Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.C([Li])CCC.[CH2:15]1[O:23][C:22]2[CH:21]=[CH:20][C:19]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:18][C:17]=2[O:16]1.[CH:30]1([CH:36]=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCCC1.CCCCCC>[CH2:15]1[O:23][C:22]2[CH:21]=[CH:20][C:19]([CH:24]([CH:36]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[OH:37])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:18][C:17]=2[O:16]1
Reactant: CCOC(=O)Cc1ccc2c(c1)OCO2
Reactant: O=CC1CCCCC1
Agent: [Li]CCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(c1ccc2c(c1)OCO2)C(O)C1CCCCC1
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
To a solution of N,N-diisopropyl-N-ethylamine (4.49 g) in tetrahydrofuran (50 ml) was added with stirring 1.6M n-butyl lithium in n-hexane solution (27.6 ml) below 0° C. under a nitrogen atmosphere. After the mixture was stirred in an ice-bath for 30 minutes, a solution of ethyl 3,4-methylenedioxyphenylacetate (3.85 g) in tetrahydrofuran (40 ml) was added at −78° C. The mixture was stirred for 30 minutes and cyclohexanecarbaldehyde (2.49 g) was added. After being stirred for 15 minutes at the same temperature, the mixture was quenched by saturated aqueous ammonium acetate. The mixture was extracted with diethyl ether (100 ml), and the solution was washed with 1M hydrochloric acid and brine successively, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=6:1) to give ethyl (2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionate (4.45 g) as an oil.
Reaction SMILES: CC(C)C(O[C@H]1[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O[C@H]([O:25][C:26]2[CH:27]=[CH:28][C:29]3[C:35]4[C:36]([O:44][CH3:45])=[C:37]([O:42][CH3:43])[C:38]([O:40][CH3:41])=[CH:39][C:34]=4[CH2:33][CH2:32][C@H:31]([NH:46][C:47](=[O:49])[CH3:48])[C:30]=3[CH:50]=2)[C@@H]1OC(=O)C(C)C)=O.[P:58](Cl)(Cl)([O:60][CH2:61][CH3:62])=[O:59].[OH2:65]>C1COCC1>[P:58]([OH:65])([O:60][CH2:61][CH3:62])([O:25][C:26]1[CH:27]=[CH:28][C:29]2[C:35]3[C:36]([O:44][CH3:45])=[C:37]([O:42][CH3:43])[C:38]([O:40][CH3:41])=[CH:39][C:34]=3[CH2:33][CH2:32][C@H:31]([NH:46][C:47](=[O:49])[CH3:48])[C:30]=2[CH:50]=1)=[O:59]
Reactant: CCOP(=O)(Cl)Cl
Reactant: O
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O[C@H]3O[C@H](COC(=O)C(C)C)[C@@H](OC(=O)C(C)C)[C@H](OC(=O)C(C)C)[C@H]3OC(=O)C(C)C)cc1[C@@H](NC(C)=O)CC2
Solvent: C1CCOC1
Product: CCOP(=O)(O)Oc1ccc2c(c1)[C@@H](NC(C)=O)CCc1cc(OC)c(OC)c(OC)c1-2
Temperature: 0 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
A solution of N-acetyl-colchicinol (1) (0.36 g; 1.0 mmol) in THF (40 ml) under argon was cooled to 0° C. and treated with a 1.0M solution of lithiumHMDS in THF (1.1 ml; 1.1 mmol). The mixture was stirred at 0° C. for 1 hour and then added in portions over about 2 hours to a solution of ethyl dichlorophosphate (400 μl; 3.3 mmol) in THF (150 ml). The mixture was stirred at ambient temperature for 15 minutes. After addition of water (200 ml) the THF was removed by evaporation. After removal of the insoluble material by filtration, the filtrate was purified on HP20 SS resin eluting with a gradient of 0–60% methanol/water. The appropriate fractions were freeze-dried to give (5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl ethyl hydrogen phosphate as a white solid (259 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:5]=[C:6]([CH:10]=[O:11])[C:7]=1[O:8][CH3:9].[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[Cl:16][C:17]1[CH:22]=[C:21]([C:2]2[C:7]([O:8][CH3:9])=[C:6]([CH:10]=[O:11])[CH:5]=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1c(Br)cc(S(N)(=O)=O)cc1C=O
Reactant: OB(O)c1cccc(Cl)c1
Product: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc(Cl)c1

Procedure:
Proceeding as in Reference 19, but substituting 3-bromo-5-formyl-4-methoxy-benzenesulfonamide and 3-chlorobenzene boronic acid, gave 3′-chloro-5-formyl-6-methoxy-biphenyl-3-sulfonamide.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH3:14])[C:5]2[C:10]([N:11]=1)=[C:9]([CH3:12])[CH:8]=[C:7]([CH3:13])[N:6]=2.O[C:16]1[CH:48]=[CH:47][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[N:23]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]2=[O:46])=[CH:18][CH:17]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:14][N:4]1[C:5]2=[N:6][C:7]([CH3:13])=[CH:8][C:9]([CH3:12])=[C:10]2[N:11]=[C:3]1[CH2:2][O:1][C:16]1[CH:48]=[CH:47][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[N:23]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]2=[O:46])=[CH:18][CH:17]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C)c2nc(CO)n(C)c2n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2nc(COc3ccc(CC4SC(=O)N(C(c5ccccc5)(c5ccccc5)c5ccccc5)C4=O)cc3)n(C)c2n1
Yield: 71.3 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 1.47 g of 2-hydroxymethyl-3,5,7-trimethylimidazo[5,4-b]pyridine (prepared as described in Preparation 86), 3.58 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 1.87 g of tributylphosphine, 2.33 g of 1,1'-(azodicarbonyl)dipiperidine and 50 ml of toluene were used. After working up the product as described in Preparation 4, the resulting crude product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.5 g of the title compound, melting at 96°-99° C. (softening).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][NH:7][C:8](=[O:17])[C:9]1[CH:14]=[C:13]([I:15])[CH:12]=[CH:11][C:10]=1[NH2:16])[CH3:2].FC(F)(F)C(O)=O.CN1C2C=CC(C#CCCCN)=CC=2C(=O)N(CCC(O)=O)CC1=O.N1C(C)=CC=CC=1C.Cl[CH:60]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][NH:7][C:8](=[O:17])[C:9]1[CH:14]=[C:13]([I:15])[CH:12]=[CH:11][C:10]=1[NH:16][CH:60]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[CH3:2]
Reactant: CCOC(=O)CCNC(=O)c1cc(I)ccc1N
Reactant: ClC(c1ccccc1)c1ccccc1
Agent: CN1C(=O)CN(CCC(=O)O)C(=O)c2cc(C#CCCCN)ccc21
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCNC(=O)c1cc(I)ccc1NC(c1ccccc1)c1ccccc1
Temperature: 50 °C
Yield: 56.2 %

Procedure:
A magnetically stirred solution of 1.1 gram of N-(2-amino-5-iodobenzoyl)-b-alanine ethyl ester (3.1 mmol), prepared by the method shown in part (b) of Example 1, 0.48 mL of 2,6-lutidine (4.1 mmol), 1.2 grams of chlorodiphenylmethane (4.7 mmol), and 10 mL of dimethylformamide was heated to 50° C. for 1 hour. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The resulting oil was dissolved in 35 mL of methylene chloride and washed with 2×50 mL 10% citric acid, 1×50 mL water, dried over sodium sulfate, decanted and concentrated in vacuo. The resulting oil was further purified by column chromatography, using silica gel, eluting with a solvent gradient of 10/90 ethyl acetate/hexane to 25/75 ethyl acetate/hexane (TLC, SiO2, 1:1 EtOAc/hexane, Rf =0.82, uv positive) to yield 0.92 gram (56%) of N-(2-diphenylmethylamino-5-iodobenzoyl)-b-alanine ethyl ester. 1H NMR (CDCl3, dTMS) 8.40 (1H, d, 3JHH =5 Hz, NHCHAr2), 7.56 (1H, d, 3JHH =2 Hz, ArH o-CON), 7.18-7.36 (11H, m, 4JHH =2 Hz, ArH Ph, ArH p-CON), 6.73 (1H, t, 3JHH =6 Hz, NHCH2), 6.29 (1H, d, 3JHH =9 Hz, ArH m-CON), 5.52 (1H, d, 3JHH =5 Hz, CHNH), 4.15 (2H, q, 3JHH =7 Hz, OCH2), 3.61 (2H, q, 3JHH =6 Hz, CH2NH), 2.58 (2H, t, 3JHH =6 Hz, CH2CO), 1.25 (3H, t, 3JHH =6 Hz, CH3CH2O).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[C:4]([CH3:28])[C:3]=1[F:29].[H-].[Na+].Br[CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36].O>CN(C)C=O>[F:29][C:3]1[C:4]([CH3:28])=[C:5]([F:27])[C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)=[CH:9][C:8](=[O:26])[C:7]=2[C:2]=1[NH:1][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36]
Reactant: Cc1c(F)c(N)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Reactant: CC(C)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(F)c(NCCC(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.7 %

Procedure:
1.03 g (2.54mmol) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methyl-4H-1-benzopyran-4-one obtained in Example 107 (1) was dissolved in 20 mL of dimethylformamide under argon atmosphere, 308 mg (7.62 mmol) of sodium hydride (60% oil dispersion) and 0.77 mL (6.4 mmol) of 1-bromo-3-methylbutane were added and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction solution, the mixture was extracted once with ethyl acetate, the organic layer was washed once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:n-hexane=3:1) to give 708 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methyl-5-(3-methylbutylamino)-4H-1-benzopyran-4-one (yield: 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](/[CH:21]=[CH:22]\[CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.[C:27]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](/[CH:21]=[CH:22]\[CH2:23][OH:24])[CH:17]=3)[N:12]([CH3:27])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(/C=C\CO)cc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(/C=C\CO)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of N-(4-chlorobenzyl)-6-[(1Z)-3-hydroxy-1-propenyl]-4-hydroxy-3-quinolinecarboxamide from Preparation No. 11 (0.184 g), K2CO3 (0.276 g) and iodomethane (0.062 mL) in DMF (2 mL) is heated in a stoppered flask at 90° C. for 1 h. Water is added and the mixture is allowed to cool and stir at room temperature for 16 h during which a precipitate formed. The precipitate is filtered and dried in vacuo at 60° C. for 48 h to give a solid. Crystallization by dissolving in CH2Cl2 with a few drops of MeOH and adding to a 1:1 solution of pentane/Et2O gave 0.085 g of the title compound as a solid.
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:36])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:38]1[N:43]=[CH:42][N:41]=[C:40]2[N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:53])[N:45]=[CH:46][C:39]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:36][C:38]1[N:43]=[CH:42][N:41]=[C:40]2[N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:53])[N:45]=[CH:46][C:39]=12)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Reactant: Cc1ccc(NC(=O)[C@@H](O)COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)[C@H](COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)Oc2ncnc3c2cnn3-c2ccccc2Cl)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
Sodium hydride (14.21 mg, 0.36 mmol) was added to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate AU2) (85 mg, 0.18 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (47.1 mg, 0.18 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×20 mL). The combined organics were washed with saturated brine (10 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 20% EtOAc in isohexane to give (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyridin-2-yl)propanamide (126 mg, 100%). 1H NMR (400 MHz, CDCl3) δ0.99 (s, 9H), 2.29 (s, 3H), 3.67-3.73 (m, 2H), 3.77-3.84 (m, 2H), 4.13-4.25 (m, 2H), 6.07 (t, 1H), 7.29-7.54 (m, 10H), 7.59-7.69 (m, 5H), 8.06-8.16 (m, 2H), 8.38 (s, 1H), 8.58 (s, 1H), 8.66 (s, 1H); m/z (ES+), (M+H)=707.62; HPLC tR=3.81 min
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14]>O1CCCC1>[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][N:10]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ncnc21
Temperature: 2.5 °C
Reaction time: 0.67 h
Yield: 99 %

Procedure:
To a 250 mL oven dried three-neck round bottom flask equipped with a stir bar, condenser, septa, nitrogen inlet and thermocouple was charged sodium hydride (NaH, 60 wt %, 1.56 g, 0.0391 mol, 1.2 equiv) and anhydrous tetrahydrofuran (THF, 26 mL, 0.320 mol). The mixture was chilled to 0-5° C. To a oven dried 100 mL round bottom flask was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 5.00 g, 0.0326 mol) and anhydrous tetrahydrofuran (42 mL, 0.520 mol), and the resulting slurry was then added portion wise via large bore canula over 15 minutes to the sodium hydride (NaH) suspension in THF. The reaction temperature rose to 6.8° C. after the addition of the substrate. The reaction mixture was stirred at 0-5° C. for 40 minutes before being charged neat triisopropylsilyl chloride (6.6 g, 7.24 mL, 0.0342 mol, 1.05 equiv) via syringe over 5 minutes. The cooling bath was removed and the reaction mixture was warmed to reflux for 4 hours. The reaction was monitored by TLC (80% hexane/ethyl acetate). When the reaction was deemed complete, the reaction mixture was cooled to room temperature and dilute with ethyl acetate (100 mL) and 20% aqueous brine (50 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic fractions were washed with 1M sodium bicarbonate (NaHCO3) aqueous solution (100 mL) and 20% aqueous brine (100 mL), dried over magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 10% ethyl acetate/hexane gradient elution) to afford 4-chloro-7-(triisopropylsilyl)-7H-pyrrolo[2,3-d]pyrimidine (3d, 10.0 g, 10.10 g theoretical, 99%) as an amber oil. For 3d: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.61 (s, 1H), 7.67 (d, 1H, J=3.7 Hz), 6.76 (d, 1H, J=3.5 Hz), 1.86 (m, 3H), 1.02 (d, 18 H, J=7.5 Hz); C15H24ClN3Si (MW, 309.91), LCMS (EI) m/e 310/312 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6]Cl.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.Cl>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][N:13]1[CH2:18][CH2:17][N:16]([CH2:6][C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:15][CH2:14]1
Reactant: C1CNCCN1
Reactant: COc1ccc(CCl)cc1OC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2CCN(Cc3ccc(OC)c(OC)c3)CC2)cc1OC
Temperature: 97.5 °C
Reaction time: 8 h

Procedure:
3,4-dimethoxybenzyl chloride (10 g, 53.6 mmol) was combined with piperazine (2.3 g, 26.8 mmol) in anhydrous DMF (30 ml) and heated with stirring under nitrogen for 8 hours at 95-100° C. The cooled reaction mixture was diluted with water (100 ml) and acidified to pH 1 with concentrated hydrochloric acid. The white precipitate was collected by filtration and washed with water (50 ml). The solid was re-suspended in water (50 ml) and the pH adjusted to >9 by the dropwise addition of sodium hydroxide solution (50% NaOH in water). The resultant white solid was collected by filtration and dried under vacuum at 50° C., yield 10 g.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[F:10].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClC(Cl)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:4][C:3]=1[F:10]
Reactant: O=Cc1ccc(Cl)c(F)c1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Fc1cc(CN2CCOCC2)ccc1Cl
Temperature: 25 °C
Yield: 60.4 %

Procedure:
4-Chloro-3-fluorobenzaldehyde (1.0 g, 6.31 mmol), morpholine (0.546 ml, 6.31 mmol) and sodium triacetoxyborohydride (1.938 g, 9.14 mmol) were mixed in dichloroethane (19 ml) and the reaction stirred at ambient temperature under an atmosphere of argon over night. 1M HCl (aq, 25 ml) was added. The mixture was extracted with dichloromethane (×4). The pH was adjusted to ca 12 by adding KOH (s). The mixture was extracted with dichloromethane (×4). The combined organic phases were dried over MgSO4 filtered and concentrated in vacuo to give 4-(4-chloro-3-fluorobenzyl)morpholine (0.875 g, 60%) as a liquid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21](O)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.[CH3:24]CN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Br:55][C:56]1[S:57][C:58]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60][C:59]=2[N:65]=1>CN(C=O)C>[Br:55][C:56]1[S:57][C:58]2[CH2:64][CH2:63][N:62]([C:21](=[O:22])[CH2:20][N:10]3[C:11]([C:13]4[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=4)=[N:12][C:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:24])=[CH:7][CH:6]=4)=[N:9]3)[CH2:61][CH2:60][C:59]=2[N:65]=1
Reactant: Brc1nc2c(s1)CCNCC2
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc(-c3ccc(F)cc3)n(CC(=O)N3CCc4nc(Br)sc4CC3)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
151 mg (3,5-bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetic acid and 84 μL DIPEA were dissolved in 2.5 mL DMF. 154 mg TBTU was added to this solution and the mixture was stirred for 10 min. at RT. Then, 112 mg 2-bromo-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine in 2.5 mL DMF was added. The mixture was stirred for 2 h at RT. The reaction-solution was purified by HPLC to yield 19.8 mg of the desired compound. Rt: 2.21 (method I), (M+H)+: 530/32
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH3:4][S:5][C:6](S)=[N:7][C:8]#[N:9]>C(#N)C>[C:8]([N:7]=[C:6]([N:2]([CH3:1])[NH2:3])[S:5][CH3:4])#[N:9]
Reactant: CNN
Reactant: CSC(S)=NC#N
Solvent: CC#N
Product: CSC(=NC#N)N(C)N
Reaction time: 16 h

Procedure:
A mixture of methyl hydrazine (0.48 ml) and cyanocarbonimidodithioic acid methyl ester (1.3 g) in acetonitrile was stirred at 25° for 16 hours. The resulting solution was evaporated to a gum which was crystallised from acetonitrile/ether to give the title compound as colourless granules (210 mg) m.p. 69°-71°.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:52][C:53]1[CH:58]=[CH:57][C:56]([CH2:59][C:60]([OH:62])=[O:61])=[CH:55][CH:54]=1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:18])[NH:52][C:53]1[CH:54]=[CH:55][C:56]([CH2:59][C:60]([OH:62])=[O:61])=[CH:57][CH:58]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)Cc1ccc(NC(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of (S)-Pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (F.W.=249.27, 1.5 g, 4.0 mmol), HATU (1.6 g, 3.9 mmol), and DIEA (0.7 mL, 4.97 mmol) in DMF (30 mL) was stirred at room temperature for 1 h. (4-Amino-phenyl)-acetic acid (FW=151.17, 0.5 g, 3.31 mmol) was added. The reaction mixture was stirred at room temperature for 20 h. The mixture was filtered and separated by reverse phase HPLC (0-100% of buffer B; buffer A: water containing 0.1% TFA; buffer B: MeCN containing 0.1% TFA). The combined fraction was evaporated to furnish the desired product (S)-2-(4-Carboxymethyl-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester.
Reaction SMILES: [H-].[Na+].[Na].[C:4]([O:11][CH3:12])(=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=1[CH2:24]Br>CCOCC.CO>[CH3:9][O:8][C:6]([C:5]1([C:4]([O:11][CH3:12])=[O:10])[CH2:24][C:16]2[C:15](=[CH:20][CH:19]=[CH:18][C:17]=2[N+:21]([O-:23])=[O:22])[CH2:14]1)=[O:7]
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1cccc(CBr)c1CBr
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C1(C(=O)OC)Cc2cccc([N+](=O)[O-])c2C1
Reaction time: 0.08 h
Yield: 70.2 %

Procedure:
To a solution stirred under nitrogen at room temperature of 5.0 mL methanol in 15.0 mL ether was added 0.84 g 60% sodium hydride (0.021 mol) in small portions (sodium hydride was used because metallic sodium was not available). After the addition was complete, the nearly clear and colorless solution was stirred for 5 minutes. To it was then added 1.3 g dimethyl malonate, giving a slightly cloudy colorless solution. To this was rapidly added a suspension of 3.1 g 1,2-bis(bromomethyl)3-nitrobenzene, which immediate gave a precipitate suspended in a dark green solution. This was removed by filtation and the filtrate was concentrated. The residue was purified on silica (20%-100% CH2Cl2 in hexanes) to give 1.93 g off-white solid (67%).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].C(N([CH2:10][CH3:11])CC)C.[C:12]1([CH3:24])[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[S:20](Cl)(=[O:22])=[O:21]>>[CH3:24][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[S:20]([NH:3][CH2:2][CH2:1][NH:4][S:20]([C:13]1[C:12]([CH3:24])=[CH:17][C:16]([CH3:18])=[CH:15][C:10]=1[CH3:11])(=[O:22])=[O:21])(=[O:22])=[O:21]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: NCCN
Reactant: CCN(CC)CC
Product: Cc1cc(C)c(S(=O)(=O)NCCNS(=O)(=O)c2c(C)cc(C)cc2C)c(C)c1

Procedure:
By a method similar to Example 152, using ethylenediamine (0.9 g, 15 mmol), triethylamine (3.03 g, 30 mmol), 2-mesitylenesulfonyl chloride (6.56 g, 30 mmol) gives the title compound. Mass spectrum (electrospray): (m/z)=425.2 (M+1); 1H NMR (DMSO-d6): δ7.28 (br, 2H), 7.01 (s, 4H), 2.69–2.68 (m, 4H), 2.47 (s, 12H), 2.28 (s, 6H).