Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[C:16]([CH:19]3[CH2:24][CH2:23][N:22](C(OCC)=O)[N:21](C(OCC)=O)[CH2:20]3)[S:17][CH:18]=2)[CH2:10]1.[OH-].[K+].Cl.C(=O)(O)[O-].[Na+]>C(O)C.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[C:16]([CH:19]3[CH2:24][CH2:23][NH:22][NH:21][CH2:20]3)[S:17][CH:18]=2)[CH2:10]1
Reactant: CCOC(=O)N1CCC(c2nc(C3=NOC(c4c(F)cccc4F)C3)cs2)CN1C(=O)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Fc1cccc(F)c1C1CC(c2csc(C3CCNNC3)n2)=NO1
Temperature: 70 °C

Procedure:
A mixture of 1,2-diethyl 4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]tetrahydro-1,2-pyridazinedicarboxylate (i.e. the product of Step G) (4.09 g, 0.0083 mol) and potassium hydroxide (2.32 g, 0.0414 mol) in ethanol (50 mL) and water (5 mL) was heated at reflux for 20 h. The reaction mixture was cooled, acidified by the addition of concentrated hydrochloric acid, and then warmed to about 70° C. for 10 minutes. The reaction mixture was cooled, neutralised by the addition of sodium bicarbonate. The reaction mixture was concentrated under reduced pressure and the resulting matterial was extracted with diethyl ether (3×), dried over magnesium sulfate, filtered and concentrated under reduced pressure to a tan oil (2.99 g). The oil was adsorbed onto Celite® (diatomaceous filter aid), and then by purified by silica gel column chromatography (5% to 100% gradient of methanol in chloroform as eluant) to provide the title compound (1.275 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][CH2:8][C:9](OCC)=[O:10])=[CH:5][N:4]=[C:3]1[CH2:14][CH3:15].[H-].[H-].[H-].[H-].[Li+].[Al+3].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[OH:10][CH2:9][CH2:8][CH2:7][C:6]1[N:2]([CH3:1])[C:3]([CH2:14][CH3:15])=[N:4][CH:5]=1
Reactant: CCOC(=O)CCc1cnc(CC)n1C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCc1ncc(CCCO)n1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 22.8 %

Procedure:
To a cooled (0° C.) solution of ethyl 3-(1-methyl-2-ethylimidazol-5-yl)propionate (1.75 g, 8:33 mmol) in 30 ml of THF was added 4.6 ml (4.6 mmol) of 1M LAH solution in THF at 0° C. After stirring at 0° C. for 15 min, the mixture was allowed to warm and stirred at 20° C. for 0.7 h. Rochelle salt solution (equiv) was added and the mixture was stirred for 20 min. The aqueous mixture was extracted with methylene chloride and filtered. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica (10 cm column, methylene chloride/methanol, 6/1-6/1) followed by recrystallization from acetonitrile/ether and methylene chloride/hexane to afford 1.268 g (90%) of 5-(3-hydroxypropyl)-1-methyl-2-ethylimidazole, as a white solid, m.p. 69°-71° C.
Reaction SMILES: [CH2:1]([CH:8]1[NH:12][CH:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C@H](C(O)=O)CS.C1(CC=O)C=CC=CC=1>>[CH2:1]([CH:8]1[NH:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CSC(Cc2ccccc2)N1
Agent: N[C@@H](CS)C(=O)O
Agent: O=CCc1ccccc1
Product: O=C(O)[C@@H]1CSC(Cc2ccccc2)N1

Procedure:
F (2RS, 4R) -2-Benzyl-4-thiazolidinecarboxylic acid may be prepared in a manner similar to that described in Example 1E, but starting with 53.7 g of L-cysteine and 56.5 g of phenylacetaldehyde. 75.8 g of (2RS,4R)-2-benzyl-4-thiazolidinecarboxylic acid, melting point 200° C., are thereby obtained.
Reaction SMILES: [CH2:1]([N:3]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:4][CH2:5][CH2:6][N:7]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:8]/[CH:9]=[CH:10]/[CH2:11][N:12]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:2].[H-].[Na+].[CH3:47]I>CN(C=O)C>[CH2:1]([N:3]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:4][CH2:5][CH2:6][N:7]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:8]/[CH:9]=[CH:10]/[CH2:11][N:12]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:13][CH2:14][CH2:15][N:16]([CH3:47])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:2]
Reactant: CCN(CCCN(C/C=C/CN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CCCN(C/C=C/CN(CCCN(C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
To a solution of 0.46 g (0.73 mmol) of (E)-1-ethyl-1,5,10,14-tetra-BOC-1,5,10,14-tetraazatetradec-7-ene (see Example 5a) in 6 ml of DMF there are added, with stirring, 0.059 g (1.47 mmol) of sodium hydride dispersion (approx. 60% ) and, after 5 min., 0.092 ml (1.47 mmol) of methyl iodide. The reaction mixture is stirred for 15 h at room temperature; a further 0.029 g (0.725 mmol) of sodium hydride dispersion (approx. 60%) and 0.045 ml (0.721 mmol) of methyl iodide are added, and the mixture is stirred for a further 96 h at 20° C. and is then concentrated by evaporation in vacuo. Working up analogously to Example 1a), but using ethyl acetate-hexane (1:2) in the flash chromatography, yields the title compound, Rf value=0.42 (silica gel/ethyl acetate:hexane (1:1)).
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[C:20]1([CH2:33][NH2:34])[C:32]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(O)C>[C:20]1([CH2:33][NH:34][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[C:32]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: NCc1cccc2c1Cc1ccccc1-2
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(NCc4cccc5c4Cc4ccccc4-5)ncnc32)[C@H](O)[C@@H]1O
Yield: 62.8 %

Procedure:
A mixture of 2.97 g of 6-chloropurine riboside, 2.25 g of fluorenylmethyl amine and 1.31 g of triethylamine is refluxed in 70 ml of ethanol under nitroen for 20 hrs. Upon cooling, solid material crystallizes out which is filtered and retreated with boiling ethanol. Solid material obtained is filtered and dried affording 2.9 g (63%) of N6 -fluorenylmethyl adenosine having a melting point of 139°-142° C.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([S:16]([OH:19])(=[O:18])=[O:17])[CH:10]=[CH:9]2.[ClH:20]>O>[Cl:20][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([S:16]([OH:19])(=[O:18])=[O:17])[CH:10]=[CH:9]2
Reactant: Nc1ccc2cc(S(=O)(=O)O)ccc2c1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)c1ccc2cc(Cl)ccc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium nitrite (2.7 g) in water (5 ml) was added during 2 hours to a stirred mixture of 6-amino-2-naphthalenesulphonic acid (8.8 g), dilute aqueous hydrochloric acid (2.8% weight/volume, 20 ml) and water (15 ml) which had been cooled to 0° C. The mixture was stirred at 0° C. for 30 minutes and then poured onto a stirred suspension of cuprous chloride (3.96 g) in dilute aqueous hydrochloric acid (2.8%, 20 ml). The mixture was stored at ambient temperature for 18 hours. The mixture was evaporated to give 6-chloro-2-naphthalenesulphonic acid which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[CH:36]1([NH2:39])[CH2:38][CH2:37]1>>[CH:36]1([NH:39][C:2]2[N:7]=[C:6]([C:8]3[S:12][C:11]([C:13]([CH3:15])([CH3:16])[CH3:14])=[N:10][C:9]=3[C:17]3[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]4[C:28]([F:34])=[CH:29][CH:30]=[CH:31][C:32]=4[F:33])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=3)[CH:5]=[CH:4][N:3]=2)[CH2:38][CH2:37]1
Reactant: NC1CC1
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(NC3CC3)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 290 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (250 mg, 0.464 mmol) and cyclopropylamine (0.163 mL, 2.31 mmol), the title compound was obtained as a white solid (40 mg, 14%). MS (ESI): 560 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][N:5]([CH3:7])[CH:6]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][C:44]=1[CH3:45])[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[N:32]=1>CN(C)C=O.CN(C)C(=O)C>[Cl:1][C:2]1[C:3]([C:8]([NH:22][C:23]2[CH:24]=[C:25]([O:26][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]5[CH2:40][CH2:41]5)=[O:38])[N:35]=4)[N:32]=3)[CH:42]=[CH:43][C:44]=2[CH3:45])=[O:10])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cn1cc(Cl)c(C(=O)O)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1nn(C)cc1Cl
Yield: 81.4 %

Procedure:
In the same manner as in Example 259 and using 4-chloro-1-methyl-1H-pyrazole-3-carboxylic acid (130 mg, 0.80 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (170 μL, 2.0 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (235 mg, 82%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=1)#[CH:13].N>>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([C:12]2[O:9][N:8]=[C:7]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:13]=2)[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=1
Reactant: C#Cc1cc(OC)cc(OC)c1
Reactant: ON=C(Cl)c1cncc(F)c1
Agent: N
Product: COc1cc(OC)cc(-c2cc(-c3cncc(F)c3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of product of Example 28B (88 mg, 0.5 mmol) and 1-ethynyl-3,5-dimethoxybenzene (Aldrich, 81 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) 83.87 (s, 6H), 6.64 (t, J=2.2 Hz, 1H), 7.06 (d, J=2.4 Hz, 2H), 7.40 (s, 1H), 8.16 (ddd, J=9.2, 2.7, 1.7 Hz, 1H), 8.60 (d, J=2.7 Hz, 1H), 8.96 (t, J=1.5 Hz, 1H) ppm; MS (DCI/NH3) m/z 301 (M+H)+.
Reaction SMILES: CCN(CC)CC.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[N:13]1([NH2:19])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(Cl)Cl>[N:13]1([NH:19][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: NN1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NN1CCOCC1
Temperature: 25 °C

Procedure:
Using the adapted Tozer procedure of Example 1, NEt3 (2.8 mL) and methanesulfonyl chloride Compound 1i (2.3 g, 20.0 mmol) were added to a solution of morpholin-4-ylamine Compound 11a (2.1 g, 20.0 mmol) in 20 mL of CH2Cl2 at 0° C. under a N2 atmosphere. The mixture was stirred and warmed to ambient temperature over a 2 hr period, then the reaction was quenched with water (10 mL). The organic layer was diluted with CH2Cl2 (60 mL) and washed with water and brine, separated and dried with anhydrous Na2SO4, then filtered and concentrated in vacuo to afford N-morpholin-4-yl-methanesulfonamide Compound 11b as an oil.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([CH3:20])[CH:14]=1)#[CH:12].N>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH:12]=2)=[CH:14][C:15]=1[CH3:20]
Reactant: ON=C(Cl)c1cccnc1
Reactant: C#Cc1ccc(F)c(C)c1
Agent: N
Product: Cc1cc(-c2cc(-c3cccnc3)no2)ccc1F

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 4-ethynyl-1-fluoro-2-methylbenzene (Aldrich, 67 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 1.96 (s, 3H), 7.38 (t, J=9.6 Hz, 1H), 7.62-7.75 (m, 2H), 7.80 (ddd, J=7.9, 5.4, 2.2 Hz, 1H), 7.89 (dd, J=6.9, 1.8 Hz, 1H), 8.42 (dt, J=8.1, 1.8, 1.6 Hz, 1H), 8.79 (dd, J=5.2, 1.6 Hz, 1H), 9.16 (d, J=2.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 255 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=O)C.[C:11]1([OH:17])C=CC=C[CH:12]=1>>[CH3:12][C:11]([C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=1)=[O:17]
Reactant: CC(=O)Oc1ccccc1
Reactant: Oc1ccccc1
Product: CC(=O)c1ccc(O)cc1

Procedure:
4-Acetoxyacetanilide is produced by subjecting phenyl acetate to a Fries rearrangement or phenol and an acetylating agent to a Friedel-Crafts acetylation to form 4-hydroxyacetophenone which is then reacted with hydroxylamine or a hydroxylamine salt to form 4-hydroxyacetophenone oxime. The oxime is then subjected to a Beckmann rearrangement and accompanying acetylation with acetic anhydride to form the 4-acetoxyacetanilide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[C:29]([Cl:36])[CH:28]=1>C1(C)C=CC=CC=1>[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([N:17]([C:16]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:35])=[C:29]([Cl:36])[CH:28]=1
Reactant: Clc1ccc(-n2nc3ccccc3c2Nc2ccccc2)cc1
Reactant: COC(=O)c1ccc(N=C=O)c(Cl)c1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(NC(=O)N(c2ccccc2)c2c3ccccc3nn2-c2ccc(Cl)cc2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-phenyl-amine (example 15.1) was reacted with 3-chloro-4-isocyanato-benzoic acid methyl ester (example 9.1) in toluene for 7 days under reflux conditions to give the title compound as yellow foam. MS: m/e=530.7 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]3[O:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[C:5]([N+:16]([O-:18])=[O:17])=[C:4](Cl)[N:3]=1.[CH:20]([NH2:23])([CH3:22])[CH3:21].C(N(CC)CC)C>ClCCl>[CH:10]12[O:15][CH:13]([CH2:12][CH2:11]1)[CH2:14][N:8]([C:6]1[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([NH:23][CH:20]([CH3:22])[CH3:21])[C:5]=1[N+:16]([O-:18])=[O:17])[CH2:9]2
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1c(Cl)nc(Cl)nc1N1CC2CCC(C1)O2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Nc1nc(Cl)nc(N2CC3CCC(C2)O3)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-(2,6-Dichloro-5-nitropyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (46, 1.53 g, 5.01 mmoles) was dissolved in dichloromethane and added to a solution of isopropylamine (0.512 mL, 6.01 mmoles) in triethylamine (0.909 mL, 6.52 mmoles) and dichloromethane at 0° C. The reaction was allowed to warm to room temperature, stirred for an additional 16 hours, and then concentrated. Purification by chromatography on silica gel (eluting with 0-25% ethyl acetate in hexanes) provided 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-chloro-N-isopropyl-5-nitropyrimidin-4-amine (47) as a yellow solid. Yield: 2.05 g (quantitative yield). LCMS (HP walk-on); 4.54 min., 328.2, M+H.
Reaction SMILES: [N:1]1[C:14]2[N:8]3[C:9](=[O:13])[NH:10][CH:11]=[CH:12][C:7]3=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CN(C=O)C>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:10]2[CH:11]=[CH:12][C:7]3=[CH:6][C:5]4[CH:4]=[CH:3][CH:2]=[N:1][C:14]=4[N:8]3[C:9]2=[O:13])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=c1[nH]ccc2cc3cccnc3n12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3cc4cccnc4n3c2=O)cc1
Reaction time: 0.17 h
Yield: 39.3 %

Procedure:
To a cooled (0° C.) solution of 11a (500 mg, 2.7 mmol) in DMF (30 ml), NaH (130 mg, 3.2 mmol) was added. The mixture was stirred for 10 min. and a solution of p-toluensulphonyl chloride (570 mg, 3.0 mmol) in DMF (10 ml) was added. The mixture was stirred at room temperature for 1 h. and quenched with water (1 ml). The solvent was evaporated and the residue dissolved in AcOEt. The organic solution was washed with aq. Na2CO3, evaporated and purified by flash column chromatography. Elution with hexane/CH2Cl2 (1/1) gave 8,9-dihydro-8-(4methylphenylsulfonyl)pyrido[3′,2′:4,5]-pyrrolo[1,2-c]pyrimidin-9-one (360 mg, 40%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19](I)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].C(=O)([O-])O.[Na+].[CH2:28]([OH:31])[CH:29]=[CH2:30]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:30][CH2:29][CH:28]=[O:31])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(I)ccc1Cl
Reactant: C=CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: O=CCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 80 °C

Procedure:
2-Chloro-5-iodo-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl-)-benzamide (5.00 g, Example 14a), tetrabutylammonium chloride (3.40 g) and sodium hydrogencarbonate (2.44 g) were charged to a flask. Pd(OAc)2 (0.0533 g), toluene (50 ml) and allyl alcohol (1.01 ml) were added to afford a pale brown mixture which was heated at 80° C. for 5 h. The resulting dark brown mixture was cooled to ambient then filtered to remove the solid residues. These were washed with further toluene (2×50 ml) and the combined toluene extracts then washed with water (100 ml), dried over MgSO4 and concentrated to a light brown solid (3.82 g).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:35]1[CH:40]=[CH:39][N:38]=[CH:37][N:36]=1)[S:7]([C:10]1[C:15]([F:16])=[CH:14][C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27](C3CCCCO3)[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:34])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:16][C:15]1[CH:14]=[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[NH:27][N:26]=[CH:25][CH:24]=2)[CH:12]=[C:11]([F:34])[C:10]=1[S:7]([NH:6][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][N:36]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2c(F)cc(O[C@H]3CCC[C@@H]3c3ccnn3C3CCCCO3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccncn1)c1c(F)cc(O[C@H]2CCC[C@@H]2c2ccn[nH]2)cc1F
Yield: 85.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclopentyl}oxy)benzenesulfonamide (121 mg, 0.185 mmol) prepared in Example 139a, triethylsilane (0.30 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (3.0 mL), to yield the title compound (67 mg, 86%) as a colorless solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:15]([C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[N:28]3)[N:18]=1)[CH3:16].ClCCl.[OH-].[Na+]>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:22][C:20]2[N:19]([C:23]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:24]=3[CH:25]=[CH:26][CH:27]=[N:28]4)[N:18]=[C:17]([CH2:15][CH3:16])[CH:21]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1cc(N)n(-c2cccc3ncccc23)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n(-c2cccc3ncccc23)n1
Temperature: 80 °C
Yield: 57.1 %

Procedure:
A mixture of 4-t-butylbenzenesulfonyl chloride (0.064 g, 0.27 mmol) and 3-ethyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (0.05 g, 0.21 mmol) in pyridine (0.5 mL) was heated at 80° C. for 15 h with stirring. After cooling to room temperature, dichloromethane was added to the reaction mixture and washed with 1 M aqueous sodium hydrogen sulfate (1 mL). The aqueous layer was further extracted with dichloromethane (2×5 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was dissolved in methanol (3 mL) and 1 M aqueous sodium hydroxide (1.0 mL, 1.0 mmol). The reaction mixture was stirred at room temperature for 1 h and the solvent was removed in vacuo. The resulting residue was partitioned between dichloromethane (3 mL) and 1 M aqueous sodium hydrogen sulfate (3 mL) and the phases were separated. The aqueous layer was extracted with dichloromethane (2×5 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.053 g, 0.12 mmol, 58%). 1H NMR (400 MHz, CDCl3) δ 9.00 (d, J=3.6 Hz, 1H), 8.23 (d, J=8.8 Hz, 1H), 8.19 (d, J=8.0 Hz, 1H), 7.79 (dd, J=8.0, 8.4 Hz, 1H), 7.69-7.65 (m, 2H), 7.59 (dd, J=4.4, 8.8 Hz, 1H), 7.51-7.47 (m, 3H), 6.05 (s, 1H), 2.69 (q, J=7.6 Hz, 2H), 1.37 (s, 9H), 1.29 (t, J=7.6 Hz, 3H); MS: (ES) m/z calculated for C24H27N4O2S [M+H]+ 435.2. found 435.2.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([Cl:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:8]=2)[CH2:3][CH2:2]1.OO.C([OH:29])CC>S(=O)(=O)(O)O>[O:29]=[S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([Cl:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: CCCO
Reactant: Clc1cccc2c(N3CCSCC3)nc(N3CCNCC3)cc12
Agent: O=S(=O)(O)O
Agent: OO
Product: O=S1CCN(c2nc(N3CCNCC3)cc3c(Cl)cccc23)CC1
Yield: 31 %

Procedure:
1-(1-Oxido-thiomorpholino)-3-piperazino-5-chloro-isoquinoline was prepared analogous to Example 12 from 1-thiomorpholino-3-piperazino-5-chloro-isoquinoline in dilute sulfuric acid by oxidation with hydrogen peroxide. M.p. 215°-217°C (from n-propanol); yield: 31% of theory.