Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.[O:7]1[C:11]2([CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(O)(=O)C>[O:7]1[C:11]2([CH2:16][CH2:15][CH:14]([NH:6][C:3]3[NH:4][CH:5]=[N:1][N:2]=3)[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Nc1nc[nH]n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: c1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.4 %

Procedure:
To a solution of 1H-1,2,4-triazol-3-amine (66.6 g) and 1,4-dioxaspiro[4.5]decan-8-one (175 g) in acetic acid (1.25 L) was gradually added sodium triacetoxyborohydride (252 g) under ice-cooling. After stirring at room temperature for 16 hr, water (1 L) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate (1 L). The mixture was neutralized with sodium bicarbonate, and extracted 3 times with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1, 2 L). The combined extracts were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was solidified with diisopropyl ether (500 mL), and the resulting solid was collected by filtration, washed twice with diisopropyl ether (250 mL), and dried to give the title compound (166 g, 94%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]2[CH2:14][CH2:15][C@:10]([CH2:16][CH2:17]O)([CH:11]=[CH:12]2)[O:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C(C(O)=O)(O)C(C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.[CH3:45][C@@H:46]1[C@@H:51]([O:52][C:53](=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:50][CH2:49][NH:48][CH2:47]1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)CC)(C)C>C(#N)CC>[C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][C:10]([CH2:16][CH2:17][N:48]3[CH2:49][CH2:50][C@H:51]([O:52][C:53](=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55])[C@@H:46]([CH3:45])[CH2:47]3)([CH2:11][CH2:12]2)[O:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1CNCC[C@@H]1OC(=O)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N1O[C@@]2(CCO)C=C[C@@H]1CC2
Agent: C[P+](C)(C)CC#N
Agent: O=C(O)C(O)(C(=O)c1ccccc1)C(O)(C(=O)O)C(=O)c1ccccc1
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: C[C@H]1CN(CCC23CCC(CC2)N(C(=O)OC(C)(C)C)O3)CC[C@@H]1OC(=O)C(C)(C)C
Temperature: 120 °C
Reaction time: 16 h

Procedure:
(1S,4S)-1-(2-Hydroxy-ethyl)-2-oxa-3-aza-bicyclo[2.2.2]oct-5-ene-3-carboxylic acid tert-butyl ester (11) (620 mg, 2.41 mmol) is dissolved in 24 ml of propionitrile and after addition of amine 6 (480 mg, 2.41 mmol), cyanomethyl-trimethyl-phosphonium iodide (796 mg, 6 mmol) and diisopropyl ethyl amine (2 ml, 12 mmol) the mixture is stirred for 16 h at 120° C. Then the mixture is evaporated under reduced pressure. The residue is diluted with ethyl acetate, washed 10% K2CO3- and NaCl-solution, and dried over Na2SO4. The crude product is purified by Flash-chromatography (ethyl acetate/hexanes (9.5:0.5), silicagel).
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[CH:8][CH:7]=1.C(O)C.[ClH:21]>O>[ClH:21].[NH:5]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]([N:15]([CH3:16])[CH3:17])=[O:14])=[CH:10][CH:11]=1)[NH2:1]
Reactant: CN(C)C(=O)Cc1ccc(N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(C)C(=O)Cc1ccc(NN)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
An ice cold solution of sodium nitrite (1.088 g) in water (6 ml) was added to a stirred solution of 2-(4-aminophenyl)-N,N-dimethylacetamide (2.67 g) in concentrated hydrochloric acid (10 ml) at -5° C. After stirring the yellow solid for 15 min, it was added to a stirred solution of stannous chloride (16.88 g) in concentrated hydrochloric acid (10 ml) at -10° C. When the addition was complete, the mixture was stirred at room temperature for a further 30 min and poured into ethanol (100 ml). The mixture was evaporated to dryness under reduced pressure, basified using 2N sodium hydroxide (350 ml) and extracted with ethyl acetate (3×200 ml). Evaporation of the dried (Na2SO4) solvent gave a pale yellow gum which was dried under high vacuum. This was dissolved in ethyl acetate (50 ml) and ethereal hydrogen chloride was added until no more solid deposited. Collection of the solid by filtration and washing with ether gave the title compound as a white powder (1.45 g) which was 82.6% pure and was used in the next stage without further purification.
Reaction SMILES: Cl.Cl.[O:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[N:18][CH:19]=3)=[CH:13][C:8]=2[CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:23]1[C:32]2[CH2:31][C:30]([CH3:34])([CH3:33])[CH:29]=[CH:28][C:27]=2[N:26]=[CH:25][N:24]=1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[CH3:33][C:30]1([CH3:34])[CH:29]=[CH:28][C:27]2[N:26]=[CH:25][N:24]=[C:23]([N:6]3[CH2:7][C:8]4[CH:13]=[C:12]([C:14]5[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[N:18][CH:19]=5)[CH:11]=[CH:10][C:9]=4[O:3][CH2:4][CH2:5]3)[C:32]=2[CH2:31]1
Reactant: CC1(C)C=Cc2ncnc(Cl)c2C1
Reactant: Nc1cc(-c2ccc3c(c2)CNCCO3)cnc1N
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C=Cc2ncnc(N3CCOc4ccc(-c5cnc(N)c(N)c5)cc4C3)c2C1
Temperature: 90 °C
Yield: 74 %

Procedure:
To a slurry of 5-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)pyridine-2,3-diamine dihydrochloride (0.92 g, 2.8 mmol) and 4-chloro-6,6-dimethyl-5,6-dihydroquinazoline (0.55 g, 2.8 mmol) in NMP was added diisopropylethylamine (2.4 mL, 14 mmol) and the reaction mixture was heated (90° C.) for 12 hours. The resulting dark red solution was loaded directly on to a column of dry silica and elution with MeOH (w/8% NH4OH v/v) in CH2Cl2 (0-5%) provided 5-[4-(6,6-dimethyl-5,6-dihydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]pyridine-2,3-diamine (0.86, 74% yield) as a brown solid. MS (EI) for C24H26N6O: 415.1 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32](=[O:37])[NH:33][CH2:34][CH2:35][NH2:36])([CH3:30])([CH3:29])[CH3:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:24]([NH:36][CH2:35][CH2:34][NH:33][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:37])=[O:26])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)NCCN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 300 mg (0.82 mmol) of N2-[(benzyloxy)carbonyl]-N5-(tert-butoxycarbonyl)-L-ornithine and 171 mg (1.06 mmol) of tert-butyl-(2-aminoethyl)carbamate are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 204 mg (1.06 mmol) of EDC and 33 mg (0.25 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is dried under high vacuum.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([NH:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]([O:39][C@H:40]1[C@@H:44]([O:45][C:46](=[O:48])[CH3:47])[C@@H:43](OC(=O)C)[O:42][C@@H:41]1[C:53]1[O:57][N:56]=[C:55]([CH2:58][CH3:59])[CH:54]=1)(=[O:38])[CH3:37].C(O[C@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)O[C@@H]1C1ON=C(CC)C=1)(=O)C>>[C:46]([O:45][C@@H:44]1[C@H:40]([O:39][C:36](=[O:38])[CH3:37])[C@@H:41]([C:53]2[O:57][N:56]=[C:55]([CH2:58][CH3:59])[CH:54]=2)[O:42][C@H:43]1[N:14]1[CH:13]=[N:12][C:11]2[C:15]1=[N:16][C:17]([C:19]([NH:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:20])=[N:18][C:10]=2[NH:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:48])[CH3:47]
Reactant: CCc1cc([C@H]2O[C@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)on1
Reactant: O=C(NCCN1CCCCC1)c1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Agent: CCc1cc([C@H]2O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)on1
Product: CCc1cc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(C(=O)NCCN5CCCCC5)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)on1

Procedure:
Prepared by the same method as Preparation 27 from 6-[(2,2-diphenylethyl)amino]-N-[2-(1-piperidinyl)ethyl]-9H-purine-2-carboxamide (Preparation 11) and a mixture of (2S,3R,4R,5R)-4,5-bis(acetyloxy)-2-(3-ethyl-5-isoxazolyl)tetrahydro-3-furanyl acetate and (2S,3R,4R,5S)-4,5-bis(acetyloxy)-2-(3-ethyl-5-isoxazolyl)tetrahydro-3-furanyl acetate (WO-A-9967262).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C(=O)([O-])O.[Na+].[CH3:15][O:16][C:17](=[O:21])[CH:18](Br)[CH3:19]>>[CH3:15][O:16][C:17](=[O:21])[CH:18]([NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[Cl:1])[CH3:19]
Reactant: Cc1cccc(Cl)c1N
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)C(C)Nc1c(C)cccc1Cl

Procedure:
35.4 g of 2-chloro-6-methylaniline, 21.3 g of sodium hydrogen carbonate and 84 ml of DL-α-bromopropionic acid methyl ester are stirred for 17 hours at 140° bath temperature. After cooling, the darkly coloured reaction mixture is filtered, and the excess α-bromopropionic acid methyl ester is distilled off in a water-jet vacuum. The residue remaining is fractionally distilled in high vacuum. There is obtained 25.9 g of α-(2-chloro-6-methylanilino)-propionic acid methyl ester, b.p. 72°-75°/0.001 Torr.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14](O)=[O:15])=[N:9]2)=[C:4]([C:17]([N:19]2[C@H:28]([CH2:29][OH:30])[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[CH:3]=1.[CH2:31]([NH:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH3:34].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([N:35]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:31][CH2:32][CH2:33][CH3:34])=[O:15])=[N:9]2)=[C:4]([C:17]([N:19]2[C@H:28]([CH2:29][OH:30])[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[CH:3]=1
Reactant: CCCCNCCCC
Reactant: Cc1cc(C(=O)O)nn1-c1ccc(Br)cc1C(=O)N1Cc2ccccc2C[C@H]1CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCCCN(CCCC)C(=O)c1cc(C)n(-c2ccc(Br)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (S)-1-(4-bromo-2-(3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5-methyl-1H-pyrazole-3-carboxylic acid (10.0 g, 21.3 mmol) in DMF (100 mL) were added dibutylamine (3.7 mL, 21.3 mmol), EDC.HCl (6.1 g, 31.9 mmol), HOBT (3.3 g, 21.3 mmol) followed by stirring at RT for 12 h. The reaction mixture was diluted with water, extracted with EtOAc (100 mL×2), twice. The combined organic layers were washed with water (100 mL), brine (50 mL), dried over sodium sulphate and concentrated invacuo. The residue was purified on silica gel (100-200 mesh) to afford the title compound as a hygroscopic solid, 4.5 g (36%). Rf=0.44 (55% EtOAc in hexane); 1H NMR (400 MHz, DMSO-d6): δ 8.00-7.40 (m, 3H), 7.30-6.80 (m, 4H), 6.50-6.20 (m, 1H), 5.10-4.00 (m, 3H), 4.00-2.40 (m, 9H), 2.40-2.00 (m, 3H), 1.60-0.50 (m, 14H); LC-MS: m/z 581.4 (M+H); HPLC: 90.74% (RT=9.216 min., method C).
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([OH:17])[CH:9]=2)=[CH:4][CH:3]=1.[C:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)(=[O:22])[CH3:21].C([O-])([O-])=O.[Na+].[Na+]>COCOC.O>[C:20]([C:23]1[CH:28]=[C:27]([C:2]2[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]3[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([OH:17])[CH:9]=3)=[CH:4][CH:3]=2)[CH:26]=[CH:25][CH:24]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: O=C(O)c1ccc(OCc2ccc(Br)cc2)cc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCOC
Product: CC(=O)c1cccc(-c2ccc(COc3ccc(C(=O)O)c(O)c3)cc2)c1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(4-bromo-benzyloxy)-2-hydroxy-benzoic acid (196.3 mg; 0.6075 mmol), 3-acetylbenzene boronic acid (99.7 mg; 0.6080 mmol) and Na2CO3 (−4 eq.) was dissolved in dimethoxymethane (4 mL) and H2O (2 mL). The solution was flushed with argon, Cl2Pd(PPh3)2 (˜2.5 mol %) was added and the mixture stirred under an atmosphere of argon at 100° C. for 16 hours. The resulting black solution was filtered (Gelman Acrodisc GHP, Ø25 mm) and slowly added to a cold 1 M HCl (aq.; 15 mL) solution. The precipitate was filtered off and thoroughly washed with water. Drying in vacuo yielded 195 mg (88%) of a greyish, solid compound with satisfactorily purity. Mp. 215-220° C. (decomposes); MS (ESI−): 361 (MH−)
Reaction SMILES: [CH3:1][Li].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11].O>CCOCC>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:8]([CH3:1])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)C=Cc1cccc(OC)c1
Reactant: [Li]C
Solvent: O
Solvent: CCOCC
Product: COC(=O)CC(C)c1cccc(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Under a N2 blanket, a solution of lithium dimethylcuprate was prepared at 0° C. from cuprous iodide (7.6 g, 0.04 mol) and a solution of methyl-lithium in ether (80 ml, 1 M, 0.08 mol). A solution of methyl m-methoxycinnamate (4.8 g, 0.025 mol) in ether (20 ml) was then added dropwise and the reaction mixture was stirred for 1 hour at 0° C. A large volume of water was cautiously added, after which the ether layer was separated, dried (anhydrous Na2SO4) and evaporated to dryness. The residue was chromatographed on silica gel (100 g) with hexane/ethyl acetate (80:20) as eluent, giving 3.65 g methyl β-(m-methoxyphenyl)-butyrate (68% yield by weight).
Reaction SMILES: [Na].Cl[C:3]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C1(C)C=CC=CC=1.[CH3:23][OH:24]>>[CH3:23][O:24][C:3]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CO
Reactant: O=[N+]([O-])c1c(Cl)ccc2cccnc12
Agent: [Na]
Solvent: Cc1ccccc1
Product: COc1ccc2cccnc2c1[N+](=O)[O-]

Procedure:
To a freshly prepared solution of sodium (16.5 g, 0.720 mol) in methanol (750 mL) was added 7-chloro-8-nitroquinoline (18.72 g, 0.090 mol) [E. Fourneau, M. and Mme. Trefouel, and A. Wancolle, Bull. Soc. Chim. Fr., 47, 738(1930); A. K. Sen, N. K. Ray, V. P. Basu, J. Sci. Ind. Res., 11B, 322(1952) (C.A. 47, 4339e)]. This mixture was refluxed for 3 hr, cooled, then filtered to collect the precipitated solid. This solid was slurried in water, collected on a filter and dried; yield, after recrystalllization from toluene, 16.12 g (88%); mp 178°-178.5°: Anal. Calcd for C10H8N2O3 : C, 58.82; H, 3.95; N, 13.72. Found: C, 58.66; H, 3.87; N, 13.69.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:12][CH2:13]Cl)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]#[N:24].[H-].[Na+]>C1COCC1.CN(C=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1([C:23]#[N:24])[CH2:2][CH2:3][N:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[CH2:12][CH2:13]1
Reactant: N#CCc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccc2Cl)CC1

Procedure:
A solution of bis(2-chloroethyl)-N-(1,1-dimethylethoxy)carbonyl amine (9.298 g, 38.4 mmol) and 2-chlorophenylacetonitrile (5.0 g, 32.0 mmol) in a 4:1 mixture of THF/DMF (15 mL) was treated with NaH (2.82 g, 70.4 mmol) at 60° C. (7 d). The solvent was removed in vacuo, the residue dissolved in EtOAc (200 ml) and washed with saturated NaHCO3 (50 ml), H2O (2×50 ml), and saturated aqueous NaCl (50 ml), dried (Na2SO4) and concentrated in vacuo. Trituration of the residue with 100% MeOH afforded 4-(2-chlorophenyl)-4-cyano-N-(1,1-dimethylethoxy) carbonyl piperidine as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].[OH-].[Na+].[CH2:14](I)[CH3:15]>CS(C)=O.O>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[O:11][CH2:14][CH3:15]
Reactant: COc1cccc(OC)c1O
Reactant: CCI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1c(OC)cccc1OC
Temperature: 50 °C
Reaction time: 4 h
Yield: 56.8 %

Procedure:
To a stirred solution of 2,6-dimethoxyphenol (10 g) in dimethylsulfoxide (100 ml) under nitrogen was added a solution of sodium hydroxide (3.2 g) in water (20 ml). The mixture was warmed to 50° C., ethyl iodide (12.4 g) added, and stirring continued at 50° C. for 4 hours. The product was poured into 1 liter of water and the mixture extracted with diethyl ether. The extract was washed sequentially with 20% potassium hydroxide, water, and brine, and then dried over magnesium sulfate. Removal of the solvent under reduced pressure gave 1,3-dimethoxy-2-ethoxybenzene as a colorless oil (6.71 g).
Reaction SMILES: [Br-].Br[CH2:3][C:4]([C:6]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=[CH:8][NH+:7]=1)=O.CN(C=O)C.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](=[S:28])[NH2:27])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]2[S:28][CH:3]=[C:4]([C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]([O:14][CH3:15])=[O:13])[N:27]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc[nH+]c1C(=O)CBr
Reactant: NC(=S)c1ccc(F)cc1
Agent: [Br-]
Solvent: CN(C)C=O
Product: COC(=O)c1cccnc1-c1csc(-c2ccc(F)cc2)n1
Temperature: 25 °C
Yield: 79.8 %

Procedure:
To a solution of 2-(2-bromoacetyl)-3-(methoxycarbonyl)pyridinium bromide (1.17 g, 3.45 mmol) in 10 ml of DMF 4-fluorobenzothioamide (0.7 g, 4.51 mmol) were added and stirred at room temperature over night. For work up the reaction mixture was evaporated to dryness and the obtained crude oil purified by chromatography on silica gel (eluent: CH2CL2+0.2% methanol) to give 865 mg of the thiazole as yellow oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:30]=[CH:29][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:28])[C:15]([CH3:27])([CH2:24][CH2:25][CH3:26])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:31](Cl)([CH3:34])(=[O:33])=[O:32].N1C=CC=CC=1>CC(C)=O>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:27])([CH2:24][CH2:25][CH3:26])[C:14](=[O:28])[C:13]=1[C:8]1[NH:7][C:6]2[CH:29]=[CH:30][C:3]([NH:2][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 89.4 %

Procedure:
A solution of Example 32B (0.050 g, 0.112 mmol), mesyl chloride (0.035 mL, 0.447 mmol), and pyridine (0.073 mL, 0.893 mmol) in acetone (1.5 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (0.049 g, 89%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][C:11]=1[NH2:12])=[O:6].N#N.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[CH2:29]Cl>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][C:11]=1[NH:12][CH2:29][C:23]1[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=1[Cl:21])=[O:6]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-c2ccccc2)cc1NCc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% dispersion in oil, 180 mg, 4.72 mmol) was added to an ice-cold solution of 3-Amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (1000 mg, 4.29 mmol) in 25 ml of dimethylformamide in an atmosphere of N2. After 5 min, 2,4-dichloro-1-chloromethyl-benzene (755 mg, 3.86 mmol) was added to the solution and then the reaction mixture was stirred for 30 min at 0° C. and 30 min at room temperature. The mixture was partitioned between ether (20 mL) and water (20 mL) and the organic layer was separated. The aqueous phase was washed twice with ether (2×20 mL) and the combined ether layer was dried (MgSO4) and concentrated. The residue obtained was then purified by precipitation. The crude product was taken in 25 ml of ethyl acetate, a yellow precipitate came out which was filtered to obtain 3-(2,4-Dichloro-benzylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester, 835 mg (55%). 1H-NMR (DMSO, 400 MHz): 7.67 ppm (m, 2H, Haro); 7.44-7.35 ppm (m, 6H, Haro); 7.26 ppm (s, 1H, Haro); 4.63 ppm (d, 2H, N—CH2); 3.75 ppm (s, 3H, O—CH3)
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32](O)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1>>[C:45]([O:44][C:43](=[O:49])[NH:42][C@H:39]1[CH2:40][CH2:41][C@@H:36]([NH:35][C:32]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:7]4[CH:8]=[C:9]([CH3:13])[C:10]([F:12])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:15]=3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:21]=2[CH3:31])=[O:33])[CH2:37][CH2:38]1)([CH3:46])([CH3:48])[CH3:47]
Reactant: Cc1cc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c11) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow foam.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[N:21]=[N:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)=[N:18]2)=[CH:13][CH:12]=1)([CH3:10])[CH3:9].[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>CN(C)C1C=CN=CC=1.ClCCl>[C:29]([O:28][C:25]1[CH:24]=[CH:23][C:22]([C:19]2[N:20]=[N:21][N:17]([C:14]3[CH:13]=[CH:12][C:11]([CH:8]([CH3:10])[CH3:9])=[CH:16][CH:15]=3)[N:18]=2)=[CH:27][CH:26]=1)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)c1ccc(-n2nnc(-c3ccc(O)cc3)n2)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccc(-n2nnc(-c3ccc(OC(=O)C(C)(C)C)cc3)n2)cc1
Reaction time: 1 h
Yield: 54.9 %

Procedure:
Triethylamine (0.167 g) and 4-dimethylaminopyridine (0.02 g) were added to a solution of 4-[2-(4-isopropylphenyl)tetrazol-5-yl]phenol (0.42 g), obtained in the reference example 2, in dichloromethane (5 ml), and pivaloyl chloride (0.199 g) was added to the solution under ice cooling. Stirring was continued for 1 h at the same temperature. The mixture was washed with water, dried and evaporated to dryness. The residue was recrystallized from ethyl acetate-hexane to give 0.3 g (55%) of the title compound.