Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[C:7]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:6][C:5]=1[NH2:21])([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH:30](OC)(OC)OC.CN(C=O)C>C(O)(=O)C>[N:15]1([C:7]2[C:8]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:9][C:4]3[NH:1][CH:30]=[N:21][C:5]=3[CH:6]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Nc1cc(N2CCCCC2)c(OC(F)(F)F)cc1[N+](=O)[O-]
Reactant: COC(OC)OC
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1cc2[nH]cnc2cc1N1CCCCC1
Temperature: 100 °C
Yield: 70.2 %

Procedure:
A mixture of 2-nitro-5-piperidin-1-yl-4-trifluoromethoxy-phenylamine (0.900 g, 2.94 mmol), sodium dithionite (2.67 g, 15.3 mmol), trimethyl orthoformate (8.72 mL, 79.6 mmol), DMF (8.56 mL), and acetic acid (1.45 mL) was heated in a sealed tube for 15 h at 100° C. The reaction mixture was cooled to 23° C. and partitioned between EtOAc (80 mL) and saturated aqueous NaHCO3 (80 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (2×80 mL). The combined organic layers were dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (0-15% MeOH/DCM) to yield the titled compound (0.589 g, 71%). MS (ESI/CI): mass calcd. for C13H14F3N3O, 285.1; m/z found, 286.1 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([C:17]([OH:19])=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:22])=O>>[C:1]1([C:7]2[CH:16]=[C:15]([C:17]([Cl:22])=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cc(-c2ccccc2)nc2ccccc12
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(-c2ccccc2)nc2ccccc12

Procedure:
2-phenyl-4-quinolinecarbonyl chloride was synthesized from commercially available 2-phenyl-4-quinolinecarboxylic acid and thionyl chloride according to a routine method.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[CH3:17][N:18]1[C:22]2[C:23]([CH3:38])=[CH:24][C:25]([C:27]([C:29]3[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31](F)[CH:30]=3)=[O:28])=[CH:26][C:21]=2[O:20][C:19]1=[O:39]>CN(C=O)C>[CH3:17][N:18]1[C:22]2[C:23]([CH3:38])=[CH:24][C:25]([C:27]([C:29]3[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31]([N:1]4[CH2:2][CH2:3][CH:4]([N:7]5[C:15]6[C:10](=[N:11][CH:12]=[CH:13][CH:14]=6)[NH:9][C:8]5=[O:16])[CH2:5][CH2:6]4)[CH:30]=3)=[O:28])=[CH:26][C:21]=2[O:20][C:19]1=[O:39]
Reactant: Cc1cc(C(=O)c2ccc(C#N)c(F)c2)cc2oc(=O)n(C)c12
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2ccc(C#N)c(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)c2)cc2oc(=O)n(C)c12
Temperature: 300 °C

Procedure:
0.26 g (1.2 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 93 mg (0.30 mmol) 4-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-2-fluoro-benzonitrile were combined and heated to 300° C. for approx. 10 min. Then the mixture was dissolved in DMF and purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down. The residue was neutralised with 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: Cl.Cl[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N+:4]=1[O-:13].[N-:14]=[N+:15]=[N-:16].[Na+].O>CC(C)=O>[N:14]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N+:4]=1[O-:13])=[N+:15]=[N-:16]
Reactant: [O-][n+]1c(Cl)ccc2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=Nc1ccc2ccccc2[n+]1[O-]

Procedure:
In this example, 2.00 grams (0.009 mol) of 2-chloroquinoline N-oxide hydrochloride and 2.00 grams (0.031 mol) of sodium azide were added to and dissolved in 50 ml. of water and 100 ml. of acetone and the resulting solution stirred for 72 hours at 25° C. A solid separated and was collected by filtration. Recrystallization of this solid from benzene gave 2-azidoquinoline N-oxide in a yield of 1.01 grams or 58% of theory having a melting point of 103.5° C. to 104.5° C. with decomposition.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C:9]1([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([C:28]3[CH:33]=[C:32]([NH:34][C:35]4[N:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][N:36]=4)[CH:31]=[C:30]([CH3:45])[CH:29]=3)[CH:27]=2)[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1>ClCCl.[NH4+].[OH-]>[CH3:45][C:30]1[CH:29]=[C:28]([C:26]2[CH:27]=[C:22]([C:9]3([OH:8])[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)[CH:23]=[N:24][CH:25]=2)[CH:33]=[C:32]([NH:34][C:35]2[N:40]=[C:39]([C:41]([F:43])([F:44])[F:42])[CH:38]=[CH:37][N:36]=2)[CH:31]=1.[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncc(C3(O)CCN(C(=O)OC(C)(C)C)CC3)c2)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncc(C3(O)CCNCC3)c2)c1
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (262 μL, 3.40 mmol) was added to a solution of tert-butyl 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-3-yl]piperidine-1-carboxylate (180 mg, 0.340 mmol) in dichloromethane (1.70 mL). The reaction mixture was stirred for 2 hours, diluted with 10% aqueous NH4OH (1.00 mL) and the precipitated solid was collected by filtration to yield 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-3-yl]piperidin-4-ol as a TFA salt. MS APCI calc'd for C22H23F3N5O [M+H]+ 430. found 430. 1H NMR (500 MHz, DMSO-d6) δ 8.82 (d, J=5.2 Hz, 1H), 8.66 (s, 2H), 8.01 (s, 1H), 7.98 (s, 1H), 7.56 (s, 1H), 7.26 (d, J=5.0 Hz, 1H), 7.20 (s, 1H), 3.04-2.92 (m, 2H), 2.76 (br m, 2H), 2.36 (s, 3H), 1.99-1.75 (br m, 2H), 1.69-1.49 (br m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][OH:5].Cl[C@@H:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C@H:14]1[NH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[Ba+2].C(OCC)(=O)C>CN(C)C=O>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]([NH:1][C@@H:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][C@H:14]2[NH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:3]([CH2:4][OH:5])[CH:6]=1
Reactant: COc1ccc(N)c(CO)c1
Reactant: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Cl
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Nc1ccc(OC)cc1CO
Yield: 43.8 %

Procedure:
A solution of 2-amino-5-methoxybenzyl alcohol (5 g; 32.7 m.mol) and trans-1-chloro-2-ethoxycarbonylaminoindane (7.83 g; 32.7 m.mol) in dimethylformamide (80 ml) was treated with barium carbonate (3.37 g; 17 m.mol) in a manner similar to that in Description 3 to give the title compound (5.1 g; 44%), m.p. 142°-144° (from ethyl acetate).
Reaction SMILES: C1C(C(CBr)=[O:8])=CC=C(Br)C=1.[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]2[C:22]3[CH:29]=[CH:28][N:27]([CH3:30])[C:23]=3[N:24]=[CH:25][N:26]=2)[CH:16]=[CH:17][C:18]=1[F:19]>C(O)(C)(C)C.C(O)(=O)C.[Zn]>[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]2[C:22]3[CH2:29][C:28](=[O:8])[N:27]([CH3:30])[C:23]=3[N:24]=[CH:25][N:26]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: Cn1ccc2c(Nc3ccc(F)c(Cl)c3)ncnc21
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: [Zn]
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: CN1C(=O)Cc2c(Nc3ccc(F)c(Cl)c3)ncnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.1 %

Procedure:
PBPB (2.8 g, 7.8 mmol) was added portionwise to the (3-chloro-4-fluoro-phenyl)-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (1.08 g, 3.9 mmol) suspended in tert-butanol (20 mL) and acetic acid (10 mL). After stirring at room temperature for 18 hours, to the mixture was added zinc dust (760 mg, 11.7 mmol) portionwise and stirring was continued for overnight. The precipitate was filtered off and the filtrate was concentrated. The residue was triturated with little water and the precipitate was collected by vacuum filtration, washed with little ethyl acetate and dried to give 1.12 g (98%) of 4-(3-chloro-4-fluoro-phenylamino)-7-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one as a tan colored solid. 1H NMR (DMSO-d6) 9.07 (s, 1H, NH), 8.42 (s, 1H), 8.01 (d, J=2.6 & 7.2 Hz, 1H) 7.56 (m, 1H), 7.34 (t,J=9.1 Hz, 1H), 3.48 (s, 2H, CH2), 3.07 (s, 3H, CH3).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][C@H:5]([OH:7])[C@H:4]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][C:14](O)=[O:15])[C@H:3]1[CH:17]=[CH:18][C@H:19]([OH:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH2:42]([NH2:44])[CH3:43]>C(Cl)Cl>[CH3:43][CH2:42][NH:44][C:14]([CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][C@@H:4]1[C@@H:3](/[CH:17]=[CH:18]/[C@@H:19]([OH:28])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:2]([OH:1])[CH2:6][C@@H:5]1[OH:7])=[O:15]
Reactant: CCN
Reactant: O=C(O)CCC/C=C\C[C@@H]1[C@@H](C=C[C@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Temperature: -10 °C
Reaction time: 2 h
Yield: 120.8 %

Procedure:
250 mL of methylene chloride were added to 12.3 g of (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenyl-pent-1-enyl)-cyclopentyl]-hept-5-enoic acid (compound (7), MW=402.54; 26.1 mmol; 1 equivalents). The solution is cooled to −10° C. At this temperature 5.1 g of triethylamine (MW=101.19; 50.4 mmol; 1.9 equivalents) and 5.1 g of ethyl chloroformate (MW=108.52; 48.1 mmol; 1.8 equivalents) were added and the mixture was stirred for two hours. A solution of 2.3 g of ethylamine (MW=45.08; 2.0 equivalents) in 10 mL methylenehloride was added. After stirring the reaction mixture for two hours at −10° C., the mixture was warmed to room temperature. The reaction was quenched by addition of 250 mL of water and the pH is adjusted to 2.0 with 1M aqueous hydrochloric acid. After separation of the layers, the organic layer was washed with 250 mL of saturated aqueous sodium bicarbonate, water and brine. After filtration the solution was concentrated under reduced pressure to give 13.1 g of bimatoprost crude (yield: 89%; as determined by NMR). Bimatoprost crude was purified as described below.
Reaction SMILES: Br[C:2]1[CH:15]=[N:14][C:5]2[NH:6][CH2:7][CH2:8][C:9](=[O:13])[N:10]([CH3:12])[CH2:11][C:4]=2[CH:3]=1.[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH:17]=[CH2:18].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:12][N:10]1[C:9](=[O:13])[CH2:8][CH2:7][NH:6][C:5]2[N:14]=[CH:15][C:2](/[CH:18]=[CH:17]/[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:3][C:4]=2[CH2:11]1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CN1Cc2cc(Br)cnc2NCCC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1Cc2cc(/C=C/C(=O)OC(C)(C)C)cnc2NCCC1=O
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A suspension of 8-bromo-5-methyl-2,3,5,6-tetrahydropyrido[2,3-b][1,5]diazocin-4(1H)-one (670 mg, 2.48 mmol), tert-butyl acrylate (1.8 mL, 12.4 mmol) and (i-Pr)2EtN (1.3 mL, 7.44 mmol) in 30 mL of DMF:Propionitriole (4:1) was de-oxygenated with Ar for 30 min. The mixture was treated with Pd(OAc)2 (19.4 mg, 0.09 mmol) and P(o-tol)3 (51.7 mg, 0.18 mmol) then heated to 110° C. for 16 h. The hot mixture was filtered through a pad of celite. The filtrate was diluted with 100 mL H2O then extracted with 2×100 mL ethyl acetate. The resulting brown solid was triturated with a solution of hexanes:ethyl acetate (4:1) followed by filtration to yield the brown solid product. Yield 391 mg (50%); 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.51 (s, 1H), 7.49 (d, J=16.4 Hz, 1H), 6.26 (d, J=16.0 Hz, 1H), 5.22 (bm, 1H), 4.55 (s, 2H), 3.66 (q, J=7.2 Hz, 2H), 3.07 (t, J=7.2 Hz, 2H), 2.81 (s, 3H), 1.55 (s, 9H); ESI MS m/z 318 [C17H23N3O3+H]+
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[F:12][C:13]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:14]=1[NH2:15]>CS(C)=O>[Br:1][C:2]1[C:3]([NH:15][C:14]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:13]=2[F:12])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Reactant: Nc1ccc(F)cc1F
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cnc(Nc2ccc(F)cc2F)c(Br)c1
Temperature: 100 °C
Yield: 53 %

Procedure:
A mixture of 3-bromo-2-chloro-5-nitropyridine (2.374 g, 10 mmol) and 2,4-difluoroaniline (2.58 g, 20 mmol) in dimethylsulfoxide (20 mL) was heated at 100° C. for 2 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate filtered, and concentrated. The residue was purified on silica gel eluting with 1:20 ethyl acetate/heptanes to give the title compound (1.75 g, 5.30 mmol, 53.0% yield) as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([CH3:13])[CH3:12])[N:6]=[C:5]2[C:14]([OH:16])=O.[NH2:17][C@@H:18]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:20]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH2:19]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([CH3:12])[CH3:13])[N:6]=[C:5]2[C:14]([NH:17][C@@H:18]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[C@H:20]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH2:19]1)=[O:16]
Reactant: COC(=O)C[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Reactant: CC(C)n1nc(C(=O)O)c2cc(F)ccc21
Product: COC(=O)C[C@@H]1C[C@H](NC(=O)c2nn(C(C)C)c3ccc(F)cc23)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 7 from 5-fluoro-1-isopropyl-1H-indazole-3-carboxylic acid (step 2 of Example 11) and tert-butyl (2S,4S)-4-amino-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (step 4 of Example 9).
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:22][CH2:21][C:20]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:23])[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2)#[N:2].[OH:33][Li].O.OO>CO>[C:1]([CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:18][CH2:19][C:20]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])([CH3:23])[CH2:21][CH2:22]4)[C:6]=3[C:5]1=2)(=[O:33])[NH2:2]
Reactant: CN(C(=O)OC(C)(C)C)C1(C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CC#N)CC4)CC1
Reactant: [Li]O
Agent: OO
Solvent: O
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C1(C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
To a solution of tert-butyl N-(4-[[(3R)-3-(cyanomethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-methylcyclohexyl)-N-methylcarbamate (100 mg, 0.2 mmol, 1.00 equiv) in 10 mL of methanol was added LiOH.H2O (30 mg, 0.7 mmol, 3.26 equiv) and H2O2 (30%, 0.8 mL) and stirred for 4 h at 0° C. The reaction was then quenched with saturated aqueous NaHSO3, extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel with EtOAc/PE (1:2) to give the desired tert-butyl N-(4-[[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-methylcyclohexyl)-N-methylcarbamate (85 mg) as a light yellow oil.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[C:5]([O:8][N:9]=[CH:10][CH:11]=[N:12][OH:13])(=[O:7])[CH3:6]>>[C:5]([O:8][N:9]=[CH:10][CH:11]=[N:12][O:13][C:3](=[O:4])[NH:2][CH3:1])(=[O:7])[CH3:6]
Reactant: CN=C=O
Reactant: CC(=O)ON=CC=NO
Product: CNC(=O)ON=CC=NOC(C)=O
Reaction time: 4 h
Yield: 90 %

Procedure:
1 Part of methylisocyanate is added to a solution of 1 part of mono-O-acetylglyoxime (Example 1) in 5 parts of acetronitrile, and stirring carried out for 4 hours at 20°. The precipitated product is filtered off; mp. 138°; yield 90%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH:10]1([C:13]([CH3:18])([CH3:17])[CH2:14][CH:15]=O)[CH2:12][CH2:11]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:15]/[CH2:14][C:13]([CH:10]1[CH2:12][CH2:11]1)([CH3:18])[CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(CC=O)C1CC1
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C/N=C/CC(C)(C)C1CC1
Yield: 75.2 %

Procedure:
Step E In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with 3-cyclopropyl-3-methyl-butyraldehyde (0.68 g, 5.3 mmol) in CH2Cl2 at room temperature for 5 h to give [3-cyclopropyl-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (0.9 g, 75%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].Br[C:20]1[S:21][C:22]([N+:25]([O-:27])=[O:26])=[N:23][N:24]=1.C([O-])([O-])=O.[K+].[K+].Cl>C(#N)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:20]3[S:21][C:22]([N+:25]([O-:27])=[O:26])=[N:23][N:24]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: O=[N+]([O-])c1nnc(Br)s1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc([N+](=O)[O-])s3)cc(C)c21
Temperature: -20 °C
Reaction time: 84 h

Procedure:
To a solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (2.55 g, 10.2 mmol) in anhydrous acetonitrile (150 mL) was added 2-bromo-5-nitro-[1,3,4]thiadiazole (3.0 g, 14.3 mmol) at 0° C. The reaction mixture was cooled to −20° C. and K2CO3 (9.87 g, 71.4 mmol) was added. After stirring at −20 to −25° C. for 3.5 days, the reaction mixture was acidified to pH 2 with dilute hydrochloric acid at 0° C. and extracted with EtOAc. The organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (EtOAc/hexanes/AcOH=2:1:trace) followed by recrystallization from methanol to give pure product as a white powder after lyophilization (1.35 g, 34.9%). 1HNMR (400 MHz, DMSO-d6) δ9.41 (s, 1H), 7.54 (d, J=2.34 Hz, 1H), 7.41 (d, J=1.76 Hz, 1H), 5.58 (dd, J=8.64, 2.78 Hz, 1H), 4.02 (q, J=7.22 Hz, 2H), 3.14 (dd, J=15.52, 2.63 Hz, 1H), 2.23-2.43 (m, 4H), 1.12 (t, 3H). MS (ESI) m/z=378 [M−H]−.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.Cl.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[CH2:22][NH:21][CH2:20][CH2:19]2.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[CH2:22][N:21]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)[CH2:20][CH2:19]2
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COc1cc2c(cc1OC)CN(CCc1ccc([N+](=O)[O-])cc1)CC2
Yield: 71.6 %

Procedure:
A mixture of 1-(2-bromoethyl)-4-nitrobenzene (9.64 g), 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline hydrochloride (10.59 g) and potassium carbonate (17.38 g) in isopropanol (150 ml) was refluxed for 48 h. The mixture was then filtered and the filtrate evaporated to dryness. The resulting residue was taken up in water and extracted with dichloromethane. The organic layer was washed with water, dried and evaporated to give an oil which crystallised in a mixture of 2-propanol and diethyl ether to give the title compound (10.27 g). M.p.: 118°-119°.
Reaction SMILES: C([O:4][C:5]([CH3:22])([CH3:21])[CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:12]([O-])=[CH:11][C:10]=2[N:9]=[CH:8]1)(=O)C.CN(C)C=O.P(Cl)(Cl)([Cl:30])=O>ClCCl>[Cl:30][C:11]1[C:10]2[N:9]=[CH:8][N:7]([CH2:6][C:5]([OH:4])([CH3:22])[CH3:21])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CC(=O)OC(C)(C)Cn1cnc2c[n+]([O-])c3ccccc3c21
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1cnc2c(Cl)nc3ccccc3c21
Reaction time: 1 h

Procedure:
To a stirred solution of 1.5 g of crude 1-(2-acetoxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-5-oxide from Part C in 10 ml of dichloromethane and 2 ml of N,N-dimethylformamide was added 0.843 g (0.0055 mole) of phosphorus oxychloride. After stirring for one hour, the mixture was evaporated to dryness. Hydrochloric acid was added to the residue, then the mixture was basified with ammonium hydroxide. The product was separated by filtration, washed with water and dried. Recrystallization from ethanol of a portion of the product provided 4-chloro-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinoline, m.p. 196°-199° C. Analysis: Calculated for C14H14ClN3O: %C, 61.0; %H, 5.2; %N, 15.2; Found: %C, 60.9; %H, 5.3; %N, 15.1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:16][CH:15]=2)=[NH:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)(O)[O-].[Na+].Br[CH2:31][C:32](=O)[C:33]([F:36])([F:35])[F:34]>CC(O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:31]=[C:32]([C:33]([F:36])([F:35])[F:34])[N:13]=[C:12]2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:16][CH:15]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: O=C(CBr)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(-c3cccs3)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccc(-c3cccs3)cc2)cc1
Temperature: 80 °C
Yield: 39.9 %

Procedure:
To a mixture of N-[4-(methylsulfonyl)phenyl]-4-(2-thienyl)benzenecarboximidamide (0.7 g, 1.96 mmol) and sodium bicarbonate (0.33 g, 3.93 mmol) in 2-propanol (30 mL) was added 3-bromo-1,1,1-trifluoroacetone (0.449 g, 2.35 mmol). After the reaction mixture was heated to 80° C. for 21 hours, the solvent was removed. The residue was redissolved in CH2Cl2 (50 mL) and washed with water (30 mL×2). The organic fractions were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was purified by flash chromatography eluting with hexane/ethyl acetate (2/1) to give the subtitle compound (0.351 g, 30.1% yield, via 2 steps).
Reaction SMILES: O.O.[Sn](Cl)Cl.[C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2C=C[C:17]([NH2:20])=[C:16]([N+:21]([O-])=O)[CH2:15]2)=[CH:10][CH:9]=1)#[N:7].[CH2:24](O)[CH3:25]>Cl.O>[NH2:21][C:16]1[CH:17]=[N:20][CH:24]=[CH:25][C:15]=1[NH:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]#[N:7])=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(N2C=CC(N)=C([N+](=O)[O-])C2)cc1
Reactant: CCO
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: N#Cc1ccc(Nc2ccncc2N)cc1
Temperature: 0 °C

Procedure:
According to a modification of the method of Pharm. Helv. Acta, 1975, 50, 188., tin dichloride dihydrate (56.4 g, 250 mmol) was added to a suspension of N-(4-cyanophenyl)-4-amino-3-nitropyridine (12.0 g, 50 mmol) in 2N aqueous hydrochloric acid (35 ml), water (150 ml) and ethanol (75 ml) and the resulting mixture was heated to reflux for 10 minutes under nitrogen. The mixture was cooled in ice, poured into ice-cold 2N aqueous sodium hydroxide (400 ml) and filtered. The creamy-coloured solid was washed with 2N aqueous sodium hydroxide and water, and then dried in a vacuum desiccator. The product, 3-amino-4-(4'-cyanophenyl)-aminopyridine, 9.31 g, gradually turns reddish brown on exposure to light and air.