Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[S:9][N:8]=1.[ClH:19].[CH3:20][O:21][C:22]1[C:30]2[O:29][C:28](C)(C)C[C:26]=2[C:25]([C:33]2[C@@H:42]3[C@@H:37]([CH2:38][CH:39]=[CH:40][CH2:41]3)[C:36](=[O:43])[N:35]([C:44]3[CH:49]=[CH:48][C:47]([C:50](N4CCN(C/C=C/C5C=CC=CC=5)CC4)=[O:51])=[CH:46][CH:45]=3)[N:34]=2)=[CH:24][CH:23]=1>>[ClH:19].[CH3:28][O:29][C:30]1[CH:26]=[C:25]([C:33]2[C@@H:42]3[C@@H:37]([CH2:38][CH:39]=[CH:40][CH2:41]3)[C:36](=[O:43])[N:35]([C:44]3[CH:45]=[CH:46][C:47]([C:50]([N:15]4[CH2:16][CH2:17][N:12]([C:10]5[S:9][N:8]=[C:7]([C:2]6[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=6[CH3:18])[N:11]=5)[CH2:13][CH2:14]4)=[O:51])=[CH:48][CH:49]=3)[N:34]=2)[CH:24]=[CH:23][C:22]=1[O:21][CH3:20]
Reactant: Cc1ccccc1-c1nsc(N2CCNCC2)n1
Reactant: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(C/C=C/c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2
Agent: Cl
Product: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(c5nc(-c6ccccc6C)ns5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from intermediate product A1 and 1-(3-o-tolyl-1,2,4-thiadiazol-5-yl)-piperazine as described for compound 8. M.p. 115–118° C.
Reaction SMILES: Cl.[CH3:2][O:3][CH:4]1[CH2:7][NH:6][CH2:5]1.Br[C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[N:13][CH:14]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>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].O1CCOCC1>[CH3:2][O:3][CH:4]1[CH2:7][N:6]([C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[N:13][CH:14]=2)[CH2:5]1
Reactant: COC1CNC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: C1COCCO1
Product: COC1CN(c2ccc([N+](=O)[O-])nc2)C1
Temperature: 100 °C
Yield: 96.3 %

Procedure:
A 100-mL round bottomed flask was equipped with a reflux condenser was charged with 3-methoxyazetidine hydrochloride (1.0 g, 8.09 mmol), 5-bromo-2-nitropyridine (1.97 g, 9.71 mmol), Pd2(dba)3 (370.1 mg, 0.404 mmol), Xantphos (467.6 mg, 0.809 mmol), Cs2CO3 (7.9 g, 24.3 mmol), and dioxane (50 mL). After bubbling nitrogen through the reaction mixture for 20 minutes, it was heated at 100° C. under N2 protection for 3 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. It was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 323a as a yellow solid (1.63 g, 96%). MS-ESI: [M+H]+ 210.2
Reaction SMILES: [CH3:1][Si:2]([CH3:10])([CH3:9])[O:3][C:4]([CH3:8])([C:6]#[CH:7])[CH3:5].[Li]CCCC.[C:16]([C:18]1[CH:29]=[CH:28][C:21]([C:22](N(OC)C)=[O:23])=[CH:20][CH:19]=1)#[N:17]>C1COCC1>[CH3:5][C:4]([O:3][Si:2]([CH3:10])([CH3:9])[CH3:1])([CH3:8])[C:6]#[C:7][C:22]([C:21]1[CH:28]=[CH:29][C:18]([C:16]#[N:17])=[CH:19][CH:20]=1)=[O:23]
Reactant: C#CC(C)(C)O[Si](C)(C)C
Reactant: CON(C)C(=O)c1ccc(C#N)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C#CC(=O)c1ccc(C#N)cc1)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 133.1 %

Procedure:
To a −78° C. stirred solution of trimethyl (2-methylbut-3-yn-2-yloxy) silane (3.3 g, 20.00 mmol) in dry THF (45 mL), n-BuLi (4.1 mL, 9.00 mmol, 1.6 M in hexane) was added dropwise over 10 minutes under an inert atmosphere. The reaction mixture was stirred for 30 min at −78° C., and then a solution of 4-cyano-N-methoxy-N-methylbenzamide (2.0 g, 10.00 mmol) in dry THF (15 mL) was added to the reaction mixture and stirring was continued for an additional 1 h at −78° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 15% EtOAc in hexanes to afford 4-(4-methyl-4-(trimethylsilyloxy)pent-2-ynoyl)benzonitrile (3.8 g, 68%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=[O:9])[N:5]=[CH:4][CH:3]=1.C1C(=O)N([Cl:18])C(=O)C1>CC#N>[Cl:18][C:3]1[CH:4]=[N:5][N:6]([CH2:7][C:8]([OH:10])=[O:9])[C:2]=1[CH3:1]
Reactant: Cc1ccnn1CC(=O)O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Cc1c(Cl)cnn1CC(=O)O
Temperature: 80 °C
Yield: 99.7 %

Procedure:
A mixture of 2-(5-methylpyrazol-1-yl)acetic acid (0.700 g, 5 mmol) and NCS (0.668 g, 5 mmol) in CH3CN (10 mL) was heated at 80° C. for 1.5 hrs. It was then cooled to rt, evaporated in vacuo, and purified by flash chromatography (SiO2, with a gradient elution of 0-20% MeOH/CH2Cl2) to afford 2-(4-chloro-5-methylpyrazol-1-yl)acetic acid (0.870 g, 100%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:7]2[C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2].[Br:19]N1C(=O)CCC1=O>>[C:1]([C:4]1[C:5]([Br:19])=[C:6]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:7]2[C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(-c2cccnc2)n2c1CCCC2
Reactant: O=C1CCC(=O)N1Br
Product: CC(=O)c1c(Br)c(-c2cccnc2)n2c1CCCC2
Yield: 37.6 %

Procedure:
1-Acetyl-2-bromo-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine is prepared as described in Example 23, from 1.2 g of 1-acetyl-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine and 1.1 g of N-bromosuccinimide. 0.6 g of 1-acetyl-2-bromo-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine are thus obtained in the form of white crystals melting at 163° C.
Reaction SMILES: [CH2:1]([CH:3]1[NH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=2)[N:5]2[CH:17]=[CH:18][CH:19]=[C:4]12)[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][C:23]=1[Cl:32]>>[Cl:32][C:23]1[CH:24]=[C:25]([S:28]([N:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=3)[N:5]3[CH:17]=[CH:18][CH:19]=[C:4]3[CH:3]2[CH2:1][CH3:2])(=[O:30])=[O:29])[CH:26]=[CH:27][C:22]=1[O:21][CH3:20]
Reactant: CCC1Nc2cc(C(F)(F)F)ccc2-n2cccc21
Reactant: COc1ccc(S(=O)(=O)Cl)cc1Cl
Product: CCC1c2cccn2-c2ccc(C(F)(F)F)cc2N1S(=O)(=O)c1ccc(OC)c(Cl)c1

Procedure:
The title compound was prepared from the product of Example 55, step 1 and 4-methoxy-3-chloro benzenesulfonyl chloride according to the procedure of Example 4 to yield light brown crystals, mp 126-129° C.
Reaction SMILES: C([N:8]1[C@@H:13]([C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:20])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[CH3:20][C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[NH:8]1
Reactant: C=CCCC(=O)[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCCC(=O)[C@H]1CCC[C@H](C)N1

Procedure:
To a stirred solution of trans-N-Boc-2-methyl-6-(ethenyl propionyl)piperidine. (1.8 g, 3.36 mmol) in 15% trifloroacetic acid (35 mL) in dichloromethane was stirred for 2 h at room temperature, and the reaction mixture was quenched with 75 mL saturated NaHCO3 solution. The mixture was extracted with ether *5 and the combined extracts were dried over K2CO3 and then concentrated to give trans-2-methyl-6-(ethenyl propionyl)piperidine as an oil. The crude oil was immediately dissolved in a small amount of ether, and ether saturated with HCl (g) was added slowly via pipette. This solution was allowed to stand for 10 minutes, and the solvent was evaporated. More ether was added and the flask was swirled constantly until crystallization occured. The solid was collected via filtration, and dried in vacuo to give the piperidinium hydrochloride as a white solid. mp 154.8-156.3; 1H NMR (300 MHz) δ9.89 (s, 2H), 7.03 (dd, 1H), 6.24 (d, 1H), 4.24-4.11 (m, 3H), 3.45 (s, 1H), 2.2-1.49 (m, 9H), 1.26-1.22 (t, 3H); 13C NMR (75 MHz) δ165.1 (s), 140.1 (s), 126.3 (s), 60.83 (s), 54.3 (s), 51.8 (s), 48.6 (s), 29.4 (s), 27.9 (s), 26.3 (s), 17.9 (s), 14.1 (s) ppm. FT-IR (neat): 3374, 3107, 2943, 1717, 1683, 1635, 1539, 1436, 1312, 1190, 1033, 981. Elemental Analysis for C11H20NO2Cl: C, 56.52%; H, 8.64%; N, 5.99%. Found: C, 56.37%; H, 8.58%; N, 5.89%.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:19]=2)[CH3:17])=[CH:6][CH:5]=1)([O-])=O.CC(O)=O.CCOC(C)=O.[H][H]>CO.[Pt]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:19]=2)[CH3:17])=[CH:6][CH:5]=1
Reactant: CC(COc1ccc([N+](=O)[O-])c2ccccc12)c1ccnc(NC(=O)OC(C)(C)C)c1
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(COc1ccc(N)c2ccccc12)c1ccnc(NC(=O)OC(C)(C)C)c1
Yield: 107.6 %

Procedure:
A solution of the nitroarene (54) (0.61 g, 1.441 mmol) in a mixture of MeOH (20.0 mL), AcOH (5.0 mL) and EtOAc (10.0 mL) was passed through a Thales H-Cube (1.0 mL·min−1, 45° C., 55 mm, 10% Pt/C Cat-Cart, full hydrogen mode). The solvent was evaporated in vacuo and the residue was partitioned between saturated aqueous NaHCO3 solution and EtOAc. The organic layer was washed with water and brine and then dried (MgSO4) and evaporated in vacuo to furnish the title compound (55) (0.61 g, 97%): m/z 394 (M+H)+ (ES+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[CH2:12]([O:14][C:15]([C@:17]1([F:37])[C@@H:22]2[C@H:18]1[CH2:19][C@@H:20]([OH:36])[C@@:21]2([N:33]=[N+:34]=[N-:35])[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[O:16])[CH3:13].C(OCC)(=O)C>N1C=CC=CC=1>[CH2:12]([O:14][C:15]([C@:17]1([F:37])[C@@H:22]2[C@H:18]1[CH2:19][C@@H:20]([O:36][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=1)[C@@:21]2([N:33]=[N+:34]=[N-:35])[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])=[O:16])[CH3:13]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](O)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](OC(=O)c3ccc(Cl)c(Cl)c3)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Temperature: 25 °C
Reaction time: 28 h
Yield: 99.9 %

Procedure:
234 mg of 3,4-dichlorobenzoyl chloride was added to 202 mg of (1R,2R,3R,5R,6R)-2-azido-6-fluoro-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester dissolved in 3.7 mL of pyridine, and the mixture was stirred for 28 hours at room temperature, under a nitrogen atmosphere. After 100 mL of ethyl acetate was added to the reaction solution, this ethyl acetate solution was washed with a saturated aqueous solution of copper sulfate and with water, and then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane-ethyl acetate=10:1), thereby yielding 298 mg of (1R,2R,3R,5R,6R)-2-azido-3-(3,4-dichlorobenzoyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N+:27]([O-])=O)(=[O:20])=[O:19])=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[N:12]3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[Sn]Cl>CCO>[NH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C:14]1[CH:15]=[CH:16][C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)(=[O:20])=[O:19]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1ccc(N2CCOCC2)c2cccnc12
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccccc1S(=O)(=O)Nc1ccc(N2CCOCC2)c2cccnc12
Yield: 75.5 %

Procedure:
In a similar fashion using route 19 general procedure 29, N-(5-morpholin-4-yl-quinolin-8-yl)-2-nitro-benzenesulfonamide 582 (216 mg, 0.52 mmol), SnCl2 (470 mg, 2.09 mmol), and EtOH (5 ml) gave the title compound (151 mg, 75%) which was used in the next step without further purification.
Reaction SMILES: C(OC1C(=O)N=C(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)N2CCN(C3CC3)C(=O)C=12)C1C=CC=CC=1.O[CH2:41][CH2:42][N:43]([CH:77]1[CH2:80][O:79][CH2:78]1)[C:44]([C:46]1[C:51]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[C:50]([OH:60])[N:49]=[C:48]([CH2:61][C:62]2([C:67]3[C:76]4[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=4)[CH:70]=[CH:69][CH:68]=3)[CH2:66][CH2:65][CH2:64][CH2:63]2)[N:47]=1)=[O:45]>>[CH2:53]([O:52][C:51]1[C:50](=[O:60])[N:49]=[C:48]([CH2:61][C:62]2([C:67]3[C:76]4[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=4)[CH:70]=[CH:69][CH:68]=3)[CH2:66][CH2:65][CH2:64][CH2:63]2)[N:47]2[CH2:41][CH2:42][N:43]([CH:77]3[CH2:78][O:79][CH2:80]3)[C:44](=[O:45])[C:46]=12)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: O=C(c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1COC1
Agent: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4cccc5ccccc45)CCCC3)n2CCN1C1CC1
Product: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4cccc5ccccc45)CCCC3)n2CCN1C1COC1

Procedure:
This compound was prepared following the same method as described for pure 9-benzyloxy-2-cyclopropyl-6-(1-naphthalen-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (356) from 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-oxetan-3-yl-amide (363) (140 mg, 0.25 mmol). The yield was 131 mg, 97%, of a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>>[CH3:22][N:23]([CH:25]=[N:19][C:17]([C:16]1[CH:15]=[N:14][N:13]2[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:9][CH:10]=[N:11][C:12]=12)=[O:18])[CH3:24]
Reactant: COC(OC)N(C)C
Reactant: Cc1cccc(-c2ccnc3c(C(N)=O)cnn23)c1
Product: Cc1cccc(-c2ccnc3c(C(=O)N=CN(C)C)cnn23)c1

Procedure:
A mixture of 6.0 g of 7-(3-methylphenyl) pyrazolo(1,5-a)pyrimidine-3-carboxamide (Example 13) and 15 ml of N,N-dimethylformamide dimethyl acetal is heated on a steam bath for 4 hours to give a solution. The solution is evaporated in vacuo to give a solid. The solid is recrystallized twice from dichloromethane-hexane to give 4.70 g of the desired product as colorless crystals, mp 165°-166° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:16]3[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=3)=[N:9][N:10]3[CH2:15][CH2:14][CH2:13][S:12][C:11]=23)=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:30]1([O:36][C:37](Cl)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[C:30]1([O:36][C:37](=[O:38])[NH:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:8]3[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[C:11]4[S:12][CH2:13][CH2:14][CH2:15][N:10]4[N:9]=3)[CH:17]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1cccc(-c2nn3c(c2-c2ccncc2)SCCC3)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-c2nn3c(c2-c2ccncc2)SCCC3)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
3-(3-Pyridin-4-yl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazin-2-yl)-phenylamine (prepared as described in Example 3) (30 mg, 0.097 mmol) was dissolved in dry DCM (1 mL) under nitrogen atmosphere. Triethylamine (0.018 mL, 0.126 mmol, 1.3 eq) and phenylchloroformate (0.015 mL, 0.117 mmol, 1.2 eq) were added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with DCM and washed with water, dried over Na2SO4 and concentrated to dryness. The residue was taken up with ethylether and filtered to give 27 mg (65%) of [3-(3-pyridin-4-yl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazin-2-yl)-phenyl]-carbamic acid phenyl ester as white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH:22]1([CH2:25][C:26]([NH2:34])([CH3:33])[C:27]2[N:31]=[C:30]([CH3:32])[O:29][N:28]=2)[CH2:24][CH2:23]1>>[CH:22]1([CH2:25][C:26]([NH:34][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])([CH3:33])[C:27]2[N:31]=[C:30]([CH3:32])[O:29][N:28]=2)[CH2:24][CH2:23]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: Cc1nc(C(C)(N)CC2CC2)no1
Agent: Cl
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and 2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine hydrochloride as starting materials. MS (D): m/e=448.5 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:15][CH2:16][C:17]([OH:28])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][C:19]([CH3:21])=[CH2:20])[C:11](=O)[O:12]C)[CH3:9])=[CH:4][CH:3]=1.[H-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:16][C@:17]([CH2:18][C:19]([CH3:21])=[CH2:20])([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:28][C:11]2=[O:12])[CH3:9])=[CH:6][CH:7]=1
Reactant: C=C(C)CC(O)(CCN(C(=O)OC)[C@@H](C)c1ccc(Br)cc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34.5 %

Procedure:
The crude methyl (S)-1-(4-bromophenyl)ethyl(3-hydroxy-5-methyl-3-phenylhex-5-enyl)carbamate from above procedure was dissolved in dry THF (75 mL), NaH (60% in mineral oil, 274 mg, 2 equiv) was added slowly at rt. After 10 min, the mixture was heated to reflux for 2 h. LC-MS found reaction completed. The mixture was cooled to 0° C., quenched with satd aq NH4Cl (10 mL), diluted with ether (100 mL), washed with 1% aq HCl (25 mL) and brine (15 mL), and dried over Na2SO4. After filtration and concentration, the crude product was purified by chromatography on a 40-g silica gel column, eluted with 10-35% EtOAc in hexanes. The second UV active peak was collected to afford (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one (490 mg 34.5% overall yield for Steps 3 and 4).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.Cl[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][N:25]=1>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][N:25]=2)[CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CN(C(=O)OC(C)(C)C)C1CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)C1CCCN(c2ccc([N+](=O)[O-])cn2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
To a solution of tert-butyl methyl(piperidin-3-yl)carbamate (1.00 g, 4.67 mmol) in THF (25 mL) was added triethylamine (0.70 mL, 5.0 mmol) and 2-chloro-5-nitropyridine (500 mg, 3.1 mmol). The reaction mixture was then stirred at room temperature for 16 h, diluted with a saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, ethyl acetate/hexanes) afforded the desired product (1.03 g, 99%) as a yellow solid. ESI MS m/z 337 [C16H24N4O4+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].Cl[C:11](Cl)(Cl)[CH:12](O)[OH:13].NO.S(=O)(=O)(O)O.O.NN.C[O-].[Na+]>C(O)C>[F:9][C:8]1[CH:7]=[C:6]2[C:4](=[CH:3][C:2]=1[F:1])[NH:5][C:12](=[O:13])[CH2:11]2
Reactant: Nc1ccc(F)c(F)c1
Reactant: OC(O)C(Cl)(Cl)Cl
Agent: C[O-]
Agent: NN
Agent: NO
Solvent: CCO
Solvent: O
Product: O=C1Cc2cc(F)c(F)cc2N1

Procedure:
Reaction of 3,4-difluoroaniline with chloral hydrate and hydroxylamine followed cyclization with sulfuric acid, in a manner analogous to Parts A and B of Preparation 9, gave 5,6-difluoroisatic, which was reacted with hydrazine hydrate followed by sodium methoxide in ethanol, in a manner analogous to Preparation 7, to give the title compound, m.p. 187°-190° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH:15]([N:18]3C(=O)C4=CC=CC=C4C3=O)[CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>C(O)C.O.NN>[NH2:18][CH:15]1[CH2:16][CH2:17][N:13]([CH2:12][CH2:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:14]1
Reactant: COc1ccc(CCN2CCC(N3C(=O)c4ccccc4C3=O)C2)cc1OC
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(CCN2CCC(N)C2)cc1OC
Yield: 100.3 %

Procedure:
1.03 g of N-(1-(2-(3,4-dimethoxyphenyl)ethyl)pyrrolidin-3-yl)phthalimide was dissolved in 50 ml of ethanol, to which 2 ml of hydrazine monohydrate was added and refluxed under heating for 14 hours. The solvent was distilled off and an aqueous diluted solution of sodium hydroxide was added to the residue and extracted with chloroform. After drying with anhydrous magnesium sulfate, the solvent was distilled off, to obtain 0.68 g of the above-captioned compound (yield: 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13](O)=[O:14])=[C:8]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:28][CH2:27]2)=[O:24])=[CH:19][CH:18]=1.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH2:47][N:48]2[CH2:53][CH2:52][CH:51]([NH2:54])[CH2:50][CH2:49]2)[CH:44]=[CH:45][CH:46]=1.COC1C=C(C=CC=1)CCl.O1C2(CCNCC2)OCC1.O>>[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH2:47][N:48]2[CH2:49][CH2:50][CH:51]([NH:54][C:13]([C:9]3[CH:10]=[N:11][C:12]4[C:7]([C:8]=3[NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([NH:25][CH:26]5[CH2:31][CH2:30][N:29]([CH2:32][C:33]6[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=6)[CH2:28][CH2:27]5)=[O:24])=[CH:21][CH:22]=3)=[CH:6][CH:5]=[CH:4][C:3]=4[O:2][CH3:1])=[O:14])[CH2:52][CH2:53]2)[CH:44]=[CH:45][CH:46]=1
Reactant: COc1cccc(CN2CCC(N)CC2)c1
Reactant: COc1cccc2c(Nc3ccc(C(=O)NC4CCN(Cc5ccccc5)CC4)cc3)c(C(=O)O)cnc12
Agent: C1CC2(CCN1)OCCO2
Agent: COc1cccc(CCl)c1
Solvent: O
Product: COc1cccc(CN2CCC(NC(=O)c3cnc4c(OC)cccc4c3Nc3ccc(C(=O)NC4CCN(Cc5ccccc5)CC4)cc3)CC2)c1

Procedure:
N-[1-[(3-Methoxyphenyl)methyl]-4-piperidinyl]-8-methoxy-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl]amino]-3-quinoline-carboxamide was prepared as a hygroscopic solid (0.76 hydrate) by coupling 8-methoxy-4 -[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl]amino]-3-quinolinecarboxylic acid and 1-[(3-methoxyphenyl)methyl]-4-piperidinamine as described for Example 17, Step 5. 1-[(3-Methoxyphenyl)methyl]-4-piperidinamine can be prepared from 3-methoxybenzyl chloride and 1,4-dioxa-8-azaspiro[4.5]-decane as described in U.S. Pat. Nos. 3,875,165 and 4,816,464: mp 135°-142° C.; 1H NMR (Me2SO-d6, 400 MHz) δ 9.48 (s, 1 H), 8.76 (s, 1 H), 8.39 (d, J=7.5 Hz, 1 H), 7.98 (d, J=7.7 Hz, 1 H), 7.68 (d, J=8.6 Hz, 2 H), 7.57 (d, J=8.6 Hz, 1H), 7.41 (m, 1H), 7.10-7.35 (m, 8 H), 6.7-6.9 (m, 4 H), 3.94 (s, 3 H), 3.6-3.8 (m, 4 H), 3.2-3.6 (m, 5 H), 2.6-2.9 (m, 4 H), 1.3-2.1 (m, 12 H); Karl Fischer, 0.76 moles of H2O.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C@H:4]1[O:17][C:15](=[O:16])[C:7]2[C@@H:8]([OH:14])[C@@H:9]3[O:13][C@@H:10]3[C:11](=[O:12])[C:6]=2[CH2:5]1>CO>[CH3:1][CH2:2][CH2:3][CH:4]1[O:17][C:15](=[O:16])[C:7]2[CH:8]([OH:14])[CH:9]([OH:13])[CH2:10][C:11](=[O:12])[C:6]=2[CH2:5]1
Reactant: CCC[C@@H]1CC2=C(C(=O)O1)[C@@H](O)[C@@H]1O[C@@H]1C2=O
Solvent: CO
Product: CCCC1CC2=C(C(=O)O1)C(O)C(O)CC2=O

Procedure:
EI-1941-3 is prepared from EI-1941-2 stored at room temperature in the dry state. EI-1941-2 (80 mg) which had been stored was dissolved in 4 ml of methanol. The solution was divided into two portions (2 ml each) and each portion was passed through HPLC column (D-ODS-5-B S-5 120A, YMC). Elution was carried out with 30% acetonitrile at a flow rate of 20 ml/min to separate EI-1941-2-containing fractions and EI-1941-3-containing fractions. The EI-1941-3-containing fractions were combined and concentrated to dryness under reduced pressure to give 13 mg of EI-1941-3.