Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]3[S:11][C:12]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])=[C:13]([C:14](OCC)=[O:15])[C:9]=3[C:8](=[O:30])[N:7]([CH3:31])[C:6]2=[O:32])[CH2:3][CH2:2]1.O>O1CCCC1>[CH:1]1([CH2:4][N:5]2[C:10]3[S:11][C:12]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:28])([F:27])[F:29])=[C:13]([CH2:14][OH:15])[C:9]=3[C:8](=[O:30])[N:7]([CH3:31])[C:6]2=[O:32])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(Cc2ccccc2C(F)(F)F)sc2c1c(=O)n(C)c(=O)n2CC1CC1
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)c2c(CO)c(Cc3ccccc3C(F)(F)F)sc2n(CC2CC2)c1=O
Temperature: 60 °C

Procedure:
The product of step b) (6.65 g) was dissolved in tetrahydrofuran (200 mls) and LiA1H(OtBu)3 (43 mls, 1M in tetrahydrofuran) was added. The reaction mixture was heated at 60° C. for 18 hrs. Water was then added and the reaction mixture was concentrated to dryness in vacuo. The residue was extracted into ethyl acetate and the solution was dried over magnesium sulphate, filtered, and concentrated in vacuo to a greenish solid which was ultrasonicated in isohexanes for 3 hrs before being collected via filtration to yield 2.76 g of the subtitle compound as a green solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]([C:10]3[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:11]=3[O:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]4[N:24]=[CH:25][S:26][CH:27]=4)(=[O:21])=[O:20])=[CH:15][C:14]=3[C:28]#[N:29])=[CH:8][CH:7]=[N:6]2)[CH2:2]1.[CH2:35](N(CC)CC)[CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)C>CO.ClCCl>[Cl:34][C:32]1[CH:31]=[CH:30][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]3[N:24]=[CH:25][S:26][CH:27]=3)(=[O:21])=[O:20])=[CH:15][C:14]=2[C:28]#[N:29])=[C:10]([C:9]2[N:5]([CH:3]3[CH2:2][N:1]([CH2:35][CH3:36])[CH2:4]3)[N:6]=[CH:7][CH:8]=2)[CH:33]=1
Reactant: N#Cc1cc(S(=O)(=O)Nc2cscn2)ccc1Oc1ccc(Cl)cc1-c1ccnn1C1CNC1
Reactant: CCN(CC)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCN1CC(n2nccc2-c2cc(Cl)ccc2Oc2ccc(S(=O)(=O)Nc3cscn3)cc2C#N)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 4-[2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4-chlorophenoxy]-3-cyano-N-1,3-thiazol-4-ylbenzenesulfonamide, Example 809 (500 mg, 0.000797 mol) in methanol (4 mL) and dichloromethane (4 mL) was added triethylamine (161 mg, 0.00159 mol) and the reaction cooled to 0° C. in an ice/water bath. To the suspension was added sodium triacetoxyborohydride (422 mg, 0.00199 mol) and the reaction was then stirred at 0° C. for 10 minutes. Acetaldehyde (105 mg, 0.00239 mol) was added dropwise and the reaction stirred at 0° C. for 1.5 hours. The solvent was removed in vacuo to give an orange oil which was partitioned between dichloromethane (25 mL) and water (25 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL) and filtered through a phase separator. The solvent was removed in vacuo to give a pink solid which was triturated in hot ethyl acetate (10.0 mL), allowed to cool to room temperature and then filtered to give the title compound as a white solid, (431 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[OH-].[Na+].[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>C(Cl)Cl>[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCc1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90.5 %

Procedure:
4-Flourobenzyl amine (27 grams, 0.22 mole) was dissolved in 200 mL of CH2Cl2. To this was added 400 mL of 1N NaOH and the resulting mixture cooled to 0° C. 4-Fluorobenzoyl chloride (33 grams, 0.21 mole) was added dropwise with stirring. The reaction was allowed to proceed for 20 min after which the organic layer was separated, dried over Na2SO4, filtered and the solvent removed under vacuum to yield 47 grams (92% yield) of 4-fluoro-N-(4-fluoro-benzyl)-benzamide as a solid. MS (M−H) calcd for C14H10F2NO: 246.1. found: 246.0. Anal. Calcd for C14H11F2NO; C, 68.01; H, 4.48; N, 5.66; found: C, 67.76; H, 4.54; N, 5.45. 1H NMR (500 MHz, DMSO) δ: 4.45 (d, 2, J=6), 7.15 (m, 2), 7.34 (overlapping m, 4), 7.97 (m, 2), 9.09 (t, 1, J=6). 13C NMR (125 MHz, DMSO) δ: 41.88, 114.81, 114.98, 115.06, 115.23, 129.08, 129.15, 129.76, 129.83, 130.60, 130.62, 135.66, 135.68, 160.10, 162.03, 162.83, 164.81, 165.04.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:15][OH:16])[C:12]([OH:14])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].F[C:18]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]>CN(C=O)C>[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][CH:26]=[C:27]([N+:28]([O-:30])=[O:29])[C:18]=1[O:16][CH2:15][C@H:11]([NH:10][C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1F
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1OC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
A suspension of NaH (60% in mineral oil, 1.48 g, 36.9 mmol, Eq: 2.10) inDMF (15 mL) was cooled to 0° C. and (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (3.61 g, 17.6 mmol, Eq: 1.00) in DMF (15 mL) was added dropwise over 15 min. The mixture was stirred at 0° C. for 30 min. and at room temp. (RT) for 30 min. The mixture was cooled to 0° C. and methyl 2-fluoro-3-nitrobenzoate (3.5 g, 17.6 mmol, Eq: 1.00) in DMF (15 mL) was added dropwise over 10 min. After 2.5 h the mixture was diluted with ice cold H2O and extracted with EtOAc. The combined extracts were dried over Na2SO4 filtered and concentrated to give a residue that was purified by chromatography to afford 2-((S)-2-tert-butoxycarbonylamino-2-carboxy-ethoxy)-3-nitrobenzoic acid methyl ester (4.3 g, 50%) as a yellow foam.
Reaction SMILES: [CH:1]([C@H:4]1[NH:9][CH2:8][CH2:7][N:6]2[C:10]3[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[CH:13][C:11]=3[N:12]=[C:5]12)([CH3:3])[CH3:2].Cl[C:26]1[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:1]([C@H:4]1[N:9]([C:26]2[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=2)[CH2:8][CH2:7][N:6]2[C:10]3[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[CH:13][C:11]=3[N:12]=[C:5]12)([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN[C@@H]3C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1nccc(C(F)(F)F)n1)[C@@H]3C(C)C
Temperature: 150 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
A mixture of (R)-methyl 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (0.9 g, 2.56 mmol), 2-chloro-4-(trifluoromethyl)pyrimidine (1.0 g, 5.1 mmol, 2 eq.) and DIEA (1.0 g, 7.7 mmol, 3 eq.) in i-PrOH (6 mL) was stirred in a microwave oven at 150° C. for 2 h. TLC showed the starting material was consumed completely (PE:EtOAc=3:1). The solvent was removed in vacuo at 40° C., and the residue was purified by column chromatography on silica gel eluting with PE/EtOAc=6/1 to give (R)-methyl 1-isopropyl-7-(methylsulfonyl)-2-(4-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (1.0 g, 78% yield) as a white solid. LC-MS m/z 498.1 [M+H]+. 1H NMR (CDCl3 300 MHz): δ 8.52 (d, J=4.8 Hz, 1H), 8.13 (s, 1H), 8.06 (s, 1H), 6.83 (d, J=4.8 Hz, 1H), 6.06 (d, J=7.8 Hz, 1H), 5.39-5.28 (m, 1H), 4.33-4.24 (m, 1H), 4.20-4.12 (m, 1H), 3.93 (s, 3H), 3.77-3.65 (m, 1H), 3.39 (s, 3H), 2.52-2.38 (m, 1H), 1.25 (d, J=6.9 Hz, 3H), 1.02 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])SCCCS2)[CH2:3][CH2:2]1.BrN1C(=[O:22])CCC1=O>CC#N.O>[CH:1]1([CH2:4][C:5](=[O:22])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1(CC2CC2)SCCCS1
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C(=O)CC1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
A solution of ethyl 2-(cyclopropylmethyl)-1,3-dithiane-2-carboxylate (19.6 g, 79.67 mmol) in CH3CN (20 mL) was slowly added, over 30 minutes, to a well-stirred suspension of NBS (N-bromosuccinimide) in CH3CN (210 mL) and water (55 mL). After the mixture was stirred for 1 h, the resulting red solution was poured into an ice-cold CH2Cl2-Hexane solution (1:1 500 mL). The resulting mixture was washed with saturated aqueous NaHSO3 and water. The colorless organic phase was carefully washed with saturated aqueous K2CO3 and water. The organic phase was dried over MgSO4, then evaporated to give 6.88 g (55%) of ethyl 3-cyclopropyl-2-oxopropanoate as a yellow oil. 1H NMR (CDCl3): δ 4.29 (2H, q, J=8 Hz), 2.71 (2H, d, J=9 Hz), 1.35 (3H, t, J=8 Hz), 1.05-0.98 (1H, m), 0.59-0.54 (2H, m), 0.17-0.14 (2H, m).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([OH:24])=O)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[NH2:25][CH2:26][C:27]1([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([Cl:47])[CH:41]=2)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1>>[Cl:47][C:42]1[CH:41]=[C:40]([C:27]2([CH2:26][NH:25][C:22](=[O:24])[C:3]3[C:2]([F:1])=[C:7]([S:8][C:9]4[S:13][C:12]([NH:14][C:15]5[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=5)=[N:11][CH:10]=4)[CH:6]=[CH:5][N:4]=3)[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH2:31][CH2:32]2)[CH:45]=[CH:44][C:43]=1[Cl:46]
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2ccc(Cl)c(Cl)c2)CC1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccc(Cl)c(Cl)c5)CCN(C(=O)OC(C)(C)C)CC4)c3F)s2)c1

Procedure:
Following the amide bond forming procedure given in example 37, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinic acid (intermediate B in example 1) and tert-butyl 4-(aminomethyl)-4-(3,4-dichlorophenyl)piperidine-1-carboxylate (amine intermediate “K”) were reacted to give the title compound. LC/MS (M+H)+: 703. Ret. time: 2.20 min. (Condition I).
Reaction SMILES: COC(=O)[NH:4][C:5]1[S:6][C:7]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=3)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[C:8]=2[N:9]=1.[OH-].[K+].Cl>C(O)CO.O>[CH3:22][O:21][C:10]1[C:8]2[N:9]=[C:5]([NH2:4])[S:6][C:7]=2[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=2)=[CH:12][CH:11]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(-c3ccnc(C)c3)c2s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: COc1ccc(-c2ccnc(C)c2)c2sc(N)nc12
Temperature: 100 °C
Yield: 83 %

Procedure:
[4-Methoxy-7-(2-methyl-pyridin-4-yl)-benzothiazol-2-yl]-carbamic acid methyl ester (100 mg, 0.24 mmol) were dissolved in ethyleneglycol (3.0 ml) and treated with potassium hydroxide (528 mg, 1.1 mmol) and heated to 100° C. for 6.5 h. The reaction mixture was cooled to room temperature, diluted with water, neutralized with 1N HCl and extracted four times with ethyl acetate. The organic layers were combined and washed with water and saturated aqueous NaCl. The organic phases were then dried and the solvent removed in vacuo. The product was obtained as a light brown solid (83%). MS: m/e=272 (M+H+).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=O)=O.[CH2:42]([O:45][CH3:46])[C:43]#[CH:44]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:46][O:45][CH2:42][C:43]#[C:44][C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: C#CCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: COCC#Cc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 72.2 %

Procedure:
In a similar manner to Step 2 of Example 161, 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (400 mg, 0.674 mmol) was dissolved in diethylamine (16 mL), and the solution was treated with bis(triphenylphosphine)dichloropalladium (56.7 mg, 0.012 mmol), copper iodide (46.2 mg, 0.243 mmol) and methyl propargyl ether (0.398 mL, 4.72 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=6/1 to 8/1) to obtain 4-(3-methoxy-1-propinyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (250 mg, yield 72%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[NH2:33][C:34]1[CH:42]=[C:41]2[C:37]([CH:38]=[CH:39][N:40]2[CH2:43][CH2:44][C@@H:45]([N:55]2[CH:59]=[C:58]([C:60]([NH2:62])=[O:61])[N:57]=[CH:56]2)[CH2:46][O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])=[CH:36][CH:35]=1>ClCCl>[Si:48]([O:47][CH2:46][C@H:45]([N:55]1[CH:59]=[C:58]([C:60]([NH2:62])=[O:61])[N:57]=[CH:56]1)[CH2:44][CH2:43][N:40]1[C:41]2[C:37](=[CH:36][CH:35]=[C:34]([NH:33][C:9](=[O:11])[CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:42]=2)[CH:38]=[CH:39]1)([C:51]([CH3:54])([CH3:52])[CH3:53])([CH3:49])[CH3:50]
Reactant: O=C(O)CCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](CCn1ccc2ccc(N)cc21)n1cnc(C(N)=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H](CCn1ccc2ccc(NC(=O)CCc3ccccc3)cc21)n1cnc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 100.3 %

Procedure:
To a stirred mixture of 3-phenylpropionic acid (46 mg, 0.304 mmol) and 1-hydroxybenzotriazol (45 mg, 0.334 mmol) in dichloromethane (5 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (52 mg, 0.334 mmol) at ice-bath temperature. The mixture was stirred for 40 minutes at room temperature. And then 1-[(R)-4-(6-aminoindol-1-yl)-1-(tert-butyldimethylsilyloxy)-2-butyl]imidazole-4-carboxamide (130 mg, 0.304 mmol) was added to the mixture at ice-bath temperature. After adding, the resulting mixture was stirred for 4 hours at room temperature. The solvent was concentrated in vacuo. And then the residue was extracted with ethyl acetate and washed with water and brine. The organic layer was dried (sodium sulfate) and concentrated in vacuo. The residue was purified by silica gel (6 g) column chromatography eluting with chloroform/methanol (30:1) to give 1-[(R)-1-(tert-butyldimethylsilyloxy)-4-(6-(3-phenylpropionylamino) indol-1-yl)-2-butyl]imidazole-4-carboxamide (170.6 mg, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:20]=[C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:17][C:13]=1[C:14](O)=O>>[CH3:1][C:2]1[CH:3]=[C:4]2[NH:9][C:14]([C:13]3[CH:17]=[CH:18][C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][C:12]=3[O:11][CH3:10])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1cnc(N)c(N)c1
Reactant: COc1cc(NS(C)(=O)=O)ccc1C(=O)O
Product: COc1cc(NS(C)(=O)=O)ccc1-c1nc2ncc(C)cc2[nH]1

Procedure:
Prepared analogously to Example 14 from 5-methyl-2,3-diaminopyridine and 2-methoxy-4-methanesulfonylamino-benzoic acid.
Reaction SMILES: [F:1][C:2]1([CH2:15][OH:16])[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.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C([O-])(O)=O.[Na+]>ClCCl>[F:1][C:2]1([CH2:15][O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:6][CH2:7]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CO)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(COS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 92.6 %

Procedure:
To a 0° C. solution of tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (2.60 g, 11.1 mmol) and triethylamine (2.33 mL, 16.7 mmol) in 55 mL dichloromethane was added neat methanesulfonyl chloride (0.949 mL, 12.3 mmol) dropwise by syringe. The reaction mixture was slowly warmed to ambient temperature and stirred at ambient temperature for 17 hours. Saturated NaHCO3 was added, the mixture was extracted with dichloromethane, and combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel (4:1 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate) to give the title compound (3.2 g, 92.2% yield) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:21][NH2:22].C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[NH:22][N:21]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NN
Reactant: CC(C)(C)OC(=O)C(=O)CC(=O)c1cc(Cl)cc(Cl)c1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1cc(-c2cc(Cl)cc(Cl)c2)n[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product from step C (6.8 g, 21.7 mmol) in 125 mL of ethanol was added hydrazine (0.75 mL, 23.9 mmol) and 10 mL of glacial acetic acid. The reaction mixture was stirred at ambient temperature for 16 h then was concentrated in vacuo and the residue suspended in ethyl acetate. The organic layer was washed successively with two portions of saturated aqueous sodium bicarbonate solution and one portion of brine. The organic layer was dried over magnesium sulfate, and concentrated in vacuo to provide the title compound as a pale yellow solid which was used without further purification.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10]([CH2:11][CH2:12][CH2:13][CH3:14])=[CH:9][N:8]=[C:7]([CH3:15])[CH:6]=1)[CH2:2][CH3:3].C(OC(=O)C)(=O)C.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH:15]([C:7]1[CH:6]=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[C:10]([CH2:11][CH2:12][CH2:13][CH3:14])=[CH:9][N:8]=1)=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCCCc1cnc(C)cc1OCCC
Reactant: O=Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCCCc1cnc(C=Cc2ccccc2)cc1OCCC

Procedure:
22.6 g of 4-n-propoxy-5-n-butyl-2-picoline and 60 ml of benzaldehyde are heated with 66 ml of acetic anhydride for 16 hours under reflux. After cooling, the mixture is evaporated, 2 N sodium hydroxide solution is added and the whole is extracted with ether. Distillation of the ether residue in a bulb tube at a temperatre of 160°-180° in a high vacuum yields 2-styryl-4-n-propoxy-5-n-butyl-pyridine.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:21][O:22][C:23](=[O:28])[C:24](OC)=[O:25].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:21][O:22][C:23](=[O:28])[C:24]([OH:25])=[CH:9][C:8](=[O:10])[N:7]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:20][CH:19]=1
Reactant: CC(=O)N(Cc1ccc(F)cc1)Cc1ccc(F)cc1
Reactant: COC(=O)C(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)cc1)Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
N,N-Bis-(4-fluoro-benzyl)-acetamide (15.0 grams, 54.5 mmol) and dimethyloxalate (9.6 grams, 81.3 mmol) were dissolved in 54 mL of THF. After cooling to 0° C. 108 mL of 1N LiHMDS (THF) was added dropwise. The reaction mixture was stirred 1 hr then quenched with 1N HCl. The resulting mixture was extracted with CH2Cl2, dried over Na2SO4, filtered and the solvent removed under vacuum. The product was purified by flash column chromatography (SiO2, 80:20 hexanes/EtOAc) to yield 10 grams (53% yield) of 3-[bis-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic acid methyl ester as a solid. Mp=118–120° C. Anal. calcd for C19H17F2NO4: C, 63.15; H, 4.74; N, 3.87. found: C, 62.97; H, 4.72; N, 3.81. 1H NMR (500 MHz, CDCl3) δ: 3.87 (s, 3), 4.46 (s, 2), 4.58 (s, 2), 6.32 (s, 1), 7.00–7.26 (overlapping m, 8). 13C NMR (125 MHz, CDCl3) δ: 47.34, 49.35, 53.03, 93.34, 115.66, 115.83, 116.00, 116.18, 128.45, 128.52, 130.03, 130.10, 131.09, 131.93, 131.95, 160.29, 161.44, 161.51, 163.10, 163.41, 163.47, 171.36.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:3].Cl[C:12]1[N:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1.C(N(CC)CC)C>C(#N)C>[CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([O:10][C:12]2[N:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: CC(C)c1cccc(O)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)c1cccc(Oc2ncc([N+](=O)[O-])cn2)c1
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To a solution of 3-(1-methylethyl)phenol (680 mg, 5 mmol, Aldrich) in acetonitrile (50 mL) were added 2-chloro-5-nitropyrimidine (800 mg, 5 mmol) and triethylamine (1.01 g, 10 mmol) and the resulting mixture was heated at reflux and stirred for 3 hours. The reaction mixture was concentrated under vacuum and water was added to the residue (80 mL). It was extracted with ethyl acetate (3 times 50 mL) and the combined organic layers were dried over sodium sulphate and evaporated to afford a brown oil, which was purified by silica gel chromatography (mobile phase: ethyl acetate: petroleum ether=0˜20%) to afford the title compound (900 mg).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[CH2:18]([NH2:21])[CH2:19][CH3:20]>C(O)C>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])=[N:21][CH2:18][CH2:19][CH3:20])#[N:2]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: CCCN
Solvent: CCO
Product: CCCN=C(NC#N)NCCSCc1[nH]cnc1C
Yield: 71.4 %

Procedure:
A solution of N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (2.69 g.) and n-propylamine (1.1 g.) in ethanol (50 ml.) was heated under reflux for 6 hours. Concentration, followed by chromatographic purification on a column of silica gel with ethyl acetate-isopropyl alcohol (4:1) as eluant and final recrystallisation from aqueous isopropyl alcohol afforded N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N"-propylguanidine (2.0 g.) m.p. 108°-110°. (Found: C, 51.4; N, 7.4; N, 30.0; S, 11.4. C12H20N6S requires: C, 51.4; H, 7.2; N, 30.0; S, 11.4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[CH:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1.ClC1C=CC=C(C(OO)=[O:32])C=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[CH:13][N:14]=[C:10]3[CH2:9][N+:8]([O-:32])=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1
Reactant: Cc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=[N+]([O-])C2
Temperature: 0 °C

Procedure:
A stirred mixture is 1.0 g. of 8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,2-a][1,4]benzodiazepine (Ia) in absolute ethanol in an ice bath is treated with 1.0 g. of m-chloroperbenzoic acid. The mixture is allowed to stand in the ice bath for about 8 hours at room temperature at about 24° C. for approximately 18 hours. It is then concentrated in vacuo, the residue thus obtained is suspended in aqueous, cold, dilute potassium carbonate solution and extracted with methylene chloride. The extract is washed with water, dried and concentrated in vacuo. The residue thus obtained is chromatographed on 100 g. of silica gel to give 8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,2-a][1,4]benzodiazepine-5-oxide