Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:15][CH2:14][CH2:13][O:12]1.ClC1N=CN=C2C=1NC=N2.[OH:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1.C(N(C(C)C)C(C)C)C>C(O)CC>[OH:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)=[CH:29][CH:28]=1
Reactant: NCc1ccc(O)cc1
Reactant: Clc1ncnc2c1ncn2C1CCCO1
Agent: Clc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCO
Product: Oc1ccc(CNc2ncnc3c2ncn3C2CCCO2)cc1
Yield: 80 %

Procedure:
A mixture of 10 mmol (2240 mg) of 6-chloro-9-(tetrahydrofuran-2-yl)purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (1478 mg) of 4-hydroxybenzylamine, and 5 ml of N-ethyldiisopropylamine was refluxed in n-propanol for 3 hours. After removal of the n-propanol by vacuum evaporation, the resulting material was treated with water and extracted into ethyl acetate. The ethyl acetate phase was evaporated and the residuum subsequently washed with 30 ml of petroleum ether. The solid residue was filtered off and the crude product crystallized from methanol. Yield 80%, white solid. TLC (EtOAc:hexane (1:1 (v:v)): single spot; HPLC: purity>98%. 1H NMR (400 MHZ, DMSO): 1.36tt (2H, Ja=7.8 Hz, Jb=2.2 Hz); 2.23m (1H); 2.32m (1H); 3.62dd (1H, Ja=10.8 Hz, Jb=3.8 Hz); 3.87dd (1H, Ja=10.8 Hz, Jb=3.8 Hz); 4.62s (2H); 6.23dd (1H, Ja=5.3 Hz, Jb=1.5 Hz); 6.71 d (2H, J=8.3 Hz); 7.21 d (2H, J=8.3 Hz); 8.06bs (1H); 8.16s (1H); 8.28s (1H); 9.23s (1H). MS (ES): [M+H]+=312 (100).
Reaction SMILES: CC1(C)C2C=C(C#CC3C=CC(C(O)=O)=CC=3)C=CC=2C(=O)CC1.[CH3:25][C:26]1([CH3:50])[C:35]2[CH:34]=[CH:33][C:32]([C:36]#[C:37][C:38]3[CH:48]=[CH:47][C:41]([C:42]([O:44]CC)=[O:43])=[CH:40][N:39]=3)=[CH:31][C:30]=2[C:29](=[O:49])[CH2:28][CH2:27]1>>[CH3:25][C:26]1([CH3:50])[C:35]2[CH:34]=[CH:33][C:32]([C:36]#[C:37][C:38]3[CH:48]=[CH:47][C:41]([C:42]([OH:44])=[O:43])=[CH:40][N:39]=3)=[CH:31][C:30]=2[C:29](=[O:49])[CH2:28][CH2:27]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)nc1
Agent: CC1(C)CCC(=O)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Product: CC1(C)CCC(=O)c2cc(C#Cc3ccc(C(=O)O)cn3)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl]ethynyl]benzoic acid (Compound 7), 300 mg (0.86 mmol) of ethyl 6-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]nicotinate (Compound 3) was converted into the title compound (pale yellow solid) using 8.6 ml (8.6 mmol) of LiOH (1M aqueous solution).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH2:24])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C.[CH:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH:24][C:38]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:39])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCN(C[C@H](N)Cc2ccccn2)CC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C[C@@H](Cc2ccccn2)NC(=O)C2CCCCC2)CC1
Temperature: 25 °C
Yield: 71.6 %

Procedure:
To a solution of (1R)-2-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-1-pyridin-2-ylmethyl-ethylamine (780 mg.; 2.4 mmol, from Example 13) in dichloromethane (30 mL) at 0° C. was added triethylamine (0.67 mL; 4.8 mmol) and a solution of cyclohexanecarbonyl chloride (0.33 mL; 2.45 mmol) in dichloromethane (5 mL). The reaction mixture was stirred while allowing to warm to ambient temperature over 1 hour. The mixture was washed with saturated NaHCO3 (15 mL), dried over MgSO4, filtered, and the solvent removed in vacuo. The crude residue was purified by flash chromatography on silica gel (2% methanol/chloroform) to afford the free base of the title compound as a white gummy foam (750 mg; 72%). Treatment with an equimolar amount of fumaric acid in ethanol yielded the fumarate salt as a white amorphous solid, m.p. 136–141° C.; MS (+) FAB [M+H]+ @ m/z 437, [M+Na]+ @ m/z 459; 1H NMR, 400 MHz, DMSO-d6. Analysis for C26H36N4O2. C4H4O4.2H2O Calculated: C, 61.21; H, 7.53; N, 9.52 Found: C, 61.79; H, 7.27; N, 9.31
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:3]=1.[CH2:17]([O:19][C:20]([C:22]1[C:23]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][C:24]=2[S:25][CH:26]=1)=[O:21])[CH3:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN1C(=O)CCC1.O>[CH2:17]([O:19][C:20]([C:22]1[C:23]2[CH:30]=[CH:29][C:28]([O:31][C:2]3[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:3]=3)=[CH:27][C:24]=2[S:25][CH:26]=1)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1csc2cc(O)ccc12
Reactant: CCCCCC(=O)OCc1nccc(Cl)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCCCC(=O)OCc1nccc(Oc2ccc3c(C(=O)OCC)csc3c2)n1
Temperature: 60 °C
Reaction time: 45 h

Procedure:
A suspension of 324 mg (1.33 mMol) hexanoic acid 4-chloro-pyrimidin-2-ylmethyl ester, 313 mg (1.41 mMol) 6-hydroxy-benzo[b]thiophene-3-carboxylic acid ethyl ester (Step 12.3) and 312 mg (1.47 mMol) K3PO4 in 5 ml NMP is stirred for 45 h at 60° C. The reaction mixture is dissolved in water and EtOAc, the aq. phase separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; CH2Cl2/ether 59:1→9:1) and crystallization from hexane gives the title compound: m.p.: 51° C.; MS: [M+1]+=429; TLC(CH2Cl2/ether 19:1): Rf=0.28.
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([NH2:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=1>>[F:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]([NH:41][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:30])([CH3:39])[CH3:40])=[CH:36][CH:37]=1
Reactant: CC(C)(N)c1ccc(F)cc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Product: CC(C)(NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C#N)CC[C@]4(C)[C@H]3CC[C@]12C)c1ccc(F)cc1
Yield: 82 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 1-(4-fluorophenyl)-1-methylethylamine (prepared as described in Preparation 10f) as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 82%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]=[N:9][CH:8]=2)=[CH:3][CH:2]=1.Cl.Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.C(OCC)(=O)C.C(O)CCC>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:21][C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=4)=[CH:14][CH:13]=3)[CH:10]=[N:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Oc1ccc(-n2cncc2-c2ccncc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: c1ccc2nc(COc3ccc(-n4cncc4-c4ccncc4)cc3)ccc2c1
Temperature: 23 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
A mixture of Preparation 84 (4-(5-(pyridin-4-yl)-1H-imidazol-1-yl)phenol, 95 mg, 0.4 mmol), 2-chloromethylquinoline hydrochloride (128 mg, 0.6 mmol), and cesium carbonate (391 mg, 1.2 mmol) in dimethylsulfoxide (2 mL) was stirred at 23° C. for 24 h. The mixture was diluted with ethyl acetate/n-butanol (100 mL/5 mL), was washed with water and then brine, and the organic layer was dried (MgSO4), was filtered, and was concentrated in vacuo. The residue was purified by silica gel chromatography using chloroform/methanol (50:1) to afford 150 mg (99% yield) of the title compound; diagnostic 13C NMR signals (100 MHz, CDCl3) δ 158.940, 157.116, 149.990, 147.836, 141.054, 137.405, 130.989, 130.204, 129.650, 129.239, 127.953, 127.871, 127.392, 127.011, 121.627, 119.324, 116.198, 71.990; MS (AP/Cl) 379.4 (M+H)+.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[S:13][CH:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:11]([NH:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:10]1=[O:33])=[O:7])(C)(C)C.CCOCC.[ClH:39]>O1CCOCC1>[ClH:39].[C:6]([CH2:8][N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[S:13][CH:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:11]([NH:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:10]1=[O:33])([OH:7])=[O:5]
Reactant: CCOC(=O)CNC1C(=O)N(CC(=O)OC(C)(C)C)c2ccccc2SC1c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCOC(=O)CNC1C(=O)N(CC(=O)O)c2ccccc2SC1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.2 g of the compound obtained in Example 24 was dissolved in 10 ml of a 6N solution of hydrogen chloride in dioxane, and the resulting solution was stirred at room temperature for 2 hours. Then, ether was added thereto so as to cause crystallization. The precipitated crystals were separated by filtration and washed with ether to obtain 1.0 g of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1.N1C=CC=CC=1.[CH3:18][C:19]1[S:23][C:22]([C:24](Cl)=[O:25])=[CH:21][CH:20]=1>ClCCl>[Cl:11][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:24]([C:22]3[S:23][C:19]([CH3:18])=[CH:20][CH:21]=3)=[O:25])[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1ccc(C(=O)Cl)s1
Reactant: Nc1nc2c(Cl)cccc2s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2nc3c(Cl)cccc3s2)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Amino-4-chlorobenzothiazol (92 mg, 0.50 mmol) is dissolved in dichloromethane (10 ml) and treated with pyridine (0.060 ml, 0.75 mmol) and 5-methyl-thiophene-2-carbonyl chloride (97 mg, 0.60 mmol). The reaction mixture is stirred at ambient temperature for 18 h and then evaporated to dryness. The residue is redissolved in ethyl acetate and water, the phases are separated and the organic layer extracted with brine. After dryin with sodium silfate, the solvent is removed in vacuo Flash chromatography on silica (eluent ethyl acetate/cyclohexane 1:4 affords the product as white solid.(88 mg, 57%). MS: m/e=308 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[CH:10](=O)[CH3:11]>O1CCCC1>[CH:10](=[N:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])[CH3:11]
Reactant: CC=O
Reactant: Cc1cccc(C)c1N
Solvent: C1CCOC1
Product: CC=Nc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2,6-Dimethylaniline (61.8 g, 0.51 mol) was added to a stirred solution of acetaldehyde (35.5 g, 0.81 mol) in tetrahydrofuran (500 mL). After stirring the reaction mixture for 1 day at room temperature, the volatiles were removed in vacuo, the residue was dissolved in THF (500 mL), acetaldehyde (35.5 g) was added to the resulting solution and the reaction mixture was allowed to react for another day at room temperature. This procedure was repeated several times until the conversion of 2,6-dimethylaniline was >98% as determined by gas chromatographic analysis. Yield: 76.7 g (102%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.C(N(CC)CC)C.[C:14]1([CH:24]=O)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.[C:26]([O:32][CH2:33][CH3:34])(=[O:31])[CH2:27][C:28]([CH3:30])=O>C(O)C>[CH3:30][C:28]1[NH:1][C:2]2[N:3]([N:4]=[N:5][N:6]=2)[CH:24]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[C:27]=1[C:26]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1nnn[nH]1
Reactant: O=Cc1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1=C(C)Nc2nnnn2C1c1cccc2ccccc12
Temperature: 25 °C
Yield: 56.1 %

Procedure:
To a solution of 5-aminotetrazole (0.85 g, 10.0 mmole) and triethylamine (0.25 ml, 1.8 mmole) in hot ethanol (25 ml) was added 1-naphthaldehyde (1.36 ml, 10.0 mmole) followed by ethyl acetoacetate (1.28 ml, 10.0 mmole). The clear solution was heated at reflux for 15 h at which time a white powdery precipitate was observed. The mixture was cooled to room temperature, filtered and washed with ethanol and ethyl ether to provide the desired product (1.88 g, 56%) as a white powder. 1H NMR (400 MHz; CDCl3) d 11.0 (s, 1H); 8.6 (d, 1H, J=8.6 Hz); 7.9 (d, 1H, J=8.2 Hz); 7.82 (d, 1H, J=7.8 Hz); 7.68 (at, 1H, J=7.4 Hz); 7.6-7.54 (m, 2H); 7.45 (dd, 1H, J=7.4, 1.1 Hz); 7.40 (at, 1H, J=7.8 Hz); 3.9 (q, 2H, J=7.0 Hz); 2.75 (s, 3H); 0.8 (t, 3H, J=7.0 Hz). LC MS shows MH+ at 336; M+Na at 358; 2M+H at 671 and 2M+Na at 693.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:29][C:30]([F:71])([F:70])[C:31]1[CH:32]=[C:33]([CH:67]=[CH:68][CH:69]=1)[CH2:34][NH:35][C:36](=[O:66])[C:37]1[CH:42]=[CH:41][N:40]=[C:39]([C:43]2[CH:48]=[C:47]([N:49]3[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]3)[CH:46]=[CH:45][C:44]=2[NH:55][C:56](=[O:65])[C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63]Br)[CH:58]=2)[CH:38]=1>CN(C)C=O>[F:29][C:30]([F:71])([F:70])[C:31]1[CH:32]=[C:33]([CH:67]=[CH:68][CH:69]=1)[CH2:34][NH:35][C:36]([C:37]1[CH:42]=[CH:41][N:40]=[C:39]([C:43]2[CH:48]=[C:47]([N:49]3[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]3)[CH:46]=[CH:45][C:44]=2[NH:55][C:56]([C:57]2[CH:58]=[C:59]([CH:60]=[CH:61][CH:62]=2)[CH2:63][N:2]([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[O:65])[CH:38]=1)=[O:66]
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CBr)c2)c1
Reactant: CNCCOCCOCCOCCC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCOCCOCCOCCC(=O)OC(C)(C)C)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Into a 8-mL round-bottom flask, was placed a solution of tert-butyl 3-(2-(2-(2-(methylamino)ethoxy)ethoxy)ethoxy)propanoate (89.3 mg, 0.31 mmol, 1.00 equiv) in N,N-dimethylformamide (6 mL), potassium carbonate (84.7 mg, 0.61 mmol, 1.99 equiv), potassium iodide (10.2 mg, 0.06 mmol, 0.20 equiv), and N-(3-(trifluoromethyl)benzyl)-2-(2-(3-(bromomethyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (200 mg, 0.31 mmol, 1.00 equiv). The resulting solution was stirred overnight at 70° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was dissolved in 20 mL of dichloromethane. The resulting mixture was washed with 2×20 mL of water. The resulting mixture was washed with 1×20 mL of brine, dried over sodium sulfate, and concentrated under vacuum. This resulted in 264 mg (crude) of product as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][C@H:9]([OH:12])[CH2:10]O)([CH3:4])([CH3:3])[CH3:2].CS(Cl)(=O)=O.[OH-].[Na+]>N1C=CC=CC=1.O.CS(C)=O>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][C@@H:9]1[CH2:10][O:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC[C@H](O)CO
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)NC[C@@H]1CO1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 49.9 %

Procedure:
((S)-2,3-Dihydroxypropyl)carbamic acid tert-butyl ester (5.00 g, 26.16 mmol) obtained in Step 1 above was dissolved in pyridine (32 ml), and cooled to 0° C. Methanesulfonyl chloride (2.22 ml, 28.71 mmol) was dropwise added to the solution, and stirred for 10 minutes. This solution was dropwise added to a solution of sodium hydroxide (3.18 g, 79.61 mmol) in water (33 ml) and dimethylsulfoxide (22 ml) at 0° C., and stirred for 10 minutes. This reaction solution was poured into ice water (300 ml), and then extracted with a mixture of n-hexane (80 ml) and ethyl acetate (320 ml). The organic layer was separated and washed with water and a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. After the inorganic salt was removed by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane to n-hexane:ethyl acetate=4:1) to yield (R)-1-oxiranylmethylcarbamic acid tert-butyl ester (2.26 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].[CH2:22](I)[CH3:23].[CH2:25](O)[CH3:26]>>[CH2:25]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([O:7][CH2:22][CH3:23])=[O:6])[CH3:26]
Reactant: CCO
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: CCI
Product: CCNc1cc(C(=O)OCC)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A mixture of 3-amino-4-phenoxy-5-sulphamyl-benzoic acid (3.08 g), ethyl iodide (20 ml), and ethanol (20 ml) was refluxed for 6 days. After cooling, the reaction mixture was evaported to dryness, and the residue was washed with a little ethanol followed by diethyl ether. The ethyl 3-ethylamino-4-phenoxy-5-sulphamyl-benzoate obtained was dissolved in 1N sodium hydroxide (35 ml) and heated on a steam bath for 30 minutes. After cooling, the reaction mixture was adjusted to pH 2.5 by addition of 4N hydrochloric acid, and the precipitated 3-ethylamino-4-phenoxy-5-sulphamyl-benzoic acid was isolated by filtration. After recrystallization from ethanol and drying in vacuo at 115°C, the compound was obtained with a melting point of 236°-237°C.
Reaction SMILES: [C:1]([N:3]=[C:4](OCC)[CH3:5])#[N:2].[C:9]([C:11]1[CH:25]=[CH:24][C:14]2[O:15][C:16]([CH3:23])([CH3:22])[C@@H:17]([OH:21])[C@H:18]([NH:19][CH3:20])[C:13]=2[CH:12]=1)#[N:10]>C(OCC)(=O)C>[C:9]([C:11]1[CH:25]=[CH:24][C:14]2[O:15][C:16]([CH3:22])([CH3:23])[C@@H:17]([OH:21])[C@H:18]([N:19]([C:4](=[N:3][C:1]#[N:2])[CH3:5])[CH3:20])[C:13]=2[CH:12]=1)#[N:10]
Reactant: CCOC(C)=NC#N
Reactant: CN[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Solvent: CCOC(C)=O
Product: CC(=NC#N)N(C)[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Reaction time: 2 h

Procedure:
To 2.80 g of ethyl N-cyanoacetimidate, 4.65 g of 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-methylamino-2H-benzo[b]pyran-3-ol was added, and the mixture was reacted under stirring at a temperature of from 100° to 120° C. for 2 hours. The reaction mixture was cooled, then dissolved in 100 ml of ethyl acetate, washed twice with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The residual solid was recrystallized from ethanol to obtain 2.34 g of the above identified compound in the form of crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9][CH2:10][N:11]([CH3:15])[CH2:12][CH2:13][NH2:14])=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23].[N:34]1([CH2:40][C:41]2[CH:42]=[C:43]([CH:49]=[CH:50][CH:51]=2)[O:44][CH2:45][CH2:46][CH2:47][NH2:48])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][NH:14][C:22]([NH:48][CH2:47][CH2:46][CH2:45][O:44][C:43]2[CH:49]=[CH:50][CH:51]=[C:41]([CH2:40][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:42]=2)=[O:23])[CH3:15])=[CH:4][CH:3]=1
Reactant: CN(CCN)CCC(c1ccc(F)cc1)c1ccccn1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CN(CCNC(=O)NCCCOc1cccc(CN2CCCCC2)c1)CCC(c1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 1 g (3.5 mmol) of N-[3-(4-fluorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,2-ethanediamine, an equimolar amount of 1,1'-carbonyldiimidazole and 0.9 g (3.6 mmol) of 3-[3-(piperidinomethyl)phenoxy]propaneamine as starting materials. Working up by chromatography (eluant: methylene chloride) analogously to Example 63 yields the purified title compound in the form of an oil; MS (EI-80 eV): m/z (rel. int.[%])=561 ([M]+., 3), 84 (70), 214 (100). For analytical purposes a sample is converted into the hydrochloride and recrystallised from ether/ethanol; m.p.: 111°-115° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][C:46]=1[O:47][CH3:48])[N:43]=[CH:42][N:41]=[C:40]2[S:49][C:50]1[CH:51]=[C:52]([CH:54]=[CH:55][CH:56]=1)[NH2:53]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:53][C:52]2[CH:54]=[CH:55][CH:56]=[C:50]([S:49][C:40]3[C:39]4[C:44](=[CH:45][C:46]([O:47][CH3:48])=[C:37]([O:36][CH3:35])[CH:38]=4)[N:43]=[CH:42][N:41]=3)[CH:51]=2)=[O:19])[N:7]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(C2CCCCC2)n1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4C4CCCCC4)c3)c2cc1OC
Temperature: 60 °C
Yield: 18 %

Procedure:
A stirred solution of phenyl 3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-ylcarbamate prepared as described in Example 330A (200 mg, 0.59 mmol), N,N-diisopropylethylamine (67 mg, 0.52 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (prepared as described in Example 115B) (85 mg, 0.27 mmol) in THF (1.0 mL) was heated at 60° C. for 15 h. After cooling to rt, the reaction solution was partitioned between dichloromethane and a saturated aqueous solution of sodium carbonate. The organic phase was separated and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (eluting with a gradient of 40:1 to 20:1 dichloromethane: methanol) then reverse-phase preparative HPLC to afford 1-(3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (52 mg, 18%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ9.17 (s, 1H), 8.71 (s, 1H), 8.53 (s, 1H), 7.84 (s, 1H), 7.26-7.55 (m, 5H), 6.06 (s, 1H), 4.00 (s, 6H), 3.94 (m, 1H), 1.62-1.81 (m, 7H), 1.24-1.36 (m, 12H); LC-MS (ESI) m/z 561 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:3]=1[CH:4]=O.[NH2:18][CH2:19][CH2:20][NH:21][C:22]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23].S1C=CC=C1>CO.[Pd]>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:3]=1[CH2:4][NH:18][CH2:19][CH2:20][NH:21][C:22]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23]
Reactant: NCCNC(=O)C1CCCCC1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1C=O
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Product: Nc1ccc(C(=O)c2ccccc2)cc1CNCCNC(=O)C1CCCCC1

Procedure:
A mixture of 2-amino-5-benzoylbenzaldehyde (0.007 mol) and cyclohexanecarboxylic acid (2-amino-ethyl)-amide (0.007 mol) in methanol was hydrogenated at 50° C. with 10% Pd/C (0.5 g) as a catalyst in the presence of thiophene solution (1 mL). After uptake of H2 gas (1 equiv.) the catalyst was filtered off and the solvent evaporated. The residue was purified by column chromatography over silica gel (Biotage column) (eluent:CH2Cl2:methanol gradient). The desired fractions were collected and the solvent evaporated to yield the title compound as a residue.