Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[OH:13][CH:14]1[CH:18]([OH:19])[CH:17]([CH2:20][OH:21])N[C:15]1=[O:22].C(=O)(O)[O-].[Na+]>CO.O.C(O)(=O)C>[CH2:1]([N:8]1[C@H:17]([CH2:20][OH:21])[C@@H:18]([OH:19])[C@@H:14]([OH:13])[C:15]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(CO)C(O)C1O
Reactant: NCc1ccccc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: O=C1[C@H](O)[C@H](O)[C@@H](CO)N1Cc1ccccc1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
Tri-O-acetyl D-erythro-4-pentulosonic acid methyl ester 6 (15.2 g) was dissolved in methanol (85 ml) and acetic acid (3.1 g) and benzylamine (5.4 g) added. Sodium cyanoborohydride (3.1 g) was then added and the mixture kept at room temperature for 24 hours to reduce the imine to an amine 3. Sodium bicarbonate (6 g) and water 20 ml was added and the mixture heated for 4 hours at 70° C. to effect cyclization to the lactam 7. The mixture was concentrated to a syrup and partitioned between ethyl acetate (300 ml) and cold saturated sodium chloride (100 ml). The ethyl acetate layer was recovered, dried (sodium sulfate) and concentrated to a syrup. The syrup was dissolved in methanol (200 ml) to which was added potassium carbonate 20 g and water 2 ml. The resulting mixture was stirred at room temperature for 14 hours, filtered, the filtrate concentrated and the resulting syrup dissolved in methanol (400 ml). Concentrated HCl (4.1 ml) was added. A white solid was formed. This was removed by filtration and the filtrate concentrated to dryness. Methanol was added again and the solution again concentrated. This was repeated one more time to give the crude N-benzyl pyrrolidone which can be converted to the pyrrolidine to reduction.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C>C(O)C>[C:1]([NH:4][C@@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@H:6]1[OH:15])(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCc2ccccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)N[C@@H]1CCc2ccccc2[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the 2-acetamido-3,4-dihydronaphthalen-1(2H)-one from Step A in absolute ethanol (150 ml) was added sodium borohydride (2.0 gms, 0.05 m) in portions. The reaction mixture was stirred at room temperature for 1/2 hour. Acetic acid was added dropwise to destroy the excess sodium borohydride. The reaction mixture was poured into water and extracted with ethyl acetate (3×150 ml). The ethyl acetate was washed with saturated aqueous sodium chloride (150 ml) and dried over anhydrous sodium sulfate. After filtration the solvent was removed under reduced pressure to yield 5.5 gms (54%, over Steps A and B), of product as a solid.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:10]=[C:9]([CH2:11][CH2:12][NH:13]C(=O)OC(C)(C)C)[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:21]([OH:27])([C:23]([F:26])([F:25])[F:24])=[O:22]>ClCCl>[F:24][C:23]([F:26])([F:25])[C:21]([OH:27])=[O:22].[NH2:13][CH2:12][CH2:11][C:9]1[S:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([OH:1])[C:3]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)NCCc1cc2c(O)ncnc2s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCc1cc2c(O)ncnc2s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
A solution of tert-butyl N-(2-[4-hydroxythieno[2,3-d]pyrimidin-6-yl]ethyl)carbamate (600 mg, 2.03 mmol, 1.00 equiv) in 25 mL of dichloromethane at 0° C. was added 4 mL of CF3COOH and the resulting solution was stirred for 6 hours at room temperature. The resulting mixture was concentrated under vacuum to give 6-(2-aminoethyl)thieno[2,3-d]pyrimidin-4-ol trifluoroacetate (570 mg, 91%) as a yellow oil which was used directly in the next step without further purification. MS (ES): m/z 196 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH:12]=O)[CH:6]=1)[CH3:2].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CCO>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH2:12][NH:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=1)[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1ccc(Br)c(C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1ccc(Br)c(CNCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Bromo-3-formyl-benzoic acid ethyl ester (3.3 g, 12.9 mmol) and benzylamine (2.1 mL, 19.3 mmol) were combined in EtOH (150 mL) with 4 Å molecular sieves. Sodium cyanoborohydride (1.21 g, 19.3 mmol) was added, followed by acetic acid (1.1 mL, 19.3 mmol), and the reaction was stirred at room temperature for 1 hour. Aqueous work-up provided 3-(benzylamino-methyl)-4-bromo-benzoic acid ethyl ester.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:41]=[CH:40][CH:39]=[CH:38][C:11]=2[C:12]=1[C:13]1[CH:37]=[CH:36][C:16]([C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:35])[CH2:24][CH:25]3[C:30](=[O:31])[O:29][C:28]([CH3:33])([CH3:32])[O:27][C:26]3=[O:34])=[CH:19][CH:18]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:44](Br)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.O>C1COCC1.CN(C=O)C.C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:44]([C:25]1([CH2:24][C:23]([C:20]2[CH:19]=[CH:18][C:17]([C:16]3[CH:15]=[CH:14][C:13]([C:12]4[C:11]5[CH:38]=[CH:39][CH:40]=[CH:41][C:10]=5[O:9][C:8]=4[CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:37][CH:36]=3)=[CH:22][CH:21]=2)=[O:35])[C:30](=[O:31])[O:29][C:28]([CH3:33])([CH3:32])[O:27][C:26]1=[O:34])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CC1(C)OC(=O)C(CC(=O)c2ccc(-c3ccc(-c4c(Cc5ccccc5)oc5ccccc45)cc3)cc2)C(=O)O1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)C(CC(=O)c2ccc(-c3ccc(-c4c(Cc5ccccc5)oc5ccccc45)cc3)cc2)(Cc2ccccc2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
A solution of 5-{2-[4′-(2-benzylbenzofuran-3-yl)-biphen-4-yl]-2-oxoethyl}-2,2-dimethyl-[1,3]dioxane-4,6-dione (200 mg, 0.37 mmol) in THF/DMF (5:1; 6 mL) was added dropwise to a stirred suspension of sodium hydride (95%, 10.2 mg, 0.40 mmol) in anhyd THF (5 mL) at room temperature. The clear solution was stirred at room temperature for 30 min and then a solution of benzyl bromide (76 mg, 0.44 mmol) in THF (5 mL) was added dropwise, followed by the addition of tetra-n-butylammonium iodide (5 mg) as a solid. The reaction mixture was warmed to 60° C. for 4 h (TLC control), cooled to room temperature and then water (10 mL) was added cautiously. The reaction mixture was extracted with diethyl ether (3×15 mL). The combined organic extracts were washed successively with water (2×10 mL), sat'd aq NaCl (3×10 mL), dried over anhyd MgSO4, filtered and concentrated in vacuo. Purification by trituration and filtration from MeOH afforded the title compound as a pale yellow solid (210 mg).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[C:7]([O:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:6][C:3]=1[CH:4]=[CH2:5].ClC1C=CC=C(C(OO)=[O:33])C=1>C1CCCCC1.C(OCC)(=O)C>[Cl:1][C:2]12[O:33][C:3]1([CH:6]=[C:7]([O:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[C:8]([O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:9]2[Cl:10])[CH:4]=[CH2:5]
Reactant: C=Cc1cc(OCOCCOC)c(OCOCCOC)c(Cl)c1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: C=CC12C=C(OCOCCOC)C(OCOCCOC)=C(Cl)C1(Cl)O2
Yield: 99.6 %

Procedure:
Using the procedure of Stage D of Example 40, 13.2 g of thee allylic alcohol of Step C and 10.3 g of m-chloro perbenzoic acid were reacted to obtain 13.7 g of the expected product with a Rf=0.25 (AcOEt-cyclohexane 6-4).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15].[C:16]([N:23]1[CH2:31][CH2:30][CH2:29][C@@H:25]([C:26](O)=[O:27])[CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:26]([C@@H:25]2[CH2:29][CH2:30][CH2:31][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:24]2)=[O:27])=[C:3]([NH:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:4]=1)#[N:7]
Reactant: COCCCNc1cc(C#N)ccc1N
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COCCCNc1cc(C#N)ccc1NC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.6 %

Procedure:
4-Amino-3-(3-methoxypropylamino)benzonitrile (41B) (3.50 mmol, 718 mg) in DMF (25 mL) was added (R)-(−)—N-Boc-Nipecotic acid (4.55 mmol, 1.04 g) and N-methylmotpholine (10.50 mmol, 1.15 mL). The reaction mixture was stirred at rt for 5 min and then added HATU (5.25 mmol, 2.00 g) and kept stirring at rt overnight. The reaction mixture was poured into H2O, extracted with EtOAc. The extract was washed with H2O, NaHCO3, brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel EtOAc-hexane: 1:2) to afford (R)-tert-butyl 3-(4-cyano-2-(3-methoxypropylamino)phenylcarbamoyl)piperidine-1-carboxylate (41C) (2.40 mmol, 1.01 g, three-step yield: 68.6%). ESI-MS: m/z 417.5 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:48]=[CH:47][C:8]2[N:9]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:10]([N:12]([CH2:21][CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][C:29]4[C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH:32]=[CH:31][CH:30]=4)[CH2:24][CH2:23]3)[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[N:11][C:7]=2[CH:6]=1)=O.[H-].[Li+].[Al+3].[H-].[H-].[H-]>O1CCCC1>[C:29]1([CH2:28][N:25]2[CH2:24][CH2:23][CH:22]([CH2:21][N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:10]3[N:9]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:44])([CH3:45])[CH3:46])[C:8]4[CH:47]=[CH:48][C:5]([CH2:3][OH:2])=[CH:6][C:7]=4[N:11]=3)[CH2:27][CH2:26]2)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccc2c(c1)nc(N(COCC[Si](C)(C)C)CC1CCN(Cc3cccc4ccccc34)CC1)n2COCC[Si](C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCN(CC1CCN(Cc2cccc3ccccc23)CC1)c1nc2cc(CO)ccc2n1COCC[Si](C)(C)C
Reaction time: 2 h

Procedure:
After dissolving 2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazole-5-carboxylic acid methyl ester (624 mg, 0.91 mmol) in anhydrous tetrahydrofuran (10 ml) under a nitrogen stream, aluminum lithium hydride (72.4 mg, 1.82 mmol) was added at 0° C., and the mixture was stirred for 2 hours. After then adding a saturated aqueous sodium sulfate solution, extraction was performed with ethyl acetate and then with dichloromethane. Each extract was washed with saturated brine, and then combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain [2-[(1-naphthalen-1-ylmethyl-piperidin -4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-5-yl]-methanol. The compound was identified by LC-MS.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]([OH:18])=[O:17])[CH:12]=2)[CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:19]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)[CH2:20][CH2:21][CH3:22]>N1C=CC=CC=1>[CH2:1]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]([O:18][C:26]3[CH:27]=[CH:28][C:23]([CH2:19][CH2:20][CH2:21][CH3:22])=[CH:24][CH:25]=3)=[O:17])[CH:12]=2)[CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1CCc2cc(C(=O)O)ccc2C1
Reactant: CCCCc1ccc(O)cc1
Solvent: c1ccncc1
Product: CCCCCC1CCc2cc(C(=O)Oc3ccc(CCCC)cc3)ccc2C1
Yield: 99 %

Procedure:
Analogously to Example 1, 2.0 g of 2-pentyl-1,2,3,4-tetrahydronaphthalene-6-carboxylic acid are converted into the acid chloride and this is reacted with 1.202 g of p-butylphenol in 5 ml of absolute pyridine. There are obtained 3.0 g of crude p-butylphenyl 2-pentyl-1,2,3,4-tetrahydro-6-naphthoate for purification, is chromatographed on 95 g of silica gel. Elution with hexane/toluene (1:1) yields 2.8 g of substance which is recrystallized from ether/hexane up to constant melting point and clearing point and dried up to constant weight in a high vacuum (0.01 mbar). There are obtained colorless crystals of p-butylphenyl 2-pentyl-1,2,3,4-tetrahydro-6-naphthoate; m.p. 48.1° C., cl.p. 80.7° C.
Reaction SMILES: [CH3:1][C:2]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([N:26]5[CH2:30][CH2:29][CH2:28][CH2:27]5)=[O:25])=[CH:20][CH:19]=4)[O:17][C:10]=23)=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:31]([C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]>>[C:31]([C:35]1[CH:36]=[CH:37][C:38]([C:39]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[C:8]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]4[CH:15]=[C:16]([C:18]5[CH:23]=[CH:22][C:21]([C:24]([N:26]6[CH2:30][CH2:29][CH2:28][CH2:27]6)=[O:25])=[CH:20][CH:19]=5)[O:17][C:10]=34)[C:2]=2[CH3:1])=[O:40])=[CH:42][CH:43]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Cc1c(N)cccc1-c1ccnc2cc(-c3ccc(C(=O)N4CCCC4)cc3)oc12
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1ccnc2cc(-c3ccc(C(=O)N4CCCC4)cc3)oc12

Procedure:
The compound was synthesized according to the procedure M using 2-methyl-3-{2-[4-(pyrrolidin-1-ylcarbonyl)phenyl]furo[3,2-b]pyridin-7-yl}aniline (50 mg, 0.13 mmol) and 4-tert-butylbenzoyl chloride (27.21 mg, 0.14 mmol). The title compound was obtained as white solid (6.00 mg, 9%). HPLC (method F): 100%, RT=4.714 min. MS: m/z=558 [M+H]+, RT=4.85 min.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19](=[O:22])[CH2:20][OH:21])[CH2:10][CH:9]2[CH3:29])=[O:7])=[CH:4][CH:3]=1.FC1C=CC(C(Cl)=O)=CC=1.O1C=CC=C1C(Cl)=O.C(OCC(Cl)=O)(=O)C.C(Cl)(=O)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19](=[O:22])[CH2:20][OH:21])[CH2:10][C@@H:9]2[CH3:29])=[O:7])=[CH:30][CH:31]=1
Reactant: CC1CC(N(C(=O)CO)c2ccccc2)c2ccccc2N1C(=O)c1ccc(F)cc1
Agent: CC(=O)OCC(=O)Cl
Agent: O=C(Cl)c1ccc(F)cc1
Agent: O=C(Cl)c1ccco1
Solvent: CC(=O)Cl
Product: C[C@H]1C[C@@H](N(C(=O)CO)c2ccccc2)c2ccccc2N1C(=O)c1ccc(F)cc1

Procedure:
(±)-N-[1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-2-hydroxy-N-phenyl-acetamide was made following general procedure A substituting 4-fluorobenzoyl chloride for 2-furoyl chloride and acetoxyacetyl chloride for acetyl chloride.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[OH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:14])=[N:12][CH:13]=1.[I:15]I.[I-].[K+]>O>[I:15][C:13]1[C:8]([OH:7])=[CH:9][CH:10]=[C:11]([CH3:14])[N:12]=1
Reactant: Cc1ccc(O)cn1
Reactant: II
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(O)c(I)n1
Temperature: 25 °C
Yield: 43.8 %

Procedure:
Sodium carbonate (68.0 g) and water (810 mL) were added to 5-hydroxy-2-methylpyridine (1-014-01) (36.11 g), and the reaction mixture was stirred at room temperature, dissolved. To the reaction mixture was added dropwise a solution of iodine (117 g) and potassium iodide (117 g) in water (810 mL) for 35 min. The resulting pink-yellow crystal was filtered and dried under reduced pressure to give 2-iodo-3-hydroxy-6-methylpyridine (2-014-01) (34.1 g, 43.9%, m.p. 187-190° C.)
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=2)O1>>[NH2:32][C:29]1[N:30]=[CH:31][C:26]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[CH:27][CH:28]=1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: N#Cc1cc(-c2ccc(N)nc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, light brown solid (46 mg, 61%), MS (ISN) m/z=304.5 [(M+H)+], mp 305° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (71.5 mg, 0.325 mmol).
Reaction SMILES: [CH:1]1([N:4]2[CH:11]=[CH:10][C:8]([NH2:9])=[N:7][C:5]2=[O:6])[CH2:3][CH2:2]1.[C:12]([NH:15][C:16]1[CH:25]=[CH:24][C:19]([S:20](Cl)(=[O:22])=[O:21])=[CH:18][CH:17]=1)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([NH:15][C:16]1[CH:25]=[CH:24][C:19]([S:20]([NH:9][C:8]2[CH:10]=[CH:11][N:4]([CH:1]3[CH2:3][CH2:2]3)[C:5](=[O:6])[N:7]=2)(=[O:22])=[O:21])=[CH:18][CH:17]=1)(=[O:14])[CH3:13]
Reactant: Nc1ccn(C2CC2)c(=O)n1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccn(C3CC3)c(=O)n2)cc1
Reaction time: 8 h

Procedure:
A mixture of 10.6 g. of 1-cyclopropylcytosine, 16.4 g. of N-acetylsulfanilyl chloride and 47 ml. of pyridine was stirred overnight after momentary cooling to maintain the reaction below 30°. The mixture was poured into 700 ml. of water, and after filtration by gravity, the solution was strongly acidified by addition of 6N hydrochloric acid. Gradual crystallization occurred overnight in a refrigerator before filtering the N4 -acetyl-N1 -(1-cyclopropyl-1,2-dihydro-2-oxo-4-pyrimidinyl)-sulfanilamide; yield 10.7 g., m.p. 139°-143°.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].C(OCC)(=O)C.N1C=CC=CC=1.[OH:26][CH2:27][C:28]1[S:32][CH:31]=[N:30][CH:29]=1>C(O)C>[CH:7]1[C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=[C:5]([O:4][C:2]([O:26][CH2:27][C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[O:3])[CH:6]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCc1cncs1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
A solution comprising 21.0 Kg. (104 mole) 4-nitrophenyl chloroformate dissolved into 75 L ethyl acetate was prepared. The solution was cooled to -5° C. and 0.4 Kg (4 mole) of pyridine dissolved, into 18 L ethyl acetate, was added. The resulting slurry was stirred at -5°±5° C. After 1 hour, 5-hydroxymethyl thiazole 10.0 Kg (87 mole), (HMT) dissolved into 75 L ethyl acetate, was added over 30-40 minutes, maintaining the reaction mixture temperature at -5°±3° C. The resulting slurry was then warmed to 0°±5° C., and stirred for at least about 24 hours. The reaction was checked for completion by HPLC. Upon completion, absolute ethanol, 32 Kg, was added to the slurry (about 15-20% of the total reaction volume), stirred for at least about 2 hours, and then centrifuged or filtered. The product solid was washed with cold ethyl acetate (2×75 L) and dried at 40°±5° C. to an LOD <2%. Yield: 25.15 Kg (93%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)[CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.C=O.[C:47](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[CH2:27][CH2:28][N:29]([CH3:47])[CH2:30][CH2:31]5)[CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[CH:12]=2)[CH:8]=[N:7]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cccc(N5CCNCC5)c4)cnc32)cc1
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cccc(N5CCN(C)CC5)c4)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
A mixture of 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(3-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step-i of example-35) (87 mg, 0.143 mmol), HCHO (13 mg, 0.43 mmol), 1,2-dichloroethane (2 ml) was stirred at RT under nitrogen for 30 minutes. Sodium triacetoxy borohydride (91 mg, 0.43 mmol) was then added and stirred at the same temperature for overnight. Reaction mass quenched water, basified by saturated sodium bicarbonate and extracted into ethyl acetate. Organic layer dried over sodium sulfate and concentrated to give 74 mg (84% yield) of the titled compound. MS: m/z=621.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:21]1([C:27]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@H:35]3[C@H:31]([CH2:32][NH:33][CH2:34]3)[C:30](=[O:36])[CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([N:33]1[CH2:32][C@H:31]2[C@H:35]([C:27]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29][C:30]2=[O:36])[CH2:34]1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC[C@@H](C(=O)O)c1ccccc1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@@H](C(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1)c1ccccc1
Reaction time: 0.25 h
Yield: 74.8 %

Procedure:
N,N'-Carbonyldiimidazole (0.5 g) is added to a solution of (S)-3-tert-butoxycarbonylamino-2-phenylpropionic acid (0.79 g) in dry dichloromethane (20 cc), cooled to +5° C. The mixture is stirred for 1 hour 15 minutes at +5° C. and a solution of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (1 g) and triethylamine (0.4 cc) in dichloromethane (25 cc) is then added. The reaction mixture is stirred for 15 minutes at +5° C. and then for 16 hours at 20° C. The reaction mixture is washed with distilled water (3×100 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.06 mm, diameter 3 cm, height 30 cm), eluting with a mixture of cyclohexane and ethyl acetate (50/50 by volume) and collecting 50 cc fractions. Fractions 2 to 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa). (3aR,7aR)-2-[(S)-2-tert-butoxycarbonylaminomethyl-2-phenylacetyl]-7,7-diphenyl-4-perhydroisoindolone (1.2 g) is obtained in the form of a white meringue.
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.[O-:38][C:39]#[N:40].[Na+]>CC(O)=O.O>[F:37][C:4]1[CH:3]=[C:2]([NH:1][C:39]([NH2:40])=[O:38])[CH:36]=[CH:35][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][CH:17]=3)[S:15][C:8]=12
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(N)=O)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.5 %

Procedure:
To a solution of compound 126 (3.0 g, 5.72 mmol) in AcOH (13.6 mL) at 0° C. was added a solution of sodium cyanate (0.743 g, 11.44 mmol, 2 eq.) in water (5.2 mL). The mixture was stirred at r.t. for 20 h. Water (100 mL) was added and the reaction mixture turned into a suspension. After 30 min, the solid was collected by filtration and the product cake was washed with water (2×20 mL), dried in vacuum and purified by Biotage SP1 Flash Purification System (eluent a gradient EA/MeOH, 100/0 to 90/10) to afford 288 as a white solid (2.0 g, 3.52 mmol, 62% yield). MS (m/z): 568.4 (M+H).