Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([C:12]2[O:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[N:3]=1.C(N(CC)CC)C.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.CCCC(C)C>C(#N)C.ClCCl.C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:17][C:14]1[O:13][C:12]([C:4]2[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][S:31]([C:28]3[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=3)(=[O:33])=[O:32])[N:7]=[C:2]([NH2:1])[N:3]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(-c2nc(N)nc(O)c2[N+](=O)[O-])o1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCC(C)C
Product: Cc1ccc(S(=O)(=O)Oc2nc(N)nc(-c3ccc(C)o3)c2[N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 3.5 h

Procedure:
A stirred suspension of 2-amino-6-(5-methyl-2-furyl)-5-nitro-4-pyrimidinol (12) (20.96 g, 0.089 mol) in dry acetonitrile (800 mL, 40 volumes) in a flame-dried three-necked flask at 22° C. was treated with triethylamine (27.24 mL, 0.196 mol, 2.2 eq). The resulting triethylamine salt was clearly insoluble in the reaction solvent, a thick yellow precipitate becoming apparent. The mixture was heated to a temperature of 50° C. and treated portionwise with para-toluenesulfonyl chloride (18.57 g, 0.097 mol, 1.1 eq). The yellow precipitate was rapidly replaced by a dark orange/brown solution. Stirring at 50° C. was continued for a further 3.5 hr, after which time LC-MS and TLC (1:1 EtOAc:iso-hexane) analysis indicated a complete reaction. The reaction mixture was cooled to 22° C. and reduced in vacuo to yield a light brown solid. This was dissolved in dichloromethane (800 mL, 40 volumes) and washed twice with 1.2-M aqueous hydrochloric acid. The organic fraction was dried over magnesium sulfate and reduced in vacuo to yield a cream coloured solid. Trituration with toluene was effective in removing excess tosyl chloride to give the required tosylate product (compound 13) as an off-white solid. Drying at 40° C. left 22.33 g (65% yield).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH:9]2[NH:14][CH2:13][CH2:12][N:11]([S:15]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)(=[O:17])=[O:16])[CH2:10]2)[CH2:4][CH2:3]1.Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:32][C:31]([F:33])([F:34])[C:30]([C:27]1[CH:26]=[CH:25][C:24]([N:14]2[CH2:13][CH2:12][N:11]([S:15]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:17])[CH2:10][CH:9]2[CH2:8][CH:5]2[CH2:6][CH2:7][O:2][CH2:3][CH2:4]2)=[CH:29][CH:28]=1)([OH:39])[C:35]([F:36])([F:38])[F:37]
Reactant: OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(c1cccs1)N1CCNC(CC2CCOCC2)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)C(CC2CCOCC2)C1
Temperature: 100 °C
Yield: 2.1 %

Procedure:
A 100 ml, round-bottomed flask was charged with 3-(tetrahydro-2H-pyran-4-ylmethyl)-1-(2-thiophenylsulfonyl)piperazine hydrochloride (0.250 g, 0.681 mmol), 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.330 g, 1.02 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), sodium tert-butoxide (0.196 g, 2.04 mmol) and 10 mL of toluene. To this was added dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.032 g, 0.068 mmol, Strem Chemical Inc, Newburyport, Mass.), tris(dibenzylideneacetone)dipalladium (0) (0.031 g, 0.034 mmol, Strem Chemical Inc, Newburyport, Mass.). The mixture was heated at 100° C. for 12 h and then diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were dried (MgSO4), concentrated, and purified by reverse-phase preparative HPLC (Phenomenex Gemini C18 column (150×30 mm, 10 μm), eluting with a 0.1% TFA in CH3CN/H2O (10% to 90% over 25 min)) to afford 1,1,1,3,3,3-hexafluoro-2-(4-(2-(tetrahydro-2H-pyran-4-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.008 g) as a mixture of two enantiomers.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:14]#[N:15])[S:12][CH:13]=2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.O.C>CO>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([C:14]#[N:15])[S:12][CH:13]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2csc(C#N)n2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CO
Product: N#Cc1nc(-c2ccc(O)cc2)cs1
Temperature: 225 °C
Yield: 66 %

Procedure:
A mixture of 4-(4-methoxyphenyl)-thiazole-2-carbonitrile (14.9 g) and pyridine hydrochloride (44.7 g) was heated at 225° C. for 1 h, then cooled and added to water (300 ml). The suspension was filtered and dried under vacuum at 50° C., to give a solid which was dissolved in methanol, treated with charcoal, filtered and recrystallised from methanol-water to give 4-(4-hydroxyphenyl)-thiazole-2-carbonitrile (9.2 g); m.p. 186°-197 ° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19](=[CH:27]O)[C:20](=[O:26])[NH:21]2>>[CH2:14]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][CH:27]=[C:19]2[C:18]3[C:22](=[CH:23][CH:24]=[CH:25][C:17]=3[CH3:16])[NH:21][C:20]2=[O:26])=[CH:11][CH:12]=1)[CH3:15]
Reactant: Cc1cccc2c1C(=CO)C(=O)N2
Reactant: CCN(CC)CCOc1ccc(N)cc1
Product: CCN(CC)CCOc1ccc(NC=C2C(=O)Nc3cccc(C)c32)cc1
Yield: 22.7 %

Procedure:
In a manner similar to that describe in Example 231, 4-(2-diethylamino-ethoxy)-phenylamine (713 mg, 1.2 equiv.) and 4-methyl-3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 2.86 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (237 mg, 23%).
Reaction SMILES: [C:1]([C:3]([CH3:12])([CH2:9][CH2:10][CH3:11])[C:4](OCC)=[O:5])#[N:2].[Cl-].[Li+].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(O)C>[C:1]([C:3]([CH3:12])([CH2:9][CH2:10][CH3:11])[CH2:4][OH:5])#[N:2]
Reactant: CCCC(C)(C#N)C(=O)OCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCC(C)(C#N)CO
Temperature: 25 °C
Yield: 0.5 %

Procedure:
A solution of 2.28 g(13.5 mM) of (-)-ethyl 2-cyano-2-methylpentanoate in 22 ml of dry tetrahydrofuran was added dropwise to a mixture of 1.14 mg (27.0 mM) of anhydrous lithium chloride and 1.02 mg (27.0 mM) of sodium borohydride under stirring at room temperature. Then, 44 ml of dry ethanol was added thereto, followed by 16 hours of reaction at room temperature. After the reaction, while the reaction mixture was cooled on an ice bath, 10% citric acid was added until the pH reached 4. A white solid recipitated at this time was separated by filtration, and the solvent was removed from the filtrate by reduced pressure distillation. Then, 5 ml of distilled water was added to the product, followed by extraction with dichloromethane. The resultant organic layer was dried on sodium sulfate, followed by distilling-off of the solvent under reduced pressure and further distillation to obtain 9.35 mg(10.6 mM) of (+)-2-cyano-2-methylpentanol. Yield:78.7%, b.p. 110° C.; [α]D -0.9 degree, [α]435 -1.6 degree (c1, CH2Cl2).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][CH2:14][OH:15].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br.O>C1COCC1>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:15][CH2:14][CH2:13][CH2:12][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH3:3]
Reactant: BrCCCCCCBr
Reactant: COc1ccccc1CCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1CCCCOCCCCCCBr
Yield: 58.8 %

Procedure:
NaH (46% dispersion in oil; 1.36 g) was added portionwise to a solution of 2-methoxybenzenebutanol (5.0 g) and 1,6-dibromohexane (13.8 g) in THF (50 ml). The suspension was refluxed for 20 h and was treated cautiously with H2O (20 ml). The resulting emulsion was extracted with ER (2×50 ml) and the dried extract was evaporated to leave a yellow oil. The oil was purified on a column of silica (Merck 9385, 600 ml) [A] to give the title compound as a colourless oil (5.6 g). T.l.c. [B] Rf 0.2.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@H:9]([CH2:25][F:26])[C@@H:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:24])(=[N:20][C:21](=[O:23])[NH2:22])=[O:19])=[CH:14][CH:13]=1)[OH:11].C([O:29][C:30](=O)[CH:31]([Cl:33])[Cl:32])C>CO>[C:21]([N:20]=[S:18]([C:15]1[CH:14]=[CH:13][C:12]([C@@H:10]([OH:11])[C@H:9]([NH:8][C:30](=[O:29])[CH:31]([Cl:33])[Cl:32])[CH2:25][F:26])=[CH:17][CH:16]=1)([CH3:24])=[O:19])(=[O:23])[NH2:22]
Reactant: CCOC(=O)C(Cl)Cl
Reactant: CS(=O)(=NC(N)=O)c1ccc([C@@H](O)[C@H](N)CF)cc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=NC(N)=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.8 %

Procedure:
To a solution of (1R,2S)-2-Amino-3-fluoro-1-(4-(N-carbamoyl-S-methylsulfonimidoyl)phenyl)-propan-1-ol TFA salt (250 mg, 0.865 mmol) in Methanol (5 mL) is added TEA (0.175 mL, 1.73 mmol) followed by addition of ethyldichloroacetate (128.72 mL, 1.038 mmol) at room temperature. The resulting reaction mixture is stirred at room temperature for 16 h. Solvent is evaporated in vacuo and obtained crude is purified by combi-flash chromatography using 6% MeOH in DCM as an eluent to give 200 mg of title compound as off white solid. 1H-NMR (400 MHz, DMSO): δ 2.99 (s, 3H), 4.25-4.32 (m, 1.5H), 4.40-4.44 (m, 0.5H), 4.56-4.59 (m, 0.5H), 4.67-4.71 (m, 0.5H), 4.97 (bs, 1H), 6.05 (bs, 1H), 6.18 (m, 1H), 6.46-6.48 (m, 1H), 7.61 (d, J=7.52 Hz, 2H), 7.86 (d, J=8 Hz, 2H), 8.63-8.67 (m, 2H). LC-MS (m/z): M+H=399.8.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:18]1[CH:19]=[C:20]2[C:31]3([CH2:35][O:34][C:33]([NH2:36])=[N:32]3)[C:30]3[C:25](=[N:26][CH:27]=[C:28]([O:37][CH2:38][C:39]([O:42][CH3:43])([CH3:41])[CH3:40])[CH:29]=3)[O:24][C:21]2=[CH:22][CH:23]=1.O>C1COCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[C:7]([C:18]2[CH:19]=[C:20]3[C:31]4([CH2:35][O:34][C:33]([NH2:36])=[N:32]4)[C:30]4[C:25](=[N:26][CH:27]=[C:28]([O:37][CH2:38][C:39]([O:42][CH3:43])([CH3:40])[CH3:41])[CH:29]=4)[O:24][C:21]3=[CH:22][CH:23]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COC(C)(C)COc1cnc2c(c1)C1(COC(N)=N1)c1cc(Br)ccc1O2
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(C)(C)COc1cnc2c(c1)C1(COC(N)=N1)c1cc(-c3cccnc3F)ccc1O2

Procedure:
A vial charged with 2-fluoropyridin-3-ylboronic acid (0.156 g, 1.105 mmol), palladiumtetrakis (0.043 g, 0.037 mmol), potassium carbonate (0.255 g, 1.842 mmol), and 7-bromo-3-(2-methoxy-2-methylpropoxy)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (0.160 g, 0.368 mmol) was dissolved in 3 mL THF and 0.5 mL water and was heated to 110° C. 2 hours. The reaction mixture was diluted with EtOAc and dried over MgSO4. The organics were concentrated then purified directly by column chromatography yielding 7-(2-fluoropyridin-3-yl)-3-(2-methoxy-2-methylpropoxy)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine.
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:15][O:16][C:17]([C:19]1[S:28][C:22]2[N:23]=[C:24](Cl)[N:25]=[CH:26][C:21]=2[C:20]=1[CH3:29])=[O:18]>>[F:14][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[C:12]([NH:13][C:26]2[C:21]3[C:20]([CH3:29])=[C:19]([C:17]([O:16][CH3:15])=[O:18])[S:28][C:22]=3[N:23]=[CH:24][N:25]=2)=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: Nc1cccnc1OCC1CC1(F)F
Reactant: COC(=O)c1sc2nc(Cl)ncc2c1C
Product: COC(=O)c1sc2ncnc(Nc3cccnc3OCC3CC3(F)F)c2c1C

Procedure:
Prepared analogously to example 32.1 using 2-((2,2-Difluorocyclopropyl)methoxy)pyridin-3-amine (200 mg) and chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (194 mg).
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.OS(O)(=O)=O.O=S(=O)=O>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([NH2:6])=[CH:8][C:9]=1[S:1]([OH:3])(=[O:5])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(N)cc1
Agent: O=S(=O)=O
Product: Cc1ccc(N)cc1S(=O)(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
107 parts of fused p-toluidine are added dropwise over 30 minutes to 183 parts of 100% sulfuric acid, while keeping the temperature at 75°-80° C. After stirring for 15 minutes the p-toluidine is completely dissolved. This sulfuric acid solution is then run into 260 parts of 66% oleum over 30 minutes, while keeping the temperature at 40°-50° C. by cooling with an ice bath. Stirring is continued for 30 minutes at 45°-50° C., after which time no more educt can be detected by HPLC. The batch is poured into 500 parts of ice/water and the precipitated 4-methylaniline-3-sulfonic acid is filtered with suction and washed with 500 parts of ice/water, affording 248 parts of moist 70.0% 4-methylaniline-3-sulfonic acid, corresponding to a yield of 93%, based on p-toluidine. No more p-toluidine and no more 4-methylaniline-2-sulfonic acid is detectable by HPLC (<0.1%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[CH:7]([NH:22][CH:23]=[O:24])[CH2:6][CH:5]1[CH3:25])(=[O:3])[CH3:2].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(O)(=O)C.C([O-])(O)=O.[Na+]>ClC(Cl)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:18][CH:19]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:22][CH:23]=[O:24])[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C=O)cc3)cc2C(NC=O)CC1C
Reactant: C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(=O)N1c2ccc(-c3ccc(CN4CCCCC4)cc3)cc2[C@H](NC=O)C[C@@H]1C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a solution of [1-acetyl-6-(4-formylphenyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]formamide (for a preparation see Intermediate 48) (95 g, 0.25 mol) and piperidine (31 g, 0.3 mol) in solution in dichloroethane (2 L) were added at room temperature triacetoxysodiumborohydride (70 g, 0.33 mol) and acetic acid (33 g). After stirring 2 hours a t.l.c monitoring indicated the completion of the reaction and the mixture was poured into a saturated solution of NaHCO3. The organic phase was extracted after addition of DCM (500 mL) and washed with brine (100 mL), dried over Na2SO4, filtered and evaporated to dryness. Trituration of the residue in a mixture of DCM/hexane afforded the title compound (109 g, 95.6%) as an off white solid. LC/MS (Method E) m/z 406 [M+H]+, Rt=2.22 min;
Reaction SMILES: S1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].Cl.NCCC(OC)=[O:19]>>[O:19]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CCNCc1cccs1
Reactant: COC(=O)CCN
Agent: Cl
Product: COC(=O)CCNCc1ccco1

Procedure:
Methyl 3-[(2-furanylmethyl)amino]propanoate (22) was prepared in the manner methyl 3-[(2-thienylmethyl)amino]propanoate (15) was prepared, as described above in Example 15, on a 6.5 mmol scale from methyl β-alaninate hydrochloride and furrural to yield 0.28 g (28%) of product.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]2[CH2:19][CH2:20][N:21]=[C:3]12.[C:22]([NH:29][C@H:30]([C:38](O)=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.C(N(CC)CC)C>[C:25]([O:24][C:22]([NH:29][C@@H:30]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:38]([NH:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]2[CH2:19][CH2:20][N:21]=[C:3]12)=[O:39])=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: NC1N=C(c2ccccc2)c2ccccc2N2CCN=C12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N2CCN=C12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Crude 4(R,S)-amino-2,4-dihydro-6-phenyl-1H-imidazo-[1,2-a]-[1,4]-benzodiazepine (1.37 g), Boc-L-phenyl-alanine (1.37 g, 5.17 mmole), 1-hydroxybenzotriazole (0.07 g, 5.17 mmole), and 1-ethyl-3-(3-dimethylaminopropyl)carbodimide hydrochloride (0.99 g, 5.17 mmole) are combined in DMF (30 mL) and stirred at room temperature. The pH of the reaction mixture is adjusted to 8.5 with triethylamine, and after 1/2 hour, the DMF is removed in vacuo, and the residue partitioned between ethyl acetate and 10% citric acid solution (10 mL). The layers are separated and the organic phase is washed with sodium bicarbonate solution (NaHCO3, saturated). The combined organic layers are washed with brine, dried over Na2SO4, filtered, and evaporated to dryness in vacuo to give the title compound as a mixture of diastereomers.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)=[O:5].[CH2:19](OC(OCC)(OCC)C)[CH3:20]>O>[CH3:19][C:20]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=2)[C:4](=[O:5])[C:3]2[C:2](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:1]=1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)c(Cl)c1
Reactant: CCOC(C)(OCC)OCC
Solvent: O
Product: Cc1nc2ccccc2c(=O)n1-c1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 62 (2.8 g, 0.009 mol) and 1,1,1-triethoxy-ethane (5.2 mL, 0.028 mol) were heated for 5 hours. The reaction mixture was poured into water, filtered, washed with water yielding compound 63 (55%). After recrystallization from EtOH, the material was used in next step without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:39]=[CH:40][C:41]=1[F:42])[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:37][CH3:38])=[CH:20][C:21]=2[O:23][CH2:24][C@@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2C(OC(C)(C)C)=O)[N:16]=[CH:15][N:14]=1.N>CO>[Cl:8][C:9]1[CH:10]=[C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:37][CH3:38])=[CH:20][C:21]=3[O:23][CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][NH:26]3)[N:16]=[CH:15][N:14]=2)[CH:39]=[CH:40][C:41]=1[F:42]
Reactant: COc1cc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1cc(OC[C@@H]2CCCN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (25 ml) was added in one portion to tert-butyl (2S)-2-[({4-[3-chloro-4-fluoro-anilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidine-1-carboxylate (1.6 g) and the solution was stirred at room temperature for 1 hour 30 minutes. The solution was then concentrated in vacuo and azeotroped three times with ether to leave an orange oil. 7N Ammonia in methanol (5 ml) was added and the mixture was stirred for 10 minutes. The mixture was then concentrated in vacuo to leave an orange oil and purified by column chromatography using 0-10% methanol in DCM as eluent to give N-(3-chloro-4-fluorophenyl)-7-methoxy-5-[(2S)-pyrrolidin-2-ylmethoxy]-quinazolin-4-amine as a light yellow solid (1.15 g, 75% over two steps); Mass spectrum MH+ 403.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO>CN(C)C=O.[Cu]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][N:7]=1
Reactant: Brc1ccccc1
Reactant: Cc1ccc(O)cn1
Agent: [Cu]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-methylpyridin-3-ol (25.2 g, 231 mmol) in N,N-dimethylformamide (100 ml) was added potassium tert-butoxide (25.9 g, 231 mmol), and the mixture was stirred at room temperature for 1 hr. The reaction solution was evaporated under reduced pressure and diluted with N,N-dimethylformamide (100 ml). A copper powder (3.7 g, 58 mmol) and bromobenzene (36.3 g, 231 mmol) were added, and the mixture was stirred at 120° C. overnight. Methanol was added to the reaction solution and insoluble material was filtered off using celite. The filtrate was diluted with water (500 ml) and the mixture was extracted with ethyl acetate (500 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the objective substance (31 g, 72%).
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]1[NH:7][CH:6](O)[C@H:5]([OH:9])[C@@H:4]([OH:10])[C@@H:3]1[OH:11].[CH2:13](O)C.C=O>O.[Pd]>[CH3:13][N:7]1[C@H:2]([CH2:1][OH:12])[C@@H:3]([OH:11])[C@H:4]([OH:10])[C@@H:5]([OH:9])[CH2:6]1
Reactant: CCO
Reactant: OC[C@H]1NC(O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Pd]
Agent: C=O
Solvent: O
Product: CN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO
Yield: 81 %

Procedure:
179 mg of nojirimycin is dissolved in 20 ml of a 50% water-containing ethanol, followed by adding 1 ml of formalin, adding 100 mg of palladium on carbon catalyst and carrying out a catalytic reduction at ordinary temperature and under atmospheric pressure. The subsequent treatments are carried out in the same manner as in Example 2 to obtain 144 mg (81%) of N-methyl moranoline.
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][C:17]([OH:19])=[O:18])[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][CH2:5][CH2:4]1)[CH3:2].[H-].[Na+].O1CCC[CH2:23]1>>[CH2:1]([C:3]1([CH2:16][C:17]([OH:19])=[O:18])[C:15]2[N:14]([CH3:23])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(CC(=O)O)CCCc2c1[nH]c1ccccc21
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CCC1(CC(=O)O)CCCc2c1n(C)c1ccccc21
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
A solution of the compound of formula 5, 1-ethyl 1,2,3,4-tetrahydrocarbazole-1-acetic acid (2.0 g, 7.4 mmole), described in Example 56, in dry tetrahydrofuran (THF, 50 ml) is added dropwise under nitrogen to a stirred suspension of sodium hydride (1 g, 50% dispersion, 0.02 mole) in dry-THF (25 ml). The reaction mixture is stirred for 15 minutes after the end of the addition. The lower alkyl halide, methyliodide (1.5 ml), is added dropwise. The reaction mixture is heated initially to 40° C. then stirred for one hour at room temperature. A small amount of water is added cautiously to destroy excess sodium hydride followed by the addition of more water (50 ml). The mixture is washed with ether then rendered acidic and extracted with ether. The ether extract is dried (MgSO4), treated with charcoal and filtered through diatomaceous earth. Evaporation of the ether gives an oil which on recrystallization from benzene affords the title compound, mp 140°-143° C., nmr (CDCl3) δ 0.72 (t, J = 7, 3H), 1.9 (m, 6H), 2.75 (m, 4H), 3.76 (s, 3H), 7.2 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:10]([F:20])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>C1COCC1.CO.O>[Cl:1][C:2]1[C:11]([CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])=[C:10]([F:20])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(F)c(CNC(=O)C(C)(C)C)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C(=O)NCc1c(F)ccc(C(=O)O)c1Cl
Yield: 74.9 %

Procedure:
The title compound was prepared following the procedure described in step-3 of Intermediate-2 using methyl 2-chloro-4-fluoro-3-(pivalamidomethyl)benzoate (350 mg, 1.16 mmol) in THF:MeOH:H2O (3:2:1; 6 mL) and NaOH (93 mg, 2.32 mmol) to afford 250 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 12.55 (br s, 1H), 7.78 (m, 2H), 7.32-7.26 (t, J=8.7 Hz, 1H), 4.38 (d, J=4.5 Hz, 2H), 1.07 (s, 9H).