Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.C(N(C(C)C)CC)(C)C.[NH2:31][CH:32]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34].[O:44]1CCC[CH2:45]1>>[CH2:36]([O:35][C:33](=[O:34])[CH:32]([NH:31][C:45]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1)[CH3:37]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCOC(=O)C(N)c1ccccn1
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(NC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Amino-1-boc-piperidine (302 mg, 1.51 mmol) and triethylamine (0.210 mL, 1.51 mmol) in tetrahydrofuran (5 mL) were added to a solution of p-nitrophenylchloroformate (970 mg, 4.8 mmol) in tetrahydrofuran (15 mL) at 0° C. After 1 h, additional diisopropylethylamine was added (0.420 mL, 3.02 mmol) along with ethyl amino(pyridin-2-yl)acetate (272 mg, 1.51 mmol). The reaction was warmed to room temperature and stirred overnight. The mixture was filtered, concentrated and redissolved in ethyl acetate. The ethyl acetate layer was washed with 1N sodium hydroxide (3×), saturated sodium bicarbonate solution, water, brine, and dried over sodium sulfate. Purification by silica gel chromatography (100% dichloromethane→10% methanol {1% ammonium hydroxide}/dichloromethane) gave the title compound (330 mg). MS 407.29 (M+1)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([OH:25])=[C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19]([OH:21])=[O:20])[CH:10]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CC(C)=O.C(OCC)C.O>[CH2:32]([O:20][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][CH:24]=[C:16]([C:12]2[CH2:13][CH2:14][CH2:15][C:11]=2[C:9]2[CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=2[O:25][CH2:11][C:9]2[CH:10]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:17]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CS(=O)(=O)c1ccc(O)c(C2=C(c3cccc(C(=O)O)c3)CCC2)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CC(C)=O
Product: CS(=O)(=O)c1ccc(OCc2ccccc2)c(C2=C(c3cccc(C(=O)OCc4ccccc4)c3)CCC2)c1

Procedure:
A stirred mixture of 3-{2-[5-methylsulfonyl-2-(hydroxy)- -phenyl]-cyclopent-1-enyl}-benzoic acid (65 mg, 0.2 mmol), potassium carbonate (138 mg, 1 mmol) and benzyl bromide (75 mg, 0.44 mmol) in acetone (4 ml) was refluxed for 16 hours then cooled and diluted with diethyl ether/water. The organic phase was dried (MgSO4), evaporated to dryness and purified using Biotage with ethyl acetate/iso-hexane (1:19) to yield the title compound as a colourless gum. (85 mg, 84%).
Reaction SMILES: [C:1]([C:5]1[C:10](=[O:11])[CH:9]=[C:8]([CH3:12])O[C:6]=1[CH3:13])([O:3][CH3:4])=[O:2].[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([N:19]2[C:8]([CH3:12])=[CH:9][C:10](=[O:11])[C:5]([C:1]([O:3][CH3:4])=[O:2])=[C:6]2[CH3:13])=[CH:17][CH:16]=1
Reactant: COC(=O)c1c(C)oc(C)cc1=O
Reactant: Nc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(C)n(-c2ccc(Cl)cc2)c(C)cc1=O
Yield: 46.8 %

Procedure:
40 g of 3-carbomethoxy-2,6-dimethylpyr-4-one and 30.2 g of 4-chloroaniline are dissolved in 400 ml of toluene along with 400 mg of p-toluenesulfonic acid monohydrate. The reaction mixture is refluxed for four hours. The solvent is removed and the product crystallized from ether to yield 30 g of N-(4-chlorophenyl)-3-carbomethoxy-2,6-dimethylpyrid-4-one (m.p. 189°-90°).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:8][C@@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=3)=[C:10]2Br)[CH2:6]1)=[O:4].[CH3:34][Sn](C)(C)C>CN(C)C=O>[CH3:1][O:2][C:3]([C@H:5]1[CH2:8][C@@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=3)=[C:10]2[CH3:34])[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1C[C@@H](n2c(Br)c(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Reactant: C[Sn](C)(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@@H](n2c(C)c(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1

Procedure:
The title compound is prepared in analogy to Example 104 starting from 6.6 g (12.6 mmol) cis-3-[4-amino-5-(3-benzyloxy-phenyl)-6-bromo-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutane-carboxylic acid methyl ester of Example 113, 0.364 g (0.315 mmol) tetrakistriphenyl palladium, and 4.39 ml (31.52 mmol) tin tetramethyl (Fluka, Buchs, Switzerland) in 20 ml dry N,N-dimethylformamide (T=100-110° C., sealed tube; reaction time=25 h). Analytical HPLC: tR=11.67 min (Grad 1); ES-MS: m/eo=443.2; NMR (DMSO-d6; not all signals reported): 8.07/s (1H), 7.25-7.5/several m's (6H), 7.03/“d” (1H); 6.95/s (1H); 6.90/“d” (1H); 5.5-6.0/b (NH2); 5.14/s (2H); 4.90/m (1H); 3.65/s (3H); 2.25/s (3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:21]=[CH:20][C:14]([C:15](=[NH:19])OCC)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:12]=[CH:13][C:14]([C:15](=[NH:19])[N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:20][CH:21]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: C1CCNC1
Reactant: CCOC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Solvent: CO
Product: N=C(c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1)N1CCCC1

Procedure:
Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml of a 0.075 M methanol solution, 0.15 mmol) was treated with pyrrolidine (19 μl, 0.23 mmol) via procedure W to afford 25 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(imino(pyrrolidin-1-yl)methyl)benzamide. MS (Q1) 405 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17]O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:43]I>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][I:43])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: II
Reactant: OCCCN1CCN(c2ccc(Cl)c(Cl)c2)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1ccc(N2CCN(CCCI)CC2)cc1Cl

Procedure:
Compound 7p was mixed with triphenylphosphine resin, imidazole and iodine in DCM as described in General Procedure B. The product compound 11p was used without further purification for the next reaction. MS (LC/MS, ESI): 399 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[N:16]([C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)=[O:12])[CH2:15][CH2:14]1
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2[nH]ncc2c1)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 39 %

Procedure:
The title compound is prepared from 1H-indazole-5-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 39% of theory; LC (method 4): tR=1.94 min; Mass spectrum (ESI+): m/z=332 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]#[N:12])=[CH:2]1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+].O>CO>[CH2:13]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]#[N:12])=[CH:2]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#CCc1c[nH]c2ccccc12
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#CCc1cn(Cc2ccccc2)c2ccccc12
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A mixture of 3-indolylacetonitrile (5 g, 32 mmol), triton B (40% in MeOH, 0.5 g), benzyl bromide (7.8 mL, 2 eq.) and aqueous NaOH (50%, 12.6 mL) was stirred for 2 hours at 20° C. Water was added. Solid was collected by filtration and washed with water and hexane and dried under high vacuum to give [1-benzyl-1H-indol-3-yl]acetonitrile (6.97 g). MS (ES): 247 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[OH:17])=[CH:4][CH:3]=1.[NH3:19]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:19])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[OH:17])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2ccc(Cl)cc2)c(O)c1
Reactant: N
Solvent: CO
Product: COc1ccc(C(=N)c2ccc(Cl)cc2)c(O)c1

Procedure:
A suspension of 132 g. of 4'-chloro-2-hydroxy-4-methoxy-benzophenone in 500 ml. of methanol is cooled to -20° C. in a 2 l. shaking autoclave and treated with 120 ml. of liquid ammonia. The mixture is then shaken at 120° C. for 20 hours under a nitrogen atmosphere. After cooling, the yellow crude product is filtered off under suction and washed with a small amount of methanol. There is obtained 4'-chloro-2-hydroxy-4-methoxy-benzophenone imine, having a melting point of 210°-212° C., which can be used in the next step without further purification. An analytical sample is obtained by recrystallization from methanol and has a melting point of 212°-214° C.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[Br:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([OH:19])=[C:12]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=1.CCOCC>CN(C)C=O>[CH3:1][O:19][C:13]1[C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:10]([Br:9])=[CH:11][C:12]=1[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1cc(Br)cc([N+](=O)[O-])c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1c([N+](=O)[O-])cc(Br)cc1C(C)(C)C
Temperature: 50 °C
Reaction time: 4 h
Yield: 90.2 %

Procedure:
Potassium carbonate (453 g) and methyl iodide (164 ml) were added to a solution of 4-bromo-2-(tert-butyl)-6-nitrophenol (600 g) in dimethylformamide (6000 ml) and the mixture was stirred at 50° C. for 4 hours. Ether (6000 ml) was added and the reaction mixture was washed 3 times with water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to yield a crude product of the title compound (569 g) as a yellow oil.
Reaction SMILES: [CH3:1][C@@H:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16]CC)=[O:15])[CH2:4][CH2:3]1.O.[OH-].[Li+].O>C(O)C>[C:10]([O:9][C:7]([N:6]1[C@@H:2]([CH3:1])[CH2:3][CH2:4][C@H:5]1[C:14]([OH:16])=[O:15])=[O:8])([CH3:11])([CH3:12])[CH3:13]
Reactant: CCOC(=O)[C@@H]1CC[C@H](C)N1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@H]1CC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
To a solution of (2S,5S)-1-tert-butyl 2-ethyl 5-methylpyrrolidine-1,2-dicarboxylate (6.46 g, 25.1 mmol) in ethanol (20 mL) was added lithium hydroxide mono hydrate (2.11 g, 50.2 mmol) and deionized water (12 mL). The mixture was allowed to stir for 16 hours then partitioned between ethylacetate and a 1:1 mixture of saturated brine and 1N HCl. The aqueous layer was extracted an additional time with ethyl acetate. The organic layers were combined, dried with sodium sulfate and the solvent was removed in vacuo to yield (2S,55)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid as a white solid (quant.) and was used directly in the following step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH3:29][O:30][C:31]1[CH:55]=[CH:54][C:34]([CH2:35][O:36][C:37]([NH:39][C:40]2[NH:41][C:42](=[O:53])[C:43]3[N:44]=[CH:45][N:46]([CH2:49][C:50](O)=[O:51])[C:47]=3[N:48]=2)=[O:38])=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[C:50](=[O:51])[CH2:49][N:46]1[CH:45]=[N:44][C:43]2[C:42](=[O:53])[NH:41][C:40]([NH:39][C:37]([O:36][CH2:35][C:34]3[CH:54]=[CH:55][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)=[O:38])=[N:48][C:47]1=2)[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1
Reactant: COc1ccc(COC(=O)Nc2nc3c(ncn3CC(=O)O)c(=O)[nH]2)cc1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1)C(=O)Cn1cnc2c(=O)[nH]c(NC(=O)OCc3ccc(OC)cc3)nc21

Procedure:
The title compound was synthesized by the reaction of N-{2-[5-(4-chloro-2-nitrophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester with [2-N-(4-methoxybenzyloxycarbonyl)-guanin-9-yl]-acetic acid as per the procedure of example 13. 1H NMR (500 MHz; DMSO-d6) δ 11.39 (brs, 0.45H), 11.36 (brs, 0.55H), 9.20 (brs, 1H), 8.39 (s, 1H), 8.01 (d, 1H), 7.95 (d, 0.55H), 7.92 (d, 0.45H), 7.82 (s, 0.55H), 7.79 (s, 0.45H), 7.37 (d, 2H), 6.95 (d, 2H), 5.17 (s, 2H), 5.13 (s, 1.1H), 4.93 (s, 0.9H), 4.45 (s, 0.9H), 4.21 (q, 0.9H), 4.08 (s, 1.1H), 4.07 (q, 1.1H), 3.76 (s, 3H), 3.66 (t, 1.1H), 3.49 (t, 1.1H), 3.43 (t, 0.9H), 3.28 (t, 0.9H), 1.25 (t, 1.35H), 1.16 (t, 1.65H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].IC.[C:13](=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:13])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(F)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1ccc(F)cc1C=O

Procedure:
20.0 g (0.143 mol) of 5-fluoro-2-hydroxybenzaldehyde are dissolved in 250 ml of acetonitrile. 81.04 g (0.57 mol) of iodomethane and 39.5 g (285 mol) of potassium carbonate are added, and the suspension is heated at reflux for 3 hours. The suspension is filtered and the mother liquor is diluted with ethyl acetate, washed twice with water, dried over magnesium sulphate and filtered, and the solvents are evaporated under reduced pressure.
Reaction SMILES: Cl[C:2]1[N:3]([C@@H:15]2[O:21][C@H:20]([CH2:22][O:23]C(=O)C)[C@@H:18]([OH:19])[C@H:16]2[OH:17])[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][C:7]([Cl:13])=[C:6]([Cl:14])[CH:5]=2.[CH3:27][O-:28].[Na+].CO.C(Cl)(Cl)Cl.CO.O>CO>[Cl:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:14])[N:3]([C@@H:15]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]1[OH:17])[C:2]([O:28][CH3:27])=[C:10]2[CH:11]=[O:12]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)c(C=O)c3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Reactant: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: COc1c(C=O)c2cc(Cl)c(Cl)cc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
2,5,6-Trichloro-3-formyl-1-(5-O-acetyl-β-D-ribofuranosyl)indole (see Chen et al.; 4.24, 148 mg, 0.35 mmol) was dissolved in dry MeOH (20 mL) to which was added sodium methoxide (21 mg, 0.39 mmol). The solution was stirred at room temperature for 30 min, then the solvent was removed under vacuum. The residue was suspended in 10% aqueous NaHCO3, and the suspension extracted with EtOAc (2×50 mL). The combined organic extracts were dried over MgSO4, filtered and evaporated to yield a white solid. The solid was dissolved in MeOH (1 mL) and subjected to column chromatography (40×350 mm) on silica gel with 20% MeOH/CHCl3. Fractions containing product were pooled and evaporated to yield a white solid (the balance of recovered material was the deprotected 2-chloro derivative). The crude product was dissolved in MeOH and subjected to column chromatography (40×350 mm) on C18-reverse phase silica gel with 75% MeOH/H2O. Fractions containing product were pooled and evaporated to yield 50 mg (42%) of 4.25 as a white crystalline solid: mp 198-199° C.; Rf 0.2 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 10.21 (s, 1H), 8.34 (s, 1H), 8.31 (s, 1H), 5.84 (d, 1H), 5.41 (d, 1H, D2O exch.), 5.30 (t, 1H, D2O exch.), 5.23 (d, 1H, D2O exch.), 4.41 (s, 4H), 4.13 (s, 1H), 3.95 (d, 1H), 3.69 (m, 2H). 13C-NMR (125 MHz, DMSO-d6): δ 183.28, 160.04, 129.51, 125.21, 124.83, 124.68, 121.12, 114.73, 100.30, 86.81, 85.93, 71.06, 69.75, 64.78, 61.18. HRMS (EI) m/z calcd. for C15H15Cl2NO6 375.0276. found 375.0278. Anal calcd for C15H15Cl2NO6: C, 47.89; H, 4.02; N, 3.72. Found: C, 47.73; H, 4.12; N, 3.72.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:18]=[C:17]([F:27])[CH:16]=1)[CH2:9][C:8]2([CH3:29])[CH3:28])=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[F:27][C:17]1[CH:16]=[C:15]([CH:10]2[CH2:9][C:8]([CH3:28])([CH3:29])[C:7]3[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=3)[NH:11]2)[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=1
Reactant: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cc(F)cc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(C)CC(c2cc(F)cc(N3CCOCC3)c2)Nc2ccc(C(=O)O)cc21
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.9 %

Procedure:
To a stirred mixture solution of 2-(3-fluoro-5-morpholin-4-yl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (398.0 mg, 1.0 mmol) in methanol (10.0 mL) and tetrahydrofuran (10.0 mL) was added 50% sodium hydroxide in water (1.5 mL). The reaction mixture was stirred at 70° C. for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-fluoro-5-morpholin-4-yl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (345.6 mg, 90%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=385.1.
Reaction SMILES: [C-:1]#[N:2].[Na+].[N:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[C:18]1(=O)[CH2:21][CH2:20][CH2:19]1>CC(O)=O>[N:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:17]=[CH:16][C:14]([NH:15][C:18]3([C:1]#[N:2])[CH2:21][CH2:20][CH2:19]3)=[CH:13][CH:12]=2)=[CH:8][CH:9]=1
Reactant: O=C1CCC1
Reactant: [C-]#N
Reactant: Nc1ccc(Oc2ccncc2)cc1
Agent: [Na+]
Solvent: CC(=O)O
Product: N#CC1(Nc2ccc(Oc3ccncc3)cc2)CCC1
Yield: 64.9 %

Procedure:
Sodium cyanide (395 mg, 8.06 mmol) was added to a mixture of 4-(pyridin-4-yloxy)aniline (500 mg, 2.69 mmol) and cyclobutanone (376 mg, 5.37 mmol) in AcOH (99%, 6 mL) in a microwave vial. The reaction mixture was irradiated with microwaves (Biotage) at 120° C. for 30 min. The slightly yellowish solution was concentrated to dryness. The residue was diluted with water and extracted with EtOAc (2×). The combined organic layers were dried over MgSO4 and concentrated to dryness to afford 463 mg (65%) of 1-(4-(pyridin-4-yloxy)phenylamino)-cyclobutanecarbonitrile as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.46-8.38 (m, 2H), 7.02-6.94 (m, 2H), 6.79 (m, 2H), 6.72-6.64 (m, 2H), 2.86-2.74 (m, 2H), 2.46-2.34 (m, 2H), 2.22 (m, 2H)
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]1[N:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:15]=1[CH2:16]Cl>O>[ClH:13].[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:15]=1[CH2:16][NH:6][C:7]1[N:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: Nc1ncccn1
Reactant: ClCc1c(Cl)cccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cl
Product: Clc1cccc(Cl)c1CNc1ncccn1
Reaction time: 4 h

Procedure:
10.5 g (0.125 mol) of sodium bicarbonate in 100 ml of distilled water are introduced into a solution of 38 g (0.4 mol) of 2-amino-pyrimidine at 90°-95° C., after which 19.55 g (0.1 mol) of 2,6-dichlorobenzyl chloride are introduced in 1 hour, and the mixture is then left at 90°-95° C. for 4 hours. It is cooled and the insoluble matter is filtered off and washed copiously with distilled water. This insoluble matter is recrystallised from ethyl acetate. Thereafter it is dissolved in hot ethyl acetate and the hydrochloride is precipitated by means of a solution of hydrogen chloride in ether.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2[N:8]=[C:9]([NH2:11])[S:10][C:4]=2[CH2:3]1.C(N(CC)C(C)C)(C)C.[C:21]([C:23]1[CH:24]=[C:25]([NH:29][C:30]([CH2:32][O:33][C:34]2[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=2)[C:37](O)=[O:38])=[O:31])[CH:26]=[CH:27][CH:28]=1)#[N:22]>CN(C)C=O.O>[C:21]([C:23]1[CH:24]=[C:25]([NH:29][C:30]([CH2:32][O:33][C:34]2[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=2)[C:37]([NH:11][C:9]2[S:10][C:4]3[CH2:3][N:2]([CH3:1])[CH2:7][CH2:6][C:5]=3[N:8]=2)=[O:38])=[O:31])[CH:26]=[CH:27][CH:28]=1)#[N:22]
Reactant: N#Cc1cccc(NC(=O)COc2cccc(C(=O)O)c2)c1
Reactant: CN1CCc2nc(N)sc2C1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCc2nc(NC(=O)c3cccc(OCC(=O)Nc4cccc(C#N)c4)c3)sc2C1
Yield: 26.3 %

Procedure:
Add 5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylamine (0.03 g, 0.18 mmol) followed by O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyl uranium hexafluorophosphate (0.07 g, 0.18 mmol) and N,N-diisopropylethyl amine (0.10 mL, 0.54 mmol) to a solution of 3-[(3-cyano-phenylcarbamoyl)-methoxy]-benzoic acid (0.05 g, 0.17 mmol) in N,N-dimethylformamide (2 mL). Sir the mixture at room temperature for 15 h then dilute with water causing a solid to precipitate from solution. Collect the solid by filtration, wash with water and dry on the filter pad. Triturate the crude product with methylene chloride and dry on the filter pad to provide 0.020 g of the title compound as a powder. MS, electrospray 448.96 (M+H), rt. 1.13 min.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:25]=[CH:26][C:27]3[O:31][CH2:30][CH2:29][C:28]=3[CH:32]=2)[CH2:20][CH2:19]1)([OH:4])=[O:3].[CH3:33]O>>[CH3:33][O:3][C:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:25]=[CH:26][C:27]3[O:31][CH2:30][CH2:29][C:28]=3[CH:32]=2)[CH2:22][CH2:23]1)=[O:4]
Reactant: O=C(O)c1ccc2[nH]cc(CCCCN3CCN(c4ccc5c(c4)CCO5)CC3)c2c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc2[nH]cc(CCCCN3CCN(c4ccc5c(c4)CCO5)CC3)c2c1

Procedure:
HCl gas is passed into a boiling solution of 2.5 g of 1-[4-(5-carboxyindol-3-yl)butyl]-4-(2,3-dihydrobenzofuran-5-yl)piperazine in 50 ml of absolute methanol for 2 hours. The mixture is then boiled for a further hour, worked up in the customary manner and gives 1-[4-(5-methoxycarbonylindol-3-yl)butyl]-4-(2,3-dihydrobenzofuran-5-yl)piperazine.