14][C:13]=2[NH2:38])[CH2:9]1>C(Cl)Cl.CO.CC#N>[CH3:39][N:7]([CH3:6])[CH:8]1[CH2:9][N:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH3:36])[CH:28]=4)[C:24]([CH3:37])=[CH:23][N:22]=3)=[CH:14][C:13]=2[NH:38][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:11]1
Reactant: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CC#N
Product: C=CC(=O)Nc1cc(Nc2ncc(C)c(-c3cn(C)c4ccccc34)n2)c(OC)cc1N1CC(N(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.4 %

Procedure:
A solution of acryloyl chloride (0.024 mL, 0.30 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred solution of 4-(3-dimethylaminoazetidin-1-yl)-6-methoxy-N-[5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 114, 130 mg, 0.28 mmol) in CH2Cl2 (5 mL), which was cooled in an ice/brine bath to approx 0° C. The mixture was stirred for 1 h, then diluted with CH2Cl2 (50 mL) and CH3OH (to fully dissolve suspension that had formed). This solution was then washed with sat. NaHCO3 (100 mL) which had been diluted with water (10 mL). The aqueous wash solution was then extracted with CH2Cl2 (2×50 mL) and the combined organic solutions were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave a dark brown solid. This solid was heated in CH3CN and isolated by vacuum filtration, to give the title compound (45 mg, 31%) as a pale brown solid. The mother liquors were concentrated in vacuo and also retained as a second batch of the title compound (30 mg, 21%) as a darker brown solid. Total yield of title compound=75 mg, 52%; 1H NMR: 2.08 (6H, s), 2.34 (3H, s), 3-3.1 (1H, m), 3.55 (2H, t), 3.83 (3H, s), 3.88 (3H, s), 3.93 (2H, t), 5.65 (1H, dd), 6.15 (1H, dd), 6.24 (1H, s), 6.44 (1H, dd), 7.13 (1H, t), 7.21 (1H, t), 7.47 (1H, d), 7.66 (1H, s), 7.81 (1H, s), 7.99 (1H, s), 8.17 (1H, s), 8.37 (1H, d), 9.19 (1H, s); m/z: ES+ MH+ 512.14.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]([CH3:16])=[C:12]([C:17]([OH:19])=O)[S:11]3)=[CH:4][CH:3]=1.[CH3:20][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C(N(CC)CC)C>CN(C=O)C>[CH3:20][N:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:17]([C:12]1[S:11][C:10]2=[N:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:15][N:14]2[C:13]=1[CH3:16])=[O:19]
Reactant: Cc1c(C(=O)O)sc2nc(-c3ccc(F)cc3)cn12
Reactant: CNc1ccccc1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N(C)c2ccccc2)sc2nc(-c3ccc(F)cc3)cn12
Yield: 13.7 %

Procedure:
6-(4-Fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acid (example 7, 50 mg, 0.18 mmol) N-methyl-phenyl-amine (29.15 mg, 0.27 mmol), TOTU (63.32 mg, 0.2 mmol) and triethylamine (100.6 μl, 0.72 mmol) in 3 ml DMF were stirred at RT for 8 hours. The mixture was evaporated. Ethyl acetate and water were added, the organic layer was separated, washed with water, dried and evaporated. The crude product was purified by preparative HPLC (RP18, acetonitrile/water 0.1% TFA) to yield 9 mg (14%) of the desired product. MS: M+H+=365.94.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10](Cl)=[N:9][N:8]=1)[CH3:2].Br[C:22]1[S:23][CH:24]=[CH:25][N:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Zn].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:9][N:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1nnc(Cl)c2cc(OC)ccc12
Reactant: Brc1nccs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Zn]
Product: CCOC(=O)CCc1nnc(-c2nccs2)c2cc(OC)ccc12
Yield: 26.6 %

Procedure:
Operating analogously at what described in example 48 starting from 3-(4-chloro-6-methoxy-phthalazin-1-yl)-propionic acid ethyl ester (4.5 g, 0.0153 mole), prepared as described in example 121, zinc (2.2 g), 2-bromothiazole (5 g, 0.0305 mole), palladium acetate (180 mg, 0.8 mmole), triphenyphosphine (630 mg, 2.4 mmoles), 1.4 g of the title compound were obtained (yield: 21%). m.p.: 153-154° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].O.[CH:14](=O)[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[OH-].[Na+]>O.CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:12])[CH:11]=[CH:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccncc1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(C=Cc1ccncc1)c1ccc([N+](=O)[O-])cc1

Procedure:
41.25 G. of 4'-nitroacetophenone are suspended in 500 ml. of water and heated at 70° C. with stirring. Then, 24 ml. of isonicotinaldehyde are added and the reaction mixture is treated three times at intervals of 30 minutes with 5 ml. each time of a 6% NaOH solution in water/methanol (2:1). Subsequently the reaction mixture is left to react at 70° C. for 8 hours. The crystals which form are filtered off, boiled up twice with 500 ml. of ethanol each time and subsequently washed with ether to yield 4'-nitro-3-(4-pyridyl)-acrylphenone with a melting point of 218°-221° C.
Reaction SMILES: [C:1]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(OCC)=[O:2].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1.C1(C)C=CC=CC=1>[CH:1]([CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)=[O:2]
Reactant: CCOC(=O)C1CCN(c2ccccc2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=CC1CCN(c2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
The product from Example 28, Step C is dissolved in THF and cooled to −78° C. under nitrogen. A solution of diisobutylaluminum hydride (1 eq.) in toluene is added dropwise. After 30 min, the reaction is quenched with saturated sodium potassium tartrate solution. The mixture is extracted with ethyl acetate, and the organic phase washed with saturated brine, and dried over MgSO4. Filtration and concentration provides the title compound
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14]C(OC(C)(C)C)=O)=[CH:11][CH:12]=2)[C:7]([CH3:22])=[CH:6][C:5]1([CH3:24])[CH3:23])(=[O:3])[CH3:2].[Al+3].[Cl-:26].[Cl-].[Cl-]>ClC1C=CC=CC=1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[CH:7]([CH3:22])[CH:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:26])=[CH:10][CH:9]=2)[C:5]1([CH3:23])[CH3:24])(=[O:3])[CH3:2]
Reactant: [Cl-]
Reactant: CC(=O)N1c2ccc(NC(=O)OC(C)(C)C)cc2C(C)=CC1(C)C
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: CC(=O)N1c2ccc(N)cc2C(C)C(c2ccc(Cl)cc2)C1(C)C
Reaction time: 1 h

Procedure:
A mixture of 1-acetyl-6-(tert-butoxycarbonyl)amino-1,2-dihydro-2,2,4-trimethylquinoline (25 mg) and AlCl3 (35 mg) in chlorobenzene (2 ml) was stirred for 1 h. The reaction mixture was quenched with water and in addition a solution of 2 M NaOH and ethyl acetate were added. The organic layer was separated, dried over MgSO4 and concentrated in vacuo.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.N>C1(C)C=CC=CC=1.O>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][O:3][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][O:20]1)[CH3:7]
Reactant: CCOC(=O)CO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)COC1CCCCO1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
100.00 kg (960.52 mol) ethyl glycolate (A) were dissolved in 180.0 L toluene and 365.22 g (1.92 mol) 4-toluenesulphonic acid monohydrate were added. At 20° C. a solution of 80.80 kg (960.52 mol) 3,4-dihydro-2H-pyran was added dropwise to the reaction mixture obtained and then the mixture was washed with 20.0 L toluene. The reaction mixture was stirred for 1 hour at 20° C. and after the reaction was complete it was combined with 100.0 L water and 6.53 kg (96.05 mol) ammonia solution (25%). After phase separation the organic phase was washed with 100.0 L water and then the solvent was distilled off completely in vacuo.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]2[C@H:10]3[CH2:16][C@H:7]([CH2:8][CH2:9]3)[C:6]=2[C:5]=1[OH:17])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([C:4]1[C:5]([O:17][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:6]2[C:11](=[C:12]([O:14][CH3:15])[CH:13]=1)[C@H:10]1[CH2:16][C@@H:7]2[CH2:8][CH2:9]1)[CH:2]=[CH2:3]
Reactant: BrCc1ccccc1
Reactant: C=CCc1cc(OC)c2c(c1O)[C@H]1CC[C@@H]2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Product: C=CCc1cc(OC)c2c(c1OCc1ccccc1)[C@H]1CC[C@@H]2C1
Yield: 90.4 %

Procedure:
Treatment of (1R*,4S*)-6-allyl-8-methoxy-1,2,3,4-tetrahydro-1,4-methanonaphthalen-5-ol (14.2 g, 61.66 mmol) with potassium carbonate (34.09 g, 0.247 mol), benzyl bromide (11.07 g, 64.74 mmol), and tetrabutylammonium iodide (0.224 g, 6.166 mmol) generally according to the procedure described for Intermediate 1 provided 17.86 g (90%) of (1R*,4S*)-6-allyl-5-(benzyloxy)-8-methoxy-1,2,3,4-tetrahydro-1,4-methanonaphthalene as a colorless oil. Anal. calcd. for C22H2402-0.5H2O: C, 80.21; H, 7.65. Found: C, 79.81; H, 7.48.
Reaction SMILES: Br[CH:2]1[CH:7]([OH:8])[C:6]2[CH:9]=[C:10]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][C:5]=2[O:4][C:3]1([CH3:21])[CH3:20].[OH-].[K+]>C(OCC)C>[CH3:20][C:3]1([CH3:21])[CH:2]2[O:8][CH:7]2[C:6]2[CH:9]=[C:10]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][C:5]=2[O:4]1
Reactant: CC1(C)Oc2ccc(C(F)(F)C(F)(F)F)cc2C(O)C1Br
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CC1(C)Oc2ccc(C(F)(F)C(F)(F)F)cc2C2OC21
Temperature: 25 °C
Reaction time: 54 h
Yield: 95.9 %

Procedure:
To 1.5 l of diethyl ether was added 12.63 g (33.67 mmol) of 3-bromo-3,4-dihydro-2,2-dimethyl-6-pentafluoroethyl-2H-1-benzopyran-4-ol synthesized according to the process of JP-B-2-237985, and 30.2 g of potassium hydroxide was added thereto, followed by stirring at room temperature for 54 hours. The insoluble material was removed by filtration, and the solvent was removed by distillation under reduced pressure to yield 9.5 g (96.2%) of 3,4-dihydro-2,2-dimethyl-3,4-epoxy-6-pentafluoroethyl-2H-1-benzopyran.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1([F:11])[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1.C(S[C:16]1[N:17]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]([F:39])([F:38])[F:37])=[CH:30][CH:29]=2)[C:18](=[O:27])[C:19]2[CH:25]=[CH:24][C:23](=[O:26])[NH:22][C:20]=2[N:21]=1)CC.O>O1CCCC1>[F:3][C:4]1([F:11])[CH2:9][CH2:8][CH:7]([O:10][C:16]2[N:17]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH2:35][C:36]([F:39])([F:38])[F:37])=[CH:32][CH:33]=3)[C:18](=[O:27])[C:19]3[CH:25]=[CH:24][C:23](=[O:26])[NH:22][C:20]=3[N:21]=2)[CH2:6][CH2:5]1
Reactant: CCCSc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: OC1CCC(F)(F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1ccc2c(=O)n(-c3ccc(OCC(F)(F)F)cc3)c(OC3CCC(F)(F)CC3)nc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.7 %

Procedure:
To a suspension of sodium hydride (60% in oil, 19 mg) in tetrahydrofuran (5 ml) was added 4,4-difluorocyclohexanol (109 mg) at room temperature, and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added 2-(propylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (165 mg), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and recrystallized from a mixed solvent of hexane/ethyl acetate to give the title compound (75 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([F:10])[C:4]=1[CH2:11]Br.[N+:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])#[C-:14].C([O-])([O-])=O.[K+].[K+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[CH2:19]([O:18][C:16]([C:15]1([N+:13]#[C-:14])[CH2:11][C:4]2[C:3](=[CH:8][CH:7]=[C:6]([F:9])[C:5]=2[F:10])[CH2:2]1)=[O:17])[CH3:20]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: Fc1ccc(CBr)c(CBr)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: CC#N
Product: [C-]#[N+]C1(C(=O)OCC)Cc2ccc(F)c(F)c2C1
Temperature: 25 °C
Yield: 23.9 %

Procedure:
A mixture of compound 1,2-bis-bromomethyl-3,4-difluoro-benzene (8 g, 0.027 mol), ethyl isocyanoacetate (3.01 g, 0.0266 mol), K2CO3 (22.07 g, 0.159 mol) and tetrabutylammonium hydrogen sulphate (5.45 g, 0.016 mol) in ACN (200 ml) is refluxed for overnight. After complete consumption of starting material the reaction mixture is cooled to RT and ACN is removed under reduced pressure. Water (300 mL) is added to the crude mass and then extracted with EtOAc (3×250 mL). The combined organic extracts are washed with water, dried and concentrated to give a crude product. The crude product is purified by column chromatography (silica, 3% EtOAc in hexane) and the solvent removed to give a viscous liquid (1.6 g, 23.7%).
Reaction SMILES: C(N=C(SC)SC)#N.CC1[CH:14]=[C:13]([CH2:15][N:16](C)C)OC=1CSCCN.[C:24]([NH:26][C:27](=[N:30][CH2:31][CH2:32][S:33][CH2:34][C:35]1[O:36][C:37]([CH2:41][N:42]([CH3:44])[CH3:43])=[CH:38][C:39]=1[CH3:40])SC)#[N:25].C(N)C#C>>[C:24]([NH:26][C:27]([NH:16][CH2:15][C:13]#[CH:14])=[N:30][CH2:31][CH2:32][S:33][CH2:34][C:35]1[O:36][C:37]([CH2:41][N:42]([CH3:44])[CH3:43])=[CH:38][C:39]=1[CH3:40])#[N:25]
Reactant: CSC(=NCCSCc1oc(CN(C)C)cc1C)NC#N
Reactant: Cc1cc(CN(C)C)oc1CSCCN
Agent: C#CCN
Agent: CSC(=NC#N)SC
Product: C#CCNC(=NCCSCc1oc(CN(C)C)cc1C)NC#N

Procedure:
When an alcohol solution of dimethyl cyanodithioimidocarbonate is reacted with 2-[(3-methyl-5-dimethylaminomethyl-2-furyl)methylthio]ethylamine, and the resultant N-cyano-N'-{2-[(3-methyl-5-dimethylaminomethyl-2-furyl)methylthio]ethyl}-S-methylisothiourea is treated with propargylamine according to the general procedure of Example 3, the title compound is produced.
Reaction SMILES: [Na].[O:2]([CH2:9][C:10](=[O:12])[CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CCO>[CH2:17]([O:16][C:14](=[O:15])[C:13](=[O:19])[CH2:11][C:10](=[O:12])[CH2:9][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:18]
Reactant: CC(=O)COc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)COc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53.9 %

Procedure:
Sodium (6.74 g, 293 mmol) was added to EtOH (808 mL) at 0° C. The mixture was stirred at 0° C. until the sodium was completely dissolved. Then phenoxy-2-propanone (53 mL, 266 mmol) was added dropwise. The mixture was stirred at 0° C. for 10 minutes and then diethyl oxalate (36 mL, 266 mmol) was added. Then the mixture was stirred at room temperature for 16 hours and the solvent was evaporated in vacuo. The residue was dissolved in H2O and the mixture was acidified with a 1M solution of HCl and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by open column chromatography (silica; DCM) to yield 2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester (35.9 g, 54% yield) as an oil.