Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[CH:13]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[C:14]([CH:17]=[O:18])=[CH:15][S:16][C@H:11]12)=[O:8].O1CCC[CH2:38]1.[Br].C[Mg].Cl>C(OCC)C.C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[CH:13]([C:19]([O:21][CH:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:20])[C:14]([CH:17]([OH:18])[CH3:38])=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: C1CCOC1
Reactant: O=CC1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Agent: C[Mg]
Agent: Cl
Agent: [Br]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(O)C1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Yield: 63.9 %

Procedure:
To a cooled (-73°), stirred solution of 5.19 g. of benzhydryl 7-(2-thienylacetamido)-3-formyl-2-cephem-4-carboxylate in 60 ml. of tetrahydrofuran under an argon atmosphere was added 10 ml. of a cold (-10°) 3 molar solution of methylmagnesium bromine in ethyl ether. The reaction mixture was stirred with cooling for 4 minutes after which time 10 ml. of 1N.HCl was added. The solution was then allowed to warm to 0° in an ice bath. The reaction mixture was transferred to separatory funnel with the aid of cold ethyl acetate and 1N.HCl. The organic layer was separated and washed with cold 1N.HCl (2X) and brine (2X), and dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness gave a crude product which was chromatographed on silica gel using a toluene-ethyl acetate gradient to give 3.40 g. (63.9 percent) of the title product as a mixture of diastereoisomeric carbinols. Although both isomers have approximately the same rf value, careful fractionation of the column resulted in the isolation of the pure isomers. Isomer I (that which was eluded from the column first) crystallized from methylene chloride/hexane to provide white crystals (m.p. 133.5°-134.5°): ir (CHCl3) 1782 cm-1 (lactam C = O); nmr (CDCl3) δ1.17 (d, 3, J = 6.0 Hz,--CH(OH)CH3), 2.85 (broad s, 1, --OH), 3.79 (s, 2, side chain CH2), 4.27 (m, 1,--CH(OH)CH3), 5.10 (s, 1, C4 --H), 5.13 (d, 1, J = 4.0 Hz, C6 --H), 5.49 (q, 1, J = 4.0 and 8.0 Hz, C7 --H) and 6.31 (s, 1, C2 --H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9]C)=O.[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH2:20]>>[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH:20][C:7]([C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([OH:1])[CH:11]=1)[C:12]([O:14][CH3:15])=[O:13])=[O:9]
Reactant: CN(C)CCN
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Product: COC(=O)c1cc(O)cc(C(=O)NCCN(C)C)c1
Temperature: 100 °C

Procedure:
A mixture of dimethyl 5-hydroxyisophthalate (2 g) and N,N-dimethylethylenediamine (1.04 ml) was heated at 100° C. for 2 hours. After being cooled to room temperature, the reaction mixture was evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of chloform, methanol and triethylamine (100:10:1) to give methyl 3-[(2-dimethylaminoethyl)carbamoyl]-5-hydroxybenzoate (1.11 g).
Reaction SMILES: [Si]([O:8][C@@H:9]([C@H:11]1[C@H:14]([CH2:15][C:16]([C:18]2[CH:22]=[C:21]([CH2:23][CH3:24])[N:20]([CH3:25])[N:19]=2)=O)[N:13]([C:26](=P(CCCC)(CCCC)CCCC)[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])[C:12]1=[O:46])[CH3:10])(C(C)(C)C)(C)C>C1(C)C=CC=CC=1>[CH2:23]([C:21]1[N:20]([CH3:25])[N:19]=[C:18]([C:16]2[CH2:15][C@@H:14]3[C@@H:11]([C@H:9]([OH:8])[CH3:10])[C:12](=[O:46])[N:13]3[C:26]=2[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])[CH:22]=1)[CH3:24]
Reactant: C=CCOC(=O)C(N1C(=O)[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@@H]1CC(=O)c1cc(CC)n(C)n1)=P(CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=CCOC(=O)C1=C(c2cc(CC)n(C)n2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12

Procedure:
Allyl 2-{(3R,4S)-3-[(R)-1-t-Butyldimethylsilyloxyethyl]-4-[2-(5-ethyl-1-methylpyrazol-3-yl)-2-oxoethyl]azetidin-2-on-1-yl }-2-(tri-n-butylphosphoranylidene)acetate (1.94 g) in toluene (650 ml; 3 mgs/ml) was heated under reflux for a total of 7 h. T.l.c. analysis showed only a small amount of unreacted starting material. The solution was concentrated and purified by silica gel chromatography, eluting with 5% then 10% acetone/ethyl acetate. The product was obtained as an off white, crystalline solid. Trituration with ether, followed by filtration gave the title compound as a colourless crystalline solid, (356 mg; 30%); (Found: M+, 345.1689. C18H23N3O4 requires M 345.1689); nmax (CH2Cl2) 3603, 1774, 1716, 1599(w) and 1542(w) cm-1 ; dH (CDCl3) 1.28 (3H, t, J7.4 Hz), 1.36 (3H, d, J6.3 Hz), 1.85 (1H, d, J5.0 Hz), 2.61 (2H, d, J7.4 Hz), 3.19 (1H, dd, J2.8,6.7 Hz), 3.27 (1H, dd, J9.0,18.5 Hz), 3.59 (1H, dd, J9.8,18.5 Hz), 3.84 (3H, s), 4.24 (2H, m), 4.79 (2H, m), 5.27 (1H, m), 5.46 (1H, m), 6.01 (1H, m) and 7.02 (1H, s).
Reaction SMILES: Cl.[C:2]1([C@H:12]([NH:14][C@H:15]2[CH2:19][CH2:18][N:17]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=3)[CH2:16]2)[CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:29](Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C)C=O>[C:24]([C:23]1[CH:27]=[CH:28][C:20]([N:17]2[CH2:18][CH2:19][C@H:15]([NH:14][C@@H:12]([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=[CH:4][CH:3]=3)[CH3:13])[CH2:16]2)=[CH:21][CH:22]=1)(=[O:26])[CH3:29]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@@H](N[C@H]1CCN(c2ccc(C(=O)O)cc2)C1)c1cccc2ccccc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)c1ccc(N2CC[C@H](N[C@H](C)c3cccc4ccccc34)C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 50 mg of 4-[(S)-3-[(R)-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzoic acid hydrochloride (the compound obtained in Example 3.001) in 5 ml of methylene chloride (MeOH free) was added dropwise 43 μl of oxalyl chloride, and then, several drops of dimethylformamide were added to the mixture, and the resulting mixture was stirred under room temperature for 16 hours. The solvent was removed from the reaction mixture to obtain the residue. (2) To the compound obtained as mentioned above were added dimethylamine (82 μl of 2M THF solution) and 10 ml of methylene chloride to dissolve them, 70.2 μl of triethylamine was added to the mixture, and the mixture was stirred under room temperature for 16 hours. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated, and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate 7:1→0:1) to obtain 22.4 mg of N,N-dimethyl-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzamide. (3) To a solution of 22.4 mg of N,N-dimethyl-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]-benzamide dissolved in 1 ml of methylene chloride was added dropwise 3 ml of a solution of 4M hydrochloric acid in dioxane, and the mixture was stirred for a while. The reaction mixture was concentrated, t-butanol was added to the residue to dissolve the same, and freeze-dried to obtain 22.9 mg of N,N-dimethyl-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzamide hydrochloride (Example 3.012 in the following Table A3).
Reaction SMILES: [F:1][CH:2]([O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[C:18]([CH2:22][CH3:23])([CH2:19]2)[CH2:17][CH2:16][C:15](=[O:24])[CH:14]=3)=[C:11]([Cl:25])[C:10]=1[Cl:26])[C:3]([O:5]CC)=[O:4].C(=O)(O)[O-].[Na+]>C(O)C.O>[F:1][CH:2]([O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[C:18]([CH2:22][CH3:23])([CH2:19]2)[CH2:17][CH2:16][C:15](=[O:24])[CH:14]=3)=[C:11]([Cl:25])[C:10]=1[Cl:26])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(F)Oc1cc2c(c(Cl)c1Cl)C1=CC(=O)CCC1(CC)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCC12CCC(=O)C=C1c1c(cc(OC(F)C(=O)O)c(Cl)c1Cl)C2
Reaction time: 0.25 h

Procedure:
Ethyl fluoro[(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetate (4.01 gm., 0.02 mole) is dissolved in ethanol (75 ml.) and treated with a solution of sodium bicarbonate (3.36 gm., 0.04 mole) in water (150 ml.). The mixture is heated and stirred on a steam bath for 15 minutes and then concentrated in vacuo to a volume of 50 ml. The residual solution is diluted with water (50 ml.) and acidified to Congo red test paper with 6 normal hydrochloric acid. The precipitate that forms is removed by filtration, washed with water and dried. The product is sufficiently pure for use but it may be further purified by recrystallization from a mixture of acetic acid and water to produce pure fluoro[(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetic acid.
Reaction SMILES: [CH:1]([NH:4][N:5]=[C:6]([NH2:8])[CH3:7])([CH3:3])[CH3:2].[CH2:9](OC(OCC)OCC)C.C(N(CC)CC)C.O1CCCC1>C(O)C>[CH:1]([N:4]1[CH:9]=[N:8][C:6]([CH3:7])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(OCC)OCC
Reactant: CC(N)=NNC(C)C
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ncn(C(C)C)n1

Procedure:
N′-isopropylacetohydrazonamide 6 was treated with triethylorthoformate in ethanol, followed by triethylamine and tetrahydrofuran to give 7 (CAS Reg. No. 1401305-30-3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)[CH3:2].[H][H]>C1COCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCN(c2ccc(N)cn2)CC1

Procedure:
A mixture of intermediate (1) (0.0102 mol) in THF (50 ml) was hydrogenated with palladium on carbon (10%; 0.3 g) as a catalyst for 30 minutes at a temperature of 50° C. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated, yielding (5′-amino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid ethyl ester (intermediate 2).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]#[C:11][C:12]2[C:13]([CH3:24])=[N:14][CH:15]=[N:16][C:17]=2[N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:5][N:4]=1.[CH3:25][N:26]1[C:30]([S:31](Cl)(=[O:33])=[O:32])=[CH:29][CH:28]=[N:27]1.N1C=CC=CC=1.O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([NH:9][S:31]([C:30]2[N:26]([CH3:25])[N:27]=[CH:28][CH:29]=2)(=[O:33])=[O:32])=[CH:7][C:6]([C:10]#[C:11][C:12]2[C:13]([CH3:24])=[N:14][CH:15]=[N:16][C:17]=2[N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[CH:5][N:4]=1
Reactant: Cn1nccc1S(=O)(=O)Cl
Reactant: COc1ncc(C#Cc2c(C)ncnc2N2CCOCC2)cc1N
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ncc(C#Cc2c(C)ncnc2N2CCOCC2)cc1NS(=O)(=O)c1ccnn1C
Temperature: 25 °C

Procedure:
To 100 mg (0.31 mmol) 2-Methoxy-5-(4-methyl-6-morpholin-4-yl-pyrimidin-5-ylethynyl)-pyridin-3-ylamine (E-9) in 5 mL DCM is added 111 mg (0.61 mmol) 1-methyl-1H-pyrazole-5-sulfonyl chloride and 72 μL (0.97 mmol) pyridine and the reaction mixture is stirred over night at RT. Water (2 mL) is added, the mixture is shaken for five minutes, the aqueous phase is separated and is extracted three times with 4 mL DCM. The combined organic phases are dried over MgSO4 and concentrated under reduced pressure. The crude product is purified by RP chromatography (C18, 20-80% ACN in water containing 1% formic acid). Yield: 32 mg (22%). HPLC-MS: M+H=470; tR=0.78 min.
Reaction SMILES: [Br:1][CH2:2][C:3]1[N:4]=[N:5][C:6]([Cl:9])=[CH:7][CH:8]=1.[NH3:10].CO>CO>[BrH:1].[Cl:9][C:6]1[N:5]=[N:4][C:3]([CH2:2][NH2:10])=[CH:8][CH:7]=1
Reactant: Clc1ccc(CBr)nn1
Reactant: N
Solvent: CO
Product: Br
Product: NCc1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of compound 10B (2.08 g, 10 mmol) in methanol (50 mL) was added into a pre-saturated ammonia/methanol solution (200 mL) at 0° C. The reaction solution was sealed and stirred at room temperature overnight. The methanol solution was concentrated and dried in vacuum to give 2.2 g of crude product (10C) as hydrobromide salt, which was used in next step without further purification. ESI-MS:m/z 144.1 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:37])=[C:23]([O:25][C@@H:26]([C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[C:30]([F:35])[C:29]=4[Cl:36])[CH3:27])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[O:38]1CCOCC1>CO>[C:26]([OH:38])(=[O:25])[CH3:28].[Cl:36][C:29]1[C:30]([F:35])=[CH:31][CH:32]=[C:33]([Cl:34])[C:28]=1[C@H:26]([O:25][C:23]1[C:22]([NH2:37])=[N:21][CH:20]=[C:19]([C:17]2[CH:16]=[N:15][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:18]=2)[CH:24]=1)[CH3:27]
Reactant: C1COCCO1
Reactant: C[C@@H](Oc1cc(-c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Solvent: CO
Product: CC(=O)O
Product: C[C@@H](Oc1cc(-c2cnn(C3CCNCC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 4—(4—{6—amino—5—[(R)—1—(2,6—dichloro—3—fluoro—phenyl)—ethoxy]—pyridin—3—yl}—pyrazol—1—yl)—piperidine—1—carboxylic acid tert—butyl ester (566.7 mg, 1.03 mmol) in methanol (5 mL) or dichlorometha[pi]e (30 mL) was added 4N HCI/dioxane (15 mL). The solution was stirred for about 1 hour or until the de-protection was complete. The solvents were evaporated and the residue was dissolved in methanol and purified on a reversed phase C-18 preparative HPLC eluting with acetonitrile/water with 0.1% acetic acid from 5% to 30% with a linear gradient. After lyophilization, 3—[(R)—1 —(2,6—dichloro—3—fluoro—phenyl)—ethoxy]—5—(1—piperidin—4—yl—1 H—pyrazol—4—yl)—pyridin—2 —ylamine acetate was obtained as a white solid (410 mg, 78% yield, 100% HPLC purity, 96.4% ee). 1H NMR (DMSO—d6, 400 MHz)δ7.84 (s, 1H), 7.68 (d, 1H), 7.50 (dd, 1H), 7.46 (s, 1H), 7.37 (t, 1H), 6.83 (d, 1H), 6.02 (q, 1H), 5.57 (bs, 2H), 4.09 (m, 1H), 2.98 (m, 2H), 2.53 (m, 2H), 1.88 (m, 2H), 1.82 (s, 3H), 1.73 (d, 3H), 1.70 (m, 2H). MS m/e 450 (M+1)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([N:18]1[CH2:24][CH2:23][CH2:22][C@H:19]1[CH2:20][OH:21])([O:13]C(C)(C)C)=[O:12].C(N(CC)CC)C>ClCCl>[CH:20]([C@@H:19]1[CH2:22][CH2:23][CH2:24][N:18]1[C:11]([OH:13])=[O:12])=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C[C@@H]1CCCN1C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 2 L, 3-necked round bottomed flask equipped with an overhead stirrer and a N2 inlet was charged with a solution of oxalyl chloride (130 mL, 0.26 mol) in dichloromethane (250 mL). The solution was cooled to −78° C., and a solution of DMSO (20 mL, 0.28 mol) in dichloromethane (30 mL) was added dropwise. After 30 minutes, a solution of (S)—N-Boc-prolinol, Int-7a (40 g, 0.20 mol) in dichloromethane (200 mL) was added dropwise. After 30 minutes, triethylamine (140 mL, 1.00 mol) was added to the solution, and the flask was transferred to an ice/water bath and allowed to stir for another 30 minutes. The reaction mixture was diluted with dichloromethane (200 mL) and washed successively with H2O, 1M HCl, saturated NaHCO3, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to provide crude (S)-2-formyl-pyrrolidine-1-carboxylic acid tort-butyl ester, Int-7b (40 g) as oil, which was used without further purification.
Reaction SMILES: [C:1]1([C:11]([N:13]2[C:17](=[O:18])[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:15][C:14]2=[O:31])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C[CH:35](I)[CH:36]([CH3:38])[CH3:37].C(OCC)(=O)C>CN(C=O)C>[CH2:35]([N:15]1[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17](=[O:18])[N:13]([C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:12])[C:14]1=[O:31])[CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)C(C)I
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1C(=O)c1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CN1C(=O)N(C(=O)c2cccc3ccccc23)C(=O)C1(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
3-Naphthylcarbonyl-5,5-diphenylimidazolidine-2,4-dione (51 mg) was dissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) was added. Then, methylisobutyl iodide (23 mg) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (9.5 mL) was added to the reaction solution, separated out white precipitates were filtered, and the filtrate was concentrated and purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 20 mg of white crystals.
Reaction SMILES: B(O)O.Br[C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[NH:13]1[C:17](B(O)O)=[CH:16][CH:15]=[N:14]1>>[NH:13]1[C:17]([C:5]2[N:12]=[CH:11][CH:10]=[CH:9][C:6]=2[CH:7]=[O:8])=[CH:16][CH:15]=[N:14]1
Reactant: OB(O)c1ccn[nH]1
Reactant: O=Cc1cccnc1Br
Agent: OBO
Product: O=Cc1cccnc1-c1ccn[nH]1

Procedure:
2-(1H-pyrazol-5-yl)nicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and (1H-pyrazol-5-yl)boronic acid (60 mg, 93.2 mg theoretical, 64.4%). LC-MS m/z 174.2 (M+1).
Reaction SMILES: [OH: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.[H-].[Na+].Cl[C:18]1[C:19]2[N:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=2[N:21]=[CH:22][N:23]=1>CN(C=O)C.O>[Cl:28][C:26]1[CH:25]=[CH:24][C:20]2[N:21]=[CH:22][N:23]=[C:18]([O:1][CH:2]3[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)[C:19]=2[N:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3ccc(Cl)nc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (0.201 g, 1.000 mmol) in DMF (5.00 ml) was added NaH (0.052 g, 55% dispersion in mineral oil, 1.20 mmol) at 0° C. After stirring for 30 min at room temperature, the reaction mixture was cooled to 0° C. and 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.2 g, 1.000 mmol) was added to the mixture. After stirring for 3 hours at room temperature, the reaction mixture was diluted with water, and extracted with EtOAc. The organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=5:1) to give tert-butyl 4-(6-chloropyrido[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxylate (0.236 g, 65%) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.49 (9H, s), 1.91-1.99 (2H, m), 2.10-2.13 (2H, m), 3.21-3.27 (2H, m), 3.83-3.97 (2H, m), 5.55-5.62 (1H, m), 7.74 (1H, d, J=8.8 Hz), 8.19 (1H, d, J=8.8 Hz), 8.41 (1H, s).
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:34]([O:41][C:42]1[C:49]([F:50])=[CH:48][C:45]([CH:46]=O)=[CH:44][C:43]=1[F:51])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>C1COCC1>[CH2:34]([O:41][C:42]1[C:49]([F:50])=[CH:48][C:45]([CH2:46][CH:2]=[O:3])=[CH:44][C:43]=1[F:51])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc(F)c(OCc2ccccc2)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=CCc1cc(F)c(OCc2ccccc2)c(F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 20.3 %

Procedure:
After methoxymethyl triphenyl phosphonium chloride (1.04 g, 3.02 mmol) was dissolved in anhydrous THF (9 mL), LiHMDS 1.0M THF solution (3 mL, 3.02 mmol) was added thereto at 0° C., and the mixture was stirred for 15 minutes. 4-Benzyloxy-3,5-difluoro-benzaldehyde (0.50 g, 2.01 mmol) obtained in Step B of Preparation Example 2 was dissolved in anhydrous THF (6 mL), and the solution was added thereto. The mixture was stirred at room temperature for 3 hours. After the termination of the reaction, the reactant was added with water, and then extracted with EtOAc. The organic layer was separated, dried with MgSO4, concentrated under reduced pressure, and then purified by column chromatography (eluent, EtOAc/Hex=1/5). After the obtained product was dissolved in THF (7.68 mL), 2N HCl (3.84 mL) was added thereto, and the mixture was stirred at 70° C. for 5 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure, added with water, and then extracted with EtOAc. The organic layer was separated, dried with MgSO4, concentrated under reduced pressure, and the purified by column chromatography (eluent, EtOAc/Hex=1/5) to obtain the title compound (0.107 g, 20%).
Reaction SMILES: CS[C:3]1[CH:4]=[CH:5][C:6]([Br:9])=[N:7][CH:8]=1.Cl[C:11]1C=CC=C(C(OO)=O)C=1.[O-:21][S:22]([O-:24])=O.[Na+].[Na+]>C(Cl)Cl>[CH3:11][S:22]([C:3]1[CH:4]=[CH:5][C:6]([Br:9])=[N:7][CH:8]=1)(=[O:24])=[O:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(Br)nc1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 5-methylthio-2-bromopyridine from step 1 (18.9 g, 0.093 mol) in methylene chloride (600 mL), m-chloroperbenzoic acid (48 g, 0.19 mol) was added portionwise at 0° C. and the mixture was stirred for 2 hours at room temperature. Aqueous saturated Na2SO3 (200 mL) was added and stirred for 15 minutes and organic phase was separated and washed with aqueous saturated sodium bicarbonate (NaHCO3) (200 mL), dried over magnesium sulfate (MgSO4), and concentrated in vacuo gave the title compound (20.9 g, 96%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:27]=[CH:26][C:9]([C:10]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][N:15]3[CH:23]=[CH:24][CH:25]=[C:14]3[CH2:13]2)=[O:11])=[CH:8][CH:7]=1.[CH2:28]=O.[CH3:30][NH:31][CH3:32].CO>O1CCCC1>[CH3:30][N:31]([CH2:28][C:23]1[N:15]2[C:14]([CH2:13][N:12]([C:10](=[O:11])[C:9]3[CH:8]=[CH:7][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[CH:27][CH:26]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16]2)=[CH:25][CH:24]=1)[CH3:32]
Reactant: CNC
Reactant: O=C(c1ccc(-c2cccs2)cc1)N1Cc2cccn2Cc2ccccc21
Reactant: C=O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)Cc1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3cccs3)cc1)C2

Procedure:
A mixture of 400 mg of 10,11-dihydro-10-[4-(2-thienyl)benzoyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 10 ml of 40% formalin and 10 ml of 40% N,N-dimethylamine in 50 ml of 1:1 tetrahydrofuran:methyl alcohol is refluxed for 3 hours. The reaction mixture is evaporated in vacuo to a residue which is extracted with chloroform, washed with water, dried over Na2SO4, filtered and the filtrate evaporated in vacuo to give a residue which is purified by column chromatography on silica gel by elution with 30% ethyl acetate-hexane to give 300 mg of the desired product as a solid. Mass spectrum: M+H:428.