Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH:8]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[N:21]1([CH2:27][CH2:28]Cl)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>CC(C)=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:28][CH2:27][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:9][CH:8]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: ClCCN1CCCCC1
Reactant: Clc1ccc(CN2CCNCC2c2ccccc2)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: Clc1ccc(CN2CCN(CCN3CCCCC3)CC2c2ccccc2)cc1
Yield: 95 %

Procedure:
31 g. of 1-(4'-chloro benzyl)-2-phenyl piperazine prepared according to Example 2 B), 25 g. of piperidino ethylchloride, 20 g. of triethylamine, and 250 cc. of acetone are boiled under reflux for 18 hours. The filtered reaction solution is freed of its solvent by concentration by evaporation. The residue is dissolved in benzene. The benzene solution is washed with water. After drying and distilling off the solvent, the base is obtained in the form of a viscous, yellow oil on distillation at 210° C./0.06 Torr. The oil crystallizes on trituration with isopropanol. After twice recrystallizing the crystals from n-heptane (41 g. of yellow crystals of the melting point 85°-87° C.) are obtained. The yield is 95 % of the theoretical yield.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]([O:14][CH:15]2[CH2:32][CH:31]3[CH:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([OH:36])=O)([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)[C:11]2[CH:10]=[CH:9][C:8]3[O:39][CH2:40][O:41][C:7]=3[C:6]=2[N:5]=1)[CH3:2].C(OC1C=C(OC2CC3C(C(=O)N(C)CCCCC=CC4C(C([NH:77][S:78]([CH:81]5[CH2:83][CH2:82]5)(=[O:80])=[O:79])=O)(NC3=O)C4)C2)C2C(=C(C)C(OC)=CC=2)N=1)C>>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]([O:14][CH:15]2[CH2:32][CH:31]3[CH:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([NH:77][S:78]([CH:81]5[CH2:83][CH2:82]5)(=[O:80])=[O:79])=[O:36])([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)[C:11]2[CH:10]=[CH:9][C:8]3[O:39][CH2:40][O:41][C:7]=3[C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc3c(c2n1)OCO3
Product: CCOc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc3c(c2n1)OCO3

Procedure:
The title compound (15) was prepared from 17-[8-ethoxy[1,3]dioxolo[4,5-h]quinolin-6-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (14) following the procedure reported for synthesis of N-[17-[2-ethoxy-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (3): m/z=669 (M+H)+.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].[Br:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br>C1COCC1>[Br:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][CH:8]1[C:7](=[O:10])[CH2:6][CH2:5][C:4]2([O:3][CH2:2][CH2:1][O:11]2)[CH2:9]1
Reactant: BrCc1ccccc1Br
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1CCC2(CC1Cc1ccccc1Br)OCCO2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 1,4-cyclohexanedione mono-ethylene acetal (20 g, 28 mmol) in THF (360 ml) is added dropwise under nitrogen to a solution, cooled to −78° C., of 1M lithium diisopropylamide in THF (150 mmol, 150 ml), and the mixture is then allowed to return to room temperature. After stirring for 1 hour, the mixture is cooled to −78° C. and 35.2 g (141 mmol) of 2-bromobenzyl bromide are added dropwise. After stirring for 30 minutes at −78° C., the temperature of the mixture is returned to 0° C. The mixture is stirred for 3 hours at 0° C. and then hydrolysed and extracted with ether. The organic phase is washed with a saturated NaCl solution, dried over MgSO4 and concentrated in vacuo. The title compound is purified by flash chromatography over a column.
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[C:11]([CH3:12])=[C:10]([NH2:13])[C:9]([O:14][CH3:15])=[CH:8][N:7]=1>O.C(O)(=O)C>[Cl:5][C:6]1[C:11]2[CH:12]=[N:1][NH:13][C:10]=2[C:9]([O:14][CH3:15])=[CH:8][N:7]=1
Reactant: O=N[O-]
Reactant: COc1cnc(Cl)c(C)c1N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cnc(Cl)c2cn[nH]c12
Temperature: 75 °C

Procedure:
A solution of sodium nitrite (98%, 326 mg, 4.63 mmol) in water (0.6 mL) was added to a solution of C4 (200 mg, 1.16 mmol) in acetic acid (8 mL), and the reaction mixture was heated at 75° C. for 1 hour. After the reaction mixture had cooled to room temperature, it was concentrated in vacuo, diluted with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (Gradient: 25% to 50% ethyl acetate in heptane) provided the product as a yellow solid. Yield: 140 mg, 0.763 mmol, 66%. LCMS m/z 184.0 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.74 (s, 1H), 4.06 (s, 3H).
Reaction SMILES: [CH:1]12[C:15](=[O:16])[NH:14][C:13](=[O:17])[CH:2]1[C:3]1[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]2=3)[CH:6]=[CH:5][CH:4]=1.[K].S(C1C=CC(C)=CC=1)(O)(=O)=O.O[CH2:31][CH2:32][N:33]1[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][N:35]=[C:34]1[CH3:41]>O>[CH3:41][C:34]1[N:33]([CH2:32][CH2:31][N:14]2[C:13](=[O:17])[CH:2]3[C:3]4[C:12]5[C:7](=[CH:8][CH:9]=[CH:10][C:11]=5[CH:1]3[C:15]2=[O:16])[CH:6]=[CH:5][CH:4]=4)[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][N:35]=1
Reactant: Cc1ncc([N+](=O)[O-])n1CCO
Reactant: O=C1NC(=O)C2c3cccc4cccc(c34)C12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K]
Solvent: O
Product: Cc1ncc([N+](=O)[O-])n1CCN1C(=O)C2c3cccc4cccc(c34)C2C1=O

Procedure:
Acenaphthene-1,2-dicarboximide is converted to the potassium salt and reacted with 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole tosylate according to the procedure described in Example 13. The crude reaction mixture is cooled and diluted with water, and then extracted with toluene. The solvent is evaporated from the toluene extract and the residue recrystallized from ethanol to give N-[2-(2-methyl-5-nitro-1-imidazolyl)ethyl]-acenaphthene-1,2-dicarboximide melting at about 183°-185° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[CH3:25][CH:26]1[S:31][CH2:30][CH2:29][NH:28][CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:28]1[CH2:29][CH2:30][S:31][CH:26]([CH3:25])[CH2:27]1)=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: CC1CNCCS1
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC1CN(C(=O)c2ccc(C(=O)NCc3nc4cc(Cl)ccc4[nH]3)cc2Cl)CCS1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, 2-methylthiomorpholine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.78 minutes; C21H20C12N4O2S (463.39); mass spectrum: (M+H)+=463.1.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][S:9]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-])=O>CCOC(C)=O.C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][S:9]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:11])=[O:10])=[CH:19][CH:20]=1
Reactant: CCOC(=O)CCS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CCS(=O)(=O)Cc1ccc(N)cc1
Reaction time: 5 h
Yield: 100 %

Procedure:
A solution of ethyl 3-(4-nitrobenzylsulfonyl)propanoate (Intermediate 41, 3.9 g; 12.9 mmol) in EtOAc (100 ml) and ethanol (200 ml) was treated with palladium (400 mg, 5% on C). The mixture was stirred under hydrogen for 5 hours, filtered and the solvent removed in vacuo to give the title compound as an off-white solid (3.5 g, quant).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([NH:14][CH:15]=[O:16])[CH:6]=[C:7]([CH2:12]Br)[CH2:8][CH2:9][O:10][CH3:11])[CH3:2].[P:18]([O:27]C(C)C)([O:23][CH:24]([CH3:26])[CH3:25])[O:19][CH:20]([CH3:22])[CH3:21]>>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([NH:14][CH:15]=[O:16])[CH:6]=[C:7]([CH2:12][P:18]([O:23][CH:24]([CH3:26])[CH3:25])([O:19][CH:20]([CH3:22])[CH3:21])=[O:27])[CH2:8][CH2:9][O:10][CH3:11])[CH3:2]
Reactant: CCOC(=O)C(C=C(CBr)CCOC)NC=O
Reactant: CC(C)OP(OC(C)C)OC(C)C
Product: CCOC(=O)C(C=C(CCOC)CP(=O)(OC(C)C)OC(C)C)NC=O
Reaction time: 18 h

Procedure:
3.38 g (11.0 mmol) of 4-bromomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester and 12.0 ml (44 mmol) of triisopropyl phosphite (96%) are heated to 80° and stirred under a pressure of approximately 130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off under reduced pressure and the evaporation residue is purified by chromatography on silica gel with ethyl acetate. 4-diisopropylphosphonomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester is obtained in the form of a yellowish oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5]([OH:7])=O.[NH2:29][C:30]([CH3:36])([CH3:35])[CH2:31][C:32]([OH:34])=[O:33]>>[F:1][C:2]1[CH:3]=[C:4]([C:5]([NH:29][C:30]([CH3:36])([CH3:35])[CH2:31][C:32]([OH:34])=[O:33])=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: CC(C)(N)CC(=O)O
Product: CC(C)(CC(=O)O)NC(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
The title compound was synthesized using the procedure described in Example 105 above, with 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzoic acid (100 mg, 0.256 mmol) and 3-amino-3-methylbutanoic acid (36 mg, 0.307 mmol). MS (ESI) m/z: Calculated: 489.2; Observed: 490.1 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][C:7]1([CH3:21])[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][C:15]([OH:20])=[C:16]([CH2:17][CH2:18][CH3:19])[C:9]=2[O:8]1)[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24].CCOCC>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][C:7]1([CH3:21])[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][C:15]([O:20][C:23](=[O:25])[CH3:24])=[C:16]([CH2:17][CH2:18][CH3:19])[C:9]=2[O:8]1)[CH3:2]
Reactant: CCCc1c(O)ccc2c1OC(C)(CCC(=O)OCC)CC2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCc1c(OC(C)=O)ccc2c1OC(C)(CCC(=O)OCC)CC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.3 %

Procedure:
To a stirred solution of 0.8 g of racemic-3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester in 8 ml of pyridine was added 0.37 ml of acetic anhydride. The solution was stirred at room temperature for 5 hours then poured into ice-water and worked up with ether in the usual manner (the combined ether extracts were additionally washed with 1N hydrochloric acid and saturated sodium bicarbonate solutions). The oily product (1.0 g) was chromatographed on 50 g of silica gel. Elution with 19:1 toluene-ethyl acetate afforded 0.575 g (63.3%) of racemic-7-acetoxy-3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester as a pale-yellow oil.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[O:7][CH2:8][C:9]([OH:11])=[O:10])=[N+:2]=[N-:3].[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>>[CH3:15][Si:16]([CH3:18])([CH3:17])[C:19]1[N:3]=[N:2][N:1]([C:4]2[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=2)[O:7][CH2:8][C:9]([OH:11])=[O:10])[CH:20]=1
Reactant: [N-]=[N+]=Nc1cccc(OCC(=O)O)c1
Reactant: C#C[Si](C)(C)C
Product: C[Si](C)(C)c1cn(-c2cccc(OCC(=O)O)c2)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a 15 mL sealed tube was added (3-azidophenoxy)-acetic acid 5 (527 mg, 2.73 mmol, 1.0 eq.) and trimethylsilylacetylene (10 mL) and a stirbar. The tube was sealed and reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered and solid was washed with ethyl ether to yield a dark gray solid (483 mg, 61%). 1H-NMR, Varian 400 MHz (DMSO-d6) δ 13.11 (bs, 1H), 8.86 (s, 1H), 7.52-7.46 (m, 3H), 7.03-7.00 (m, 1H), 4.80 (d, 2H), 0.31 (s, 9H) ppm.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:16]#[C:17][Si](C)(C)C)[CH:6]=[C:7]2[C:12]=1[C:11](=[O:13])[CH2:10][CH2:9][C:8]2([CH3:15])[CH3:14])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([C:3]1[CH:4]=[C:5]([C:16]#[CH:17])[CH:6]=[C:7]2[C:12]=1[C:11](=[O:13])[CH2:10][CH2:9][C:8]2([CH3:14])[CH3:15])[CH3:2]
Reactant: CCc1cc(C#C[Si](C)(C)C)cc2c1C(=O)CCC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(CC)c2c(c1)C(C)(C)CCC2=O

Procedure:
Following General Procedure F and using 8-ethyl-4,4-dimethyl-6-(trimethylsilanyl)ethynyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 179, 0.66 g, 2.2 mmol), methanol (10 mL) and potassium carbonate (0.4 g, 2.9 mmol) the title compound was obtained as an orange oil (0.59 g, 100%). 1H NMR (300 MHz, CDCl3): δ 7.51 (d, 1H, J=1.51 Hz), 7.37 (d, 1H, J=1.5 Hz), 3.32 (s, 1H), 3.10 (q, 2H, J=7.3 Hz), 2.84 (t, 2H, J=6.7 Hz), 2.08 (t, 2H, J=6.7 Hz), 1.48 (s, 6H), 1.33 (t, 3H, J=7.3 Hz).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[C:13](C(OCC)=O)[C:12]2=[O:30])=[CH:2]1>CN(C)C(=O)C.O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[C:12](=[O:30])[CH:13]=[C:14]([NH:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[O:15]2)=[CH:2]1
Reactant: CCOC(=O)C1=C(NCc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C1C=C(NCc2ccc(F)cc2)OC1=Cc1c[nH]c2ncccc12
Temperature: 25 °C
Yield: 6.7 %

Procedure:
A solution of the compound (0.10 g, 0.31 mmol) of Example 45 in N,N-dimethylacetamide (3.0 mL) was refluxed for 7 h. Cooled to ambient temperature, the reaction mixture was diluted with water and the precipitate was collected by filtration. The solid was washed with water and diethyl ether then dried to afford the titled compound as solid (0.0070 g, y. 9%).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=O.[CH:17]1([C:20](=[O:25])[CH2:21][C:22](=O)[CH3:23])[CH2:19][CH2:18]1>C(O)(=O)C.S(=O)(=O)(O)O>[CH:17]1([C:20]([C:21]2[C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[C:3]3[C:4]4[CH2:9][CH2:8][CH2:7][C:5]=4[S:6][C:2]3=[N:1][C:22]=2[CH3:23])=[O:25])[CH2:19][CH2:18]1
Reactant: CC(=O)CC(=O)C1CC1
Reactant: Nc1sc2c(c1C(=O)c1cccs1)CCC2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3c(c2c(-c2cccs2)c1C(=O)C1CC1)CCC3
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 18.4 %

Procedure:
To a stirred solution of 60 mg (0.24 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-thiophen-2-yl-methanone) (the preparation of which is described in example 2) in 2 ml acetic acid was added 40 mg (0.32 mmol) of 1-cyclopropyl-butane-1,3-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 15 mg (19%) cyclopropyl-(2-methyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[4.5]thieno[2,3-b]pyridin-3-yl)-methanone as a light brown oil. ES-MS m/e (%): 340 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:30][CH2:31][O:32][N:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1)[CH3:35])(=O)=O>>[F:48][C:45]1[CH:44]=[CH:43][C:42]([C:39]2[CH:40]=[CH:41][C:36]([C:34](=[N:33][O:32][CH2:31][CH2:30][O:20][C:17]3[CH:16]=[CH:15][C:14]([CH2:13][CH:7]([O:6][C:5]4[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=4)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:19][CH:18]=3)[CH3:35])=[CH:37][CH:38]=2)=[CH:47][CH:46]=1
Reactant: CC(=NOCCOS(C)(=O)=O)c1ccc(-c2ccc(F)cc2)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(Cc1ccc(OCCON=C(C)c2ccc(-c3ccc(F)cc3)cc2)cc1)Oc1ccc(F)cc1

Procedure:
The target compound (1.45 g) was obtained as a white powder by carrying out the reaction and the post-treatment according to Reference example 2 using ethyl 2-(4-fluorophenoxy)-3-(4-hydroxyphenyl)propionate (1.8 g) obtained from Reference example 25(b), sodium hydride (55%, 271 mg), and 2-[[1-(4′-fluoro-4-biphenylyl)ethylidene]aminoxy]ethyl methanesulfonate (2.14 g) obtained from Reference example 26(b).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-])=O.[C:9]([C:12](=[CH:18]OCC)[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:11])[CH3:10]>C(O)C.[Pd]>[C:9]([C:12](=[CH:18][NH:1][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:11])[CH3:10]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(=CNc1cn[nH]c1)C(C)=O
Reaction time: 3.5 h
Yield: 69 %

Procedure:
A solution of 4-nitropyrazole (5.6 g, 50 mmol)in ethanol (200 ml) was hydrogenated over 10% palladium on charcoal (0.5 g) at room temperature and pressure for 3.5 h. The catalyst was filtered off and ethyl 2-acetyl-3-ethoxyacrylate (9.3 g, 50 mmol) was added to the solution under nitrogen. After 5 min, the solution was evaporated in vacuo and the residual solid was recrystallised from ethyl acetate/pentane (charcoal) to give the title compound (7.7 g, 69%), m.p. 126°-128° C. Found: C, 49.96; H, 6.28; N, 17.34%. C10H13N3O3.H2O requires C, 49.78; H, 6.27; N, 17.41%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:13])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-])=O.[CH3:14]N.CO>>[CH3:14][NH:1][C:4]1[CH:5]=[C:6]([CH3:13])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: CN
Reactant: Cc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Solvent: CO
Product: CNc1cc(C)ccc1[N+](=O)[O-]
Yield: 96 %

Procedure:
A solution of 9.10 g of 3,4-dinitrotoluene in 100 ml of 30% methylamine/methanol was reacted at 150° C. for 6 hours in a sealed tube. The reaction solution was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography (200 g). Elution with ethyl acetate-hexane (1 : 3) gave 7.95 g (96%) of 3-(N-methylamino)-4-nitrotoluene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[CH2:6][C:7]1[C:8]2[CH2:29][NH:28][CH2:27][CH2:26][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])=[CH:16][CH:15]=2)[N:12]=1.[CH:33](=O)[CH2:34][OH:35]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[CH2:6][C:7]1[C:8]2[CH2:29][N:28]([CH2:33][CH2:34][OH:35])[CH2:27][CH2:26][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])=[CH:18][CH:19]=2)[N:12]=1
Reactant: O=CCO
Reactant: COc1cccc(Cc2nc(Nc3ccc(-n4ccnc4C)cc3)nc3c2CNCC3)c1
Product: COc1cccc(Cc2nc(Nc3ccc(-n4ccnc4C)cc3)nc3c2CN(CCO)CC3)c1
Yield: 13 %

Procedure:
2-(4-(3-Methoxybenzyl)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanol (19.6 mg, 13%) was synthesised from 4-(3-methoxybenzyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (Example 53a) and glycolaldehyde according to the general procedure for reductive amination. MS (ES+) m/z 471.3 (M+H)+
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[OH-].[Na+].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.Cl>O.C(#N)C>[S:18]([N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3])([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(C)c(=O)[nH]c2=O)cc1
Temperature: 2.5 °C
Reaction time: 0.83 h
Yield: 97.4 %

Procedure:
To a mechanically stirred solution of 200.0 g thymine (1.586 mol) in a mixture of 1.33 l water and 65 g sodium hydroxide (1.6 mol) under nitrogen atmosphere were added simultaneously a solution of 378.1 g p-toluenesulphonyl chloride (1.98 mol) in 1.0 l acetonitrile over 60 min and a solution of 95.16 g NaOH (2.38 mol) in 0.330 l water added over 65 min while cooling the reaction in a water bath from an initial temperature of 40° C. to about 35° C. The reaction was stirred an additional 50 min following completion of the additions, and then cooled to 0-5° C. The reaction mixture was then acidified by adding 242 g conc. HCl (2.45 mol) over 10 min. The reaction mixture was stirred an additional 20 min at 0-5° C. followed by vacuum filtration. The solid was vacuum dried at 55° C. overnight. 433.1 g 1-tosylthymine (97% yield, white crystals) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:12])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:10]([CH3:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: Nc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 54 %

Procedure:
To a stirring solution of 17 mL (180 mmol) of 4-fluoroaniline in 550 mL of THF at RT is added 26.7 mL (180 mmol, 1.0 equiv) of acetone, 10.3 mL (180 mmol, 1.0 equiv) acetic acid, and 57.22 g (270 mmol, 1.5 equiv) of sodium triacetoxyborohydride. The solution is stirred at RT for 15 h, cooled to 0° C., and then quenched by addition of H2O. The reaction mixture warmed to RT and is poured into EtOAc, the organic layer is separated, washed with brine (1×200 mL), dried (MgSO4) and the solvents removed in vacuo. Purification of the material by silica gel flash column chromatography using EtOAc/hexane 1:1 as eluent afforded 14.9 g (54%) of (4-Fluoro-phenyl)-isopropyl amine. A solution of 6.68 g (43.6 mmol) of (this material in 50 mL of DCM is cooled to 0° C. and 6 mL (43.6 mmol, 1.0 equiv) triethyl amine is added, followed by dropwise addition of 2.27 mL (43.6 mmol, 1.0 equiv) of bromoacetyl bromide. The solution is stirred at RT for 15 h and then poured into DCM (200 mL). The organic layer is separated, washed with saturated aq NaHCO3 (4×50 mL), 1N HCl (6×50 mL), brine (1×50 mL), dried (MgSO4) and the solvents removed in vacuo. Purification of the material by silica gel flash column chromatography using EtOAc/hexane (3:17) as eluent afforded 5.32 g of 2-Bromo-N-(4-fluoro-phenyl)-N-isopropyl-acetamide: 1HNMR (CDCl3, 300 MHz) δ7.26-7.09 (m, 4H), 4.85 (m,1H), 3.51 (s, 2H), 1.05 (d, 6H, J=6.9); low resolution MS(FAB) m/e 274 (MH+).