Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([S:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[N:13]([CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])[C:12]=2[CH:33]=1.[C:34](Br)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O>[C:34]([NH:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([S:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[N:13]([CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])[C:12]=2[CH:33]=1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Br)c1ccccc1
Reactant: CC(C)=CCn1c(SCCCNC(=O)OC(C)(C)C)nc2ccc(N)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)=CCn1c(SCCCNC(=O)OC(C)(C)C)nc2ccc(NC(=O)c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.9 %

Procedure:
24 mg (0.07 mmol) of cesium carbonate were added to a solution of 58 mg of tert-butyl {3-[6-amino-1-(3-methylbut-2-enyl)-1H-benzimidazol-2-ylsulfanyl]propyl}carbamate (obtained analogously to examples 1a-c) in 5 ml of dimethylformamide, and the mixture was stirred at room temperature for 30 minutes. Subsequently, 17 μl (0.15 mmol) of benzoyl bromide were added and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure and partitioned between water and dichloromethane. The organic phase was dried, concentrated under reduced pressure and purified by means of preparative HPLC (acetonitrile/water+0.5% trifluoroacetic acid, gradient: 20/80 to 100/0). 33 mg (44%) of the desired product were obtained.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.[OH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=O>>[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH:26][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][OH:28])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Reactant: O=CCCCCO
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NCCCCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described via a reductive amination starting from 50 mg (0.08 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrochloride and 8 mg (0.08 mmol) of 5-hydroxypentanal.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:27])=[C:9]([CH:19]([CH2:24][CH2:25][CH3:26])[C:20]([O:22]C)=[O:21])[C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[S:5][C:4]=1[CH3:28])[CH3:2].[OH-].[Na+]>CO.C(O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:27])=[C:9]([CH:19]([CH2:24][CH2:25][CH3:26])[C:20]([OH:22])=[O:21])[C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[S:5][C:4]=1[CH3:28])[CH3:2]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc(C)c(CC)c2c1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2sc(C)c(CC)c2c1-c1ccc(C)cc1
Temperature: 25 °C
Yield: 54.2 %

Procedure:
To a solution of methyl 2-(3-ethyl-2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate (0.130 g; 0.329 mmol) in methanol (7 mL) and ethanol (3.5 mL) was added a 5% sodium hydroxide solution (9 mL; 11.25 mmol). The reaction mixture was heated under reflux for 5 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was suspended in water, acidified with 1N HCl (pH˜2) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.068 g (54%) of the title compound as a white powder.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[C:9]([CH3:18])=[C:8]([I:19])[C:7]2=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:28])C=CC=CC=1>ClCCl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:28])[N:14]=[CH:15][C:10]=3[C:9]([CH3:18])=[C:8]([I:19])[C:7]2=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSc1ncc2c(C)c(I)c(=O)n(C3CCCC3)c2n1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Product: Cc1c(I)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Temperature: 25 °C
Yield: 73.9 %

Procedure:
8-Cyclopentyl-6-iodo-5-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.51 g, 3.76 mmol) and 2-benzenesulfonyl-3-phenyloxaziridine (0.98 g, 3.76 mmol) were combined in dichloromethane (14 mL) and stirred at room temperature until no starting material remained. The solvent was removed in vacuo and the residue was purified by chromatography (gradient 50% ethyl acetate in heptane to 100% ethyl acetate) to provide 8-cyclopentyl-6-iodo-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.16 g, 74%) as a white solid. MS (ESI); M++1: Calc'd, 418, Found 418. 1H NMR δ (300 MHz, CDCl3) 9.13 (s, 1H), 6.14–6.02 (m, 1H), 2.98 (s, 3H), 2.80 (s, 3H), 2.27–2.06 (m, 4H), 2.00–1.87 (m, 2H), 1.72–1.63 (m, 2H).
Reaction SMILES: Cl.C1C2C(COC([N:19]3[CH2:24][C@@H:23]([C:25](=[O:44])[N:26]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([O:38][CH2:39][CH2:40][CH2:41][O:42][CH3:43])[CH:32]=4)[CH:27]4[CH2:29][CH2:28]4)[CH2:22][C@@H:21]([NH2:45])[CH2:20]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[CH:46]1([C:50](Cl)=[O:51])[CH2:49][CH2:48][CH2:47]1>CC#N>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:26]([CH:27]2[CH2:29][CH2:28]2)[C:25]([CH:23]2[CH2:22][CH:21]([NH:45][C:50]([CH:46]3[CH2:49][CH2:48][CH2:47]3)=[O:51])[CH2:20][NH:19][CH2:24]2)=[O:44])=[CH:32][C:33]=1[O:38][CH2:39][CH2:40][CH2:41][O:42][CH3:43]
Reactant: O=C(Cl)C1CCC1
Reactant: COCCCOc1cc(CN(C(=O)[C@H]2C[C@@H](N)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)ccc1Cl
Agent: Cl
Solvent: CC#N
Product: COCCCOc1cc(CN(C(=O)C2CNCC(NC(=O)C3CCC3)C2)C2CC2)ccc1Cl

Procedure:
The title compound is prepared analogously as described in Example 61 using (3R*,5S*)-3-amino-5-{[4-chloro-3-(3-methoxy-propoxy)-benzyl]-cyclopropyl-carbamoyl}piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester, hydrochloride (Example 92A.) and cyclobutanecarbonyl chloride. MS: 478.4 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 4.97 min.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11][C:12]2[S:13][C:14]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[C:15]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[O:10])[CH:6]=[CH:5][N:4]=1.[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][NH:32][CH3:33]>>[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][N:32]([CH2:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11][C:12]2[S:13][C:14]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[C:15]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[O:10])[CH:6]=[CH:5][N:4]=1)[CH3:33]
Reactant: CNCCN(C)C
Reactant: O=C(Nc1nc(-c2ccco2)c(-c2ccncc2)s1)c1ccnc(CCl)c1
Product: CN(C)CCN(C)Cc1cc(C(=O)Nc2nc(-c3ccco3)c(-c3ccncc3)s2)ccn1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Compound 107 (150 mg, 0.387 mmol) was dissolved in N,N,N′-trimethylethylenediamine (1 mL), followed by stirring at 60° C. for 4 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=20:1) and then crystallized from diisopropyl ether to afford the entitled Compound 109 (70 mg, 40. %) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.[CH:12]1[N:16]=[CH:15][N:14]([C:17](N2C=NC=C2)=[O:18])[CH:13]=1>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH:9][C:17]([N:14]3[CH:13]=[CH:12][N:16]=[CH:15]3)=[O:18])[S:8][C:4]=2[CH:3]=1
Reactant: Nc1nc2ccc(Br)cc2s1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(Nc1nc2ccc(Br)cc2s1)n1ccnc1

Procedure:
A suspension of 6-bromo-benzothiazol-2-ylamine (5 g, 21.83 mmol) in DCM (250 ml) is treated with CDI (3.54 g, 21.83 mmol) and the reaction mixture is heated to reflux for 2 hours. The reaction mixture is filtered and the resulting solid is dried in the vacuum oven overnight to afford the title compound.
Reaction SMILES: [C:1]([O:5][CH3:6])(=O)[CH:2]=[CH2:3].[NH2:7][C:8]1[NH:9][C:10]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19]C)=[CH:13][C:11]=2[N:12]=1>CO>[CH3:6][O:5][C:1]1[C:15]([O:17][CH3:18])=[CH:16][C:10]2[N:9]=[C:8]3[NH:7][C:14](=[O:19])[CH2:13][CH2:11][N:12]3[C:3]=2[CH:2]=1
Reactant: COc1cc2nc(N)[nH]c2cc1OC
Reactant: C=CC(=O)OC
Solvent: CO
Product: COc1cc2nc3n(c2cc1OC)CCC(=O)N3
Reaction time: 90 h
Yield: 66 %

Procedure:
Methyl acrylate (6.1 g.) was added to a solution of 2-amino-5,6-dimethoxybenzimidazole (12.2 g.) in methanol (70 ml.) and the mixture was stirred for 90 hours. The crystalline precipitate was separated by filtration and washed with ethanol and then ether to give 7,8-dimethoxy-3,4-dihydropyrimido[1,2-a]-benzimidazol-2(1H)-one (10.3 g.), m.p. 264°-5° C.; microanalysis, C12H13N3O3 requires: C, 58.3; H, 5.3; N, 17.0%; found: C, 58.0; H, 5.2; N, 16.8%; NMR: δ2.82 (t, 2 protons, C3-H2); 3.72 (s, 3 protons, CH3O); 3.76 (s, 3 protons, CH3O); 4.15 (t, protons C4 -H2); 7.00 (s, 1 proton, C6-H); 7.04 (s, 1 proton, C9-H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4]([CH2:12][CH2:13][OH:14])=[CH:5][NH:6]2.N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4]([CH2:12][CH2:13][O:14][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[CH:5][NH:6]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc(Br)c2c(CCO)c[nH]c12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(Br)c2c(CCO[Si](C)(C)C(C)(C)C)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
A mixture of 2-(4-bromo-7-methyl-1H-indol-3-yl)-ethanol (2.51 g, 9.89 mmol), imidazole (1.68 g, 24.7 mmol) and tert-butyldimethylsilyl chloride (1.79 g, 11.9 mmol) in DMF (30 mL) was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (200 mL). The organic solution was washed with H2O (5×200 mL) and brine (200 mL), dried (Na2SO4), and concentrated to give 3.49 g (96%) of title compound as yellow oil. 1H NMR (CDCl3): 300 MHz δ 8.14 (bs, 1H), 7.11 (d, J=7.59 Hz, 1H), 6.99 (s, 1H), 6.72 (d, J=7.59 Hz, 1H), 3.90 (t, J=7.17 Hz, 2H), 3.19 (t, J=7.17 Hz, 2H), 2.31 (s, 3H), 0.87 (s, 9H), −0.08 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:15](Cl)[CH:14]=[CH:13][C:3]=1[O:4][C:5](=[CH:10][O:11][CH3:12])[C:6]([O:8][CH3:9])=[O:7].[Br:18]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>>[Br:18][CH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5](=[CH:10][O:11][CH3:12])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC=C(Oc1ccc(Cl)cc1C)C(=O)OC
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: COC=C(Oc1ccccc1CBr)C(=O)OC

Procedure:
A mixture of 5.13 g of methyl 2-(2-methyl-4-chlorophenoxy)-3-methoxyacrylate, 3.56 g of N-bromosuccinimide, and a catalytic amount of azobisisobutyronitrile was heated at reflux with light irradiation for 4 hours. The mixture was filtered through silica gel, and the solvent evaporated to give a crude sample of methyl 2-(2-bromomethylphenoxy)-3-methoxyacrylate. A mixture of this crude material and 2.46 g of sodium acetate in N,N-dimethylformamide was heated at 100 C. for 4 hours. Water was added and the mixture extracted with ethyl acetate, dried with anhydrous sodium sulfate, evaporated and the residue purified by silica gel column chromatography to give methyl 2-(2-acetyloxymethyl-4-chlorophenoxy)-3-methoxyacrylate) (3.2 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:19])[CH2:18][N:6]2[CH2:7][CH2:8][N:9](CC3C=CC=CC=3)[CH2:10][CH:5]2[CH2:4]1.C([O-])=O.[NH4+]>CO.[Pd]>[OH:1][CH2:2][C:3]1([CH3:19])[CH2:18][N:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH:5]2[CH2:4]1
Reactant: CC1(CO)CC2CN(Cc3ccccc3)CCN2C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC1(CO)CC2CNCCN2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.65 g (6.35 mmol) of (7RS,8aSR)-7-hydroxymethyl-7-methyl-2-phenylmethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 4) in 20 mL of methanol was mixed with 4.44 mL (22.2 mmol) of 5M aqueous ammonium formate, an aqueous slurry of 0.825 g of 10% palladium on carbon was added and the mixture was stirred at ambient temperature overnight. The solution was filtered through Celite and evaporated to give (7RS,8aSR)-7-hydroxymethyl-7-methyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine of sufficient purity for use in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9](O)[CH3:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH2:10])=[CH:7][N:8]=1
Reactant: COc1ccc(C(C)O)cn1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=Cc1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 37.2 %

Procedure:
To a solution of 1-(6-methoxy-pyridin-3-yl)-ethanol (14.3 g, 93.5 mmol) in anhydrous THF was added triethylamine (32.3 mL), followed by MsCl (8.6 mL, 112 mmol). The resulting mixture was stirred at room temperature for 15 hours before it was filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography to afford the desired product (4.7 g, 37% yield). 1H NMR (300 MHz, CDCl3): δ 3.94 (s, 3 H), 5.20–5.23 (m, 1H), 5.61–5.67 (m, 1 H), 6.60–6.78 (m, 2 H), 7.67–7.72 (m, 1 H), 8.12 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].[CH3:21][N:22]1[CH2:29][CH2:28][CH:27]2[CH:23]1[CH2:24][NH:25][CH2:26]2>>[Cl:1][C:2]1[C:3]([N:25]2[CH2:24][CH:23]3[CH:27]([CH2:28][CH2:29][N:22]3[CH3:21])[CH2:26]2)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18]
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: CN1CCC2CNCC21
Product: CN1CCC2CN(c3c(F)cc4c(=O)c(C(=O)O)cn(C5CC5)c4c3Cl)CC21

Procedure:
Thus, for example, 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid can be reacted with 2-methyl-2,7-diazabicyclo[3.3.0]octane to give 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(2-methyl-2,7-diazabicyclo[3.3.0]oct-7-yl)-4-oxo-3-quinolinecarboxylic acid, which has a high antibacterial activity.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH3:34][O:35][CH2:36][C:37]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:38]
Reactant: COCC(=O)Cl
Reactant: N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from cis-4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A141) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][C:8](=[O:20])[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)([CH3:11])[CH3:10]>>[CH3:6][O:7][C:8](=[O:20])[C:9]([C:12]1[CH:17]=[CH:16][C:15]([S:2]([Cl:1])(=[O:5])=[O:3])=[C:14]([O:18][CH3:19])[CH:13]=1)([CH3:11])[CH3:10]
Reactant: COC(=O)C(C)(C)c1cccc(OC)c1
Reactant: O=S(=O)(O)Cl
Product: COC(=O)C(C)(C)c1ccc(S(=O)(=O)Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
Chlorosulfonic acid (11.5 mL) was cooled to 0° C. Then compound 21A (4.6 g, 22 mmol) was added over 15 min. The mixture was stirred at RT for 3 h and then poured into ice (100 g). The cloudy solution was extracted with CH2Cl2 (2×50 mL) The extracts were dried with MgSO4 and concentrated to give a purple oil which was passed through a short pad of silica gel to afford the desired product 21B (2.43 g 36%) as an orange oil. MS m/z 271 (M−Cl). Step 3. Preparation of 2-(4-Mercapto-3-methoxy-phenyl)-2-methyl propionic acid methyl ester (Compound 21C)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2].[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][C:11]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([F:22])=[CH:24][CH:25]=2)=[O:13])=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2]
Reactant: Nc1ccc(F)cc1
Reactant: CC(C)CN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1
Product: CC(C)CN(CC(=O)Nc1ccc(F)cc1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described for Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-isobutylglycine and 4-fluoroaniline: MS (APCI) m/z 394 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:30][C:31]1[C:39]([OH:40])=[CH:38][CH:37]=[C:36]2[C:32]=1[CH:33]=[CH:34][NH:35]2>CC(N(C)C)=O>[Br:30][C:31]1[C:39]([O:40][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:38][CH:37]=[C:36]2[C:32]=1[CH:33]=[CH:34][NH:35]2
Reactant: Oc1ccc2[nH]ccc2c1Br
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3Br)ncnc2cc1OCCCN1CCCCC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 44.3 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (380 mg, 1.13 mmol), (prepared as described for the starting material in Example 67), potassium carbonate (469 mg, 3.4 mmol), 4-bromo-5-hydroxyindole (240 mg, 1.13 mmol) and DMA (4.0 ml) were stirred at 90° C. for 3 hours and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate evaporated under vacuum. The residue was purified by column chromatography eluting with dichloromethane/methanolic ammonia (7M) (95/5) to give an oil. This oil was further purified by column chromatography eluting with dichloromethane/methanol (60/40) to give 4-(4-bromoindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (256 mg, 44%).
Reaction SMILES: [C:1]([N:5]1[C:29](=[O:30])[C:28]2[N:13]3[CH2:14][CH2:15][C:16]4[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:20][C:21]=4[C:12]3=[CH:11][C:10]=2[CH2:9][O:8][CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Br:31]N1C(=O)CCC1=O.O>CN(C=O)C.[O-]S([O-])(=S)=O.[Na+].[Na+]>[C:1]([N:5]1[C:29](=[O:30])[C:28]2[N:13]3[CH2:14][CH2:15][C:16]4[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[CH:20][C:21]=4[C:12]3=[C:11]([Br:31])[C:10]=2[CH2:9][O:8][CH2:7][CH2:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2c(cc1OC(C)C)-c1cc3c(n1CC2)C(=O)N(C(C)(C)C)CCOC3
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1OC(C)C)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCOC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a solution of 180 mg of 18c in 2 ml of DMF was added 85 mg of N-bromosuccinimide. The mixture was stirred for ½ hr at RT. 3 ml of water was added and two drops of sat. aq. Na2S2O3 and the mixture was stirred for ½ hr. The precipitate was filtered and washed with water, dried and then triturated with diisopropyl ether, to provide 175 mg of 18d as white crystalline material. Mp 160-162° C.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[N:14]=[C:13]([CH2:15][CH:16]([OH:20])[CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=1.C[N+]1([O-])CCOCC1>ClCCl.C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]1([CH3:21])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[N:14]=[C:13]([CH2:15][C:16](=[O:20])[CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=1
Reactant: CCCC(O)Cc1cccc(-c2c(C)cc(C)cc2C)n1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CCCC(=O)Cc1cccc(-c2c(C)cc(C)cc2C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
1-(6-Mesitylpyridin-2-yl)pentan-2-ol (2.91 g, 10.3 mmol) in 100 mL of dichloromethane and 20 mL of acetonitrile was combined with 4 angstrom crushed molecular sieves (2.5 g) and N-methylmorpholine-N-oxide (1.80 g, 15.4 mmol). Tetrapropylammonium perruthenate (0.54 g, 1.54 mmol) was added last. The reaction stirred at room temperature for 1 h. The reaction was filtered and concentrated. Flash chromatography (10% ethyl acetate/hexanes) gave 0.87 g (30%) of the title compound as an yellow oil.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10](O)=[O:11])(=[O:4])=[O:3].[C:15](N1C=CN=C1)([N:17]1C=CN=C1)=O.CN>C1COCC1>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([NH:17][CH3:15])=[O:11])(=[O:4])=[O:3]
Reactant: NS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cc(S(N)(=O)=O)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
To a solution of 5-(aminosulfonyl)-2-fluorobenzoic acid [prepared according to Chem. Pharm. Bull. 1995, 43, 582-7] (22.98 g, 105 mmol) in THF (500 mL) at room temperature under nitrogen was added carbonyldiimidazole (17 g, 105 mmol). After stirring for 2.25 h a solution of methylamine in THF (2M, 70 mL, 140 mmol) was added dropwise and the reaction was allowed to stir for 18 h. The crude reaction mixture was concentrated to a low volume and EtOAc (150 mL) was added to the resulting thick oil. This mixture was stirred and a granular precipitate formed which was collected by filtration. This crude product, contaminated with imidazole, was suspended in DCM (300 mL) and heated at reflux for 5 h. After cooling to room temperature the mixture was filtered to give the desired product (19.8 g, 81%) containing <2% w/w imidazole; 1H NMR δH (300 MHz, d4-MeOH) 2.97 (3H, s), 7.40 (1H, t), 8.05 (1H, m), 8.29 (1H, d); MS m/z (TS+) 250 (MNH4+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[C:20]([C:22]3[CH:23]=[N:24][C:25]([N:28]4[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]4[CH3:34])=[N:26][CH:27]=3)[S:21][C:14]=12>>[CH3:34][C:29]1[N:28]([C:25]2[N:26]=[CH:27][C:22]([C:20]3[S:21][C:14]4[C:15](=[N:16][CH:17]=[CH:18][C:13]=4[NH:11][C:7]4[CH:8]=[C:9]5[C:4](=[CH:5][CH:6]=4)[NH:3][C:2]([CH3:1])=[CH:10]5)[CH:19]=3)=[CH:23][N:24]=2)[C:32]([CH3:33])=[CH:31][CH:30]=1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: Cc1ccc(C)n1-c1ncc(-c2cc3nccc(Cl)c3s2)cn1
Product: Cc1cc2cc(Nc3ccnc4cc(-c5cnc(-n6c(C)ccc6C)nc5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-5-aminoindole and 7-chloro-2-[2-(2,5-dimethyl-pyrrol-1-yl)-pyrimidin-5-yl]-thieno[3,2-b]pyridine by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ9.18 (s, 2H), 8.17 (d, 1h), 7.80 (s, 1H), 7.37 (s, 1H), 7.34 (d, 1H), 6.98 (d, 1H), 6.62 (d, 1H), 6.17 (s, 1H), 5.83 (s, 1H), 2.47 (s, 3H), 2.33 (s, 6H); RP18-HPLC RT: 6.81 minutes; API MS: 451 (M+1).