Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1.O>CS(C)=O>[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][C:12]2([CH3:11])[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)=[CH:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Reactant: NCc1ccc(F)cc1
Solvent: CS(C)=O
Solvent: O
Product: CC1(NCc2ccc(F)cc2)COc2ccc3c(c2O1)CC(=O)N3
Temperature: 85 °C
Yield: 61.5 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.15 g, 3.07 mmole) and 4-fluorobenzylamine (1.56 ml, 13.6 mmole) were combined in 15 ml of dry DMSO and heated to 85° C. for 3.5 hours under a nitrogen atmosphere. After cooling to room temperature, 150 ml of water was added and the mixture was extracted twice with 250 ml portions of 50% ethyl acetate in hexane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuum to yield an oil, which was column chromatographed on silica gel using 0.75% methanol/CH2Cl2 as eluant. The free base of the title compound (0.62 g, 62%) thus obtained was crystallized from ethanol with the addition of one equivalent of fumaric acid to give 0.69 g of the (S) enantiomer of the title compound as an off-white solid fumarate, m.p. 218-220° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[C:13](=[O:16])(O)O.[NH2:17][NH:18][C:19]([NH2:21])=[NH:20]>>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][O:16][C:13]1[CH:9]=[C:10]([C:11](=[N:17][NH:18][C:19](=[NH:21])[NH2:20])[CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=C(O)O
Reactant: N=C(N)NN
Product: CC(=NNC(=N)N)c1cccc(OCc2ccc3ccccc3n2)c1
Yield: 65 %

Procedure:
In a similar manner to Example 1A and using 2-chloromethyl quinoline, 3-(2-quinolinylmethoxy)acetophenone is prepared (13.1 g, m.p. 57°-59° C., 47% yield). This product is reacted with amino guanidine bicarbonate as in 1B above to give 2.35 g of product (65% yield), m.p. 168°-170° C.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:7][NH:6][CH2:5][C@H:4]1[C:8]1[N:12]2[C:13]3[CH:19]=[CH:18][N:17](S(C4C=CC(C)=CC=4)(=O)=O)[C:14]=3[N:15]=[CH:16][C:11]2=[N:10][N:9]=1)[CH3:2].Cl.CCN(C(C)C)C(C)C.C1N=CN([C:45]([N:47]2C=N[CH:49]=[CH:48]2)=[O:46])C=1.NCC1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1>C1COCC1.CN(C1C=CN=CC=1)C>[CH2:1]([C@H:3]1[C@@H:4]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:5][N:6]([C:45]([NH:47][CH2:48][CH:49]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)=[O:46])[CH2:7]1)[CH3:2]
Reactant: NCC1CCOCC1
Reactant: CC[C@H]1CNC[C@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC[C@@H]1CN(C(=O)NCC2CCOCC2)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.5 %

Procedure:
To a solution of 1-((cis)-4-ethylpyrrolidin-3-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine•hydrochloride (0.075 g, 0.168 mmol, Example #36, step F) in THF (1.00 mL) was added DIEA (0.150 mL, 0.861 mmol) and CDI (0.027 g, 0.168 mmol). After about 1 h, 4-aminomethyltetrahydropyran (0.020 g, 0.17 mmol, Acros) was added and the reaction mixture was stirred at ambient temperature for about 16 h. The reaction mixture was heated at about 55° C. for about 24 h. DMAP (0.021 g, 0.168 mmol) was added and continued stirring at about 55° C. for about 48 h. 4-aminomethyltetrahydropyran (0.400 g, 3.47 mmol, Acros) was added and continued stirring at about 55° C. for about 24 h. The solvent was removed under reduced pressure. The crude material was purified by RP-HPLC (Table 1, Method m) to afford (cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidine-1-carboxamide (0.007 g, 10%) as product: LC/MS (Table 1, Method a) Rt=1.32 min; MS m/z: 398 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([CH3:14])[CH2:3][O:4][C:5]1[C:6]([CH3:13])=[CH:7][C:8]([CH:11]=O)=[N:9][CH:10]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[F:1][C:2]([F:15])([CH3:14])[CH2:3][O:4][C:5]1[C:6]([CH3:13])=[CH:7][C:8](/[CH:11]=[N:22]/[S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])=[N:9][CH:10]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: Cc1cc(C=O)ncc1OCC(C)(F)F
Product: Cc1cc(/C=N/[S@](=O)C(C)(C)C)ncc1OCC(C)(F)F
Yield: 74 %

Procedure:
The title compound is prepared in 74% yield (1.10 g, pale yellow solid) from 5-(2,2-difluoropropoxy)-4-methylpicolinaldehyde (1.01 g, 4.68 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (851 mg, 7.02 mmol) in a similar manner to Step-6 of Amine-49.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:14]([C:15](=[O:17])[CH:16]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[Br:22]N1C(=O)CCC1=O>O>[Br:22][C:16]1[C:15](=[O:17])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1cc(-c2ccccc2)oc2ccccc12
Solvent: CC(=O)O
Solvent: O
Product: O=c1c(Br)c(-c2ccccc2)oc2ccccc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
To a round-bottom flask was added 2-phenyl-chromen-4-one (0.94 g, 4.23 mmol), acetic acid (40 mL) and N-bromosuccinimide (0.83 g, 4.65 mmol). The reaction mixture was heated to 100° C. using a hot oil bath with a water cooled reflux condenser, while stirring for 1 hour. The reaction mixture was cooled to RT and the solvents were removed in vacuo. The residue was suspended in ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution, dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (10:1 hexane:EtOAc) to give a white solid (527 mg, 41%). 1H-NMR (400 MHz, CDCl3) δ 8.31 (d, 1H), 7.75 (d, 2H), 7.72 (dd, 1H), 7.45-7.56 (m, 5H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:36]1([CH2:43][C:44]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[O:45])[CH2:42][CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:39]3[CH2:40][CH2:41][CH2:42][N:36]([CH2:43][C:44]([N:46]4[CH2:47][CH2:48][O:49][CH2:50][CH2:51]4)=[O:45])[CH2:37][CH2:38]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CN1CCCNCC1)N1CCOCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCCN(CC(=O)N2CCOCC2)CC1
Product: Cl

Procedure:
2-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-[1,4]diazepan-1-yl}-1-morpholin-4-yl-ethanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 2-[1,4]diazepan-1-yl-1-morpholin-4-yl-ethanone (example 20a) in an analogous manner as described in example 25. LR-MS: 720.5 [(M+H)+]
Reaction SMILES: [CH3:1][NH:2]N.[C:4]([N:6]=[C:7](SC)[S:8][CH3:9])#[N:5].C(#[N:14])C>>[NH2:14][C:4]1[N:6]=[C:7]([S:8][CH3:9])[N:2]([CH3:1])[N:5]=1
Reactant: CC#N
Reactant: CSC(=NC#N)SC
Reactant: CNN
Product: CSc1nc(N)nn1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0°, 6.5 grams of methyl hydrazine was added dropwise to a stirred suspension of 20.0 grams (0.137 mole) dimethyl cyanodithioimidocarbonate in 35 ml of acetonitrile. A yellow solution immediately formed after the addition followed by precipitation of a white solid. The ice bath was removed, and upon warming to room temperature a yellow solution formed which was stirred at room temperature overnight. After stirring overnight, a solid precipitated which was filtered, washed with cold acetonitrile, followed by 1-chlorobutane, yield 8.5 grams, m.p. 104°-109°. The literature [Journal of Organic Chemistry, 39, 1522 (1974)] reported a similar melting point of 103°-106° for the title compound, however, a different isomeric structure was assigned to the compound (5-amino-1-methyl-3-methylthio-1H-1,2,4-triazole). The assignment of 3-amino-1-methyl-5-methylthio-1H-1,2,4-triazole as the correct structure was verified by X-ray crystal structure analysis.
Reaction SMILES: [C:1](=O)(OC)OC.N1C2C(=CC=CC=2)C=C1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2>>[CH3:1][N:23]1[C:24]2[C:20](=[CH:19][C:18]([O:17][CH3:16])=[CH:26][CH:25]=2)[CH:21]=[CH:22]1
Reactant: COc1ccc2[nH]ccc2c1
Reactant: COC(=O)OC
Agent: c1ccc2[nH]ccc2c1
Product: COc1ccc2c(ccn2C)c1

Procedure:
With dimethyl carbonate as a methylating agent, the N-methylation of indole system containing electron-donating groups was also studied. For an example, N-methylation of 5-methoxyindole with dimethyl carbonate at reflux temperature for 5 hours gave 1-methyl-5-methoxyindole in 97% isolated yield. However, other indole substrates, such as gramine, indole-3-methanol, indole3-ethanol and tryptamine gave a complex mixture of unidentified products. These results indicated that N-methylation with dimethyl carbonate is not applicable to such indole systems.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]#[N:22].[CH2:25]=[O:26].Cl>C1COCC1.O>[F:12][C:13]([F:23])([F:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([CH2:25][OH:26])[C:21]#[N:22]
Reactant: N#CCc1ccccc1C(F)(F)F
Reactant: C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: N#CC(CO)c1ccccc1C(F)(F)F
Reaction time: 0.75 h
Yield: 94 %

Procedure:
A 50 μL (0.33 mmol) sample of DBU was injected into a stirred solution of 2-(2-(trifluoromethyl)phenyl)ethanenitrile (0.995 g, 4.86 mmol) and formaldehyde (600 μL of 30%) in THF (3 mL), producing a mild exotherm. After 45 min, the mixture was acidified (3N HCl), diluted with water and extracted with ethyl acetate. The organic phase was water washed, dried (MgSO4) and stripped. The resulting colorless oil was flash chromatographed on silica gel (22 g) eluting with CH2Cl2 →40% ethyl acetate/CH2Cl2. Fractions containing only product (Rf 0.5 (silica gel, EtOAc:hexane=1:4)) were stripped to give 1.08 g (94% yield) of the desired alcohol.
Reaction SMILES: [CH:1]1([N:7]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[N:31]3)=[CH:26][C:25]=2[CH3:39])[C:8]2[CH:22]=[CH:21][C:11]([C:12]([NH:14][CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[O:13])=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)=O.CC(O)C>>[CH:1]1([N:7]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[N:31]3)=[CH:26][C:25]=2[CH3:39])[C:8]2[CH:22]=[CH:21][C:11]([C:12]([NH:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:13])=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCNC(=O)c1ccc(N(Cc2ccc(-n3cc(C(F)(F)F)cn3)cc2C)C2CCCCC2)nc1
Agent: O=C=O
Solvent: CC(C)O
Product: Cc1cc(-n2cc(C(F)(F)F)cn2)ccc1CN(c1ccc(C(=O)NCCC(=O)O)cn1)C1CCCCC1

Procedure:
The title compound was prepared by a method analogous to that described in Step D of Example 82, using Isomer 2 of methyl 3-(6-(cyclohexyl(2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methylamino)nicotinamido)propanoate. 1H NMR (400 MHz, CD3OD, δ): 8.68 (s, 1H), 8.41 (d, 1H), 7.95 (s, 1H), 7.72-7.75 (m, 1H), 7.54-7.57 (m, 2H), 7.45 (d, 1H), 6.49 (d, 1H), 5.08 (d, 1H), 3.55 (t, 2H), 2.56-2.60 (m, 5H), 2.08 (m, 1H), 1.68-1.79 (m, 4H), 1.40-1.50 (m, 1H), 1.00-1.35 (m, 5H). MS (M+1) 530.1. Chiral SFC: Chiralpak AD-3, 4.6×50 mm, 3 μm. Modifier: 0.05% DEA. Mobile Phase: 60/40 CO2/2-propanol. Flow: 4 mL/min. Retention time: 1.46 minutes, 100% ee (Isomer 2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[N:16][C:17]([CH:21]=[CH2:22])=[CH:18][CH:19]=2)[CH2:14][O:13]1.C[O:24][CH2:25][CH2:26][NH:27][CH3:28]>CC(O)=O.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[N:16][C:17]([CH2:21][CH2:22][N:27]([CH2:26][CH2:25][OH:24])[CH3:28])=[CH:18][CH:19]=2)[CH2:14][O:13]1
Reactant: C=Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Reactant: CNCCOC
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CN(CCO)CCc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
Following the method described in Example 19, 5-fluoro-3-(2-vinyl-7H-furo[3,4-b]pyridin-5-ylidene)-1,3-dihydro-indol-2-one (65 mg, 0.22 mmol) and (2-methoxyethyl)methylamine (300 mg, 3.99 mmol) and AcOH (12 drops) are heated 100° C. for 2 h. Additional (2-methoxyethyl)methylamine is added and heating is continued for 1 hr. The reaction mixture is cooled and treated with triethylamine (10 drops). The reaction mixture is loaded onto silica gel and purified by chromatography (silica gel, MeOH-Chloroform). The product containing fractions are concentrated and the residue is triturated with EtOAc-hexane. The solid which formed is collected by filtration and dried under vacuum to provide the title compound (53 mg, 65%) as a yellow solid.
Reaction SMILES: C(C[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH2:13][CH:12]=1)(O)=O.[CH2:14](N(CC)CC)C.[CH3:21][O:22][C:23](Cl)=[O:24]>CCOCC>[CH2:21]([O:22][C:23](=[O:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH2:13][CH:12]=1)[CH3:14]
Reactant: CCN(CC)CC
Reactant: COC(=O)Cl
Reactant: O=C(O)CCCCCCCC1=CC1
Solvent: CCOCC
Product: CCOC(=O)CCCCCCC1=CC1
Reaction time: 2 h
Yield: 3.9 %

Procedure:
A solution of 220 mg (1.3 mmol) of 1-(7-carboxyheptyl)-cyclopropene in ether was cooled to 0° C. Triethylamine (0.20 g, 2 mmol) was added, then 0.12 g (1.3 mmol) of methylchloroformate was added. After 2 hours at 0° C., the reaction mixture was transferred to a separatory funnel. The ether phase was washed with water (2×) and brine, dried over magnesium sulfate, filtered and stripped. The product was dissolved in ethanol, cooled in an ice bath and treated with 1 ml of a 21% sodium ethoxide in ethanol solution. The reaction mixture was stirred ½ hour, then water and ether were added. The ether phase was washed with 1N sodium hydroxide solution, water, and brine, dried over magnesium sulfate, filtered and stripped to give 10 mg of 75% pure 7-cycloprop-1-enyl-heptanoic acid ethyl ester.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].CCN(CC)CC.[C:13](Cl)(=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17]>C(Cl)Cl>[CH3:2][O:3][N:4]([CH3:5])[C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CNOC
Reactant: CCCCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)N(C)OC
Reaction time: 2 h

Procedure:
To a CH2Cl2 solution (200 mL) containing N-methoxy-N-methylamine hydrochloride (8.09 g, 82.9 mmol) and Et3N (12.6 g, 124 mmol) was added valeryl chloride (10 g, 82.9 mmol) dropwise at room temperature. The resulting solution bubbled vigorously and stirred for 2 hours after which time it was carefully quenched with H2O. The organic layer was separated and washed with 2.0 N NaOH. The organics were extracted with CH2Cl2, dried (MgSO4) and the solvent removed in vacuo. The resulting colorless oil was taken on without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](=[O:23])[N:6]([CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[N:7]=1.Br[C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([F:34])[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)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.O>[F:34][C:27]1[CH:26]=[C:25]([C:2]2[CH:3]=[CH:4][C:5](=[O:23])[N:6]([CH2:8][CH2:9][O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[N:14]=[CH:13][CH:12]=3)[N:7]=2)[CH:33]=[CH:32][C:28]=1[C:29]([OH:31])=[O:30]
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: COc1ccc2c(OCCn3nc(Cl)ccc3=O)ccnc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(OCCn3nc(-c4ccc(C(=O)O)c(F)c4)ccc3=O)ccnc2c1
Reaction time: 0.33 h
Yield: 65.1 %

Procedure:
To a 5 ml CEM microwave tube was added 6-chloro-2-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridazin-3(2H)-one (0.1 g, 0.3 mmol), 4-bromo-2-fluorobenzoic acid (0.08 g, 0.5 mmol), sodium carbonate (0.10 g, 0.9 mmol), dichlorobis(triphenylphosphine)-palladium(II) (30 mg, 0.05 mmol), and DMF (4 mL)-water (0.4 mL). The vial was sealed and placed in CEM microwave for 20 min at 130° C., with 100 Watts of power via Powermax. The reaction mixture was extracted with EtOAc (3×10 mL). The combined organic layers were dried over MgSO4 and concentrated (toluene was added in order to removed most of DMF). The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep®, P/N 68-2203-026, 12 g SiO2, isocratic 5% MeOH in DCM with 1% AcOH, Flow=30 mL/min). The peak at 30 min was collected to afford the desired product as white solid (85 mg). MS (ESI pos. ion) m/z (M+1): 436.2. Calc'd exact mass for C23H18FN3O5: 357.41. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.86 (s, 3 H) 4.70 (s, 4 H) 6.96-7.04 (m, 2 H) 7.13 (d, J=9.79 Hz, 1 H) 7.25-7.30 (m, 1 H) 7.69-7.73 (m, 1 H) 7.75 (s, 1 H) 7.86 (s, 1 H) 7.87-7.95 (m, 2 H) 8.12 (d, J=9.79 Hz, 1 H) 8.64 (d, J=5.26 Hz, 1 H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)([OH:10])[CH3:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl.O.C(=O)(O)[O-].[Na+]>[OH:10][C:8]([C@H:5]1[CH2:6][CH2:7][C@H:2]([NH:1][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:3][CH2:4]1)([C:11]1[S:12][CH:13]=[CH:14][N:15]=1)[CH3:9]
Reactant: CC(O)(c1nccs1)[C@H]1CC[C@H](N)CC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(O)(c1nccs1)[C@H]1CC[C@H](NS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-(trans-4-aminocyclohexyl)-1-(1,3-thiazol-2-yl)ethanol (100 mg, 0.44 mmol) in dichlormethane (2.9 mL) and triethylamine (0.31 mL, 2.21 mmol) at 0° C. was added methanesulfonyl chloride (34 μL, 0.44 mmol) and the reaction was allowed to stir for 10 minutes at 0° C. and then diluted with water, dichloromethane and aqueous saturated sodium bicarbonate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate gradient in hexanes) to afford N-{trans-4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexyl}methanesulfonamide. MS ESI calc'd. for C12H21N2O3S2 [M+H]+ 305. found 305. 1H NMR (500 MHz, CDCl3) δ 7.70 (d, J=3.2, 1H), 7.28 (d, J=3.2, 1H), 4.25-4.14 (m, 1H), 3.30-3.13 (m, 1H), 2.95 (s, 3H), 2.18-2.09 (m, 1H), 2.09-2.02 (m, 2H), 1.96-1.88 (m, 1H), 1.80-1.69 (m, 1H), 1.64-1.53 (m, 3H), 1.40-1.28 (m, 1H), 1.28-1.13 (m, 3H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:50]([Cl:51])=[CH:49][CH:48]=[CH:47][C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:50]([Cl:51])=[CH:49][CH:48]=[CH:47][C:46]=3[Cl:52])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1cccc(Cl)c1CBr
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3c(Cl)cccc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-1,3-dichlorobenzene and isolated as white solid (5.8 mg, 32%). MS (m/e): 441.4 (MH+).
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[NH2:2].[Cl:6][S:7]([OH:10])(=O)=[O:8].S(Cl)([Cl:13])=O>>[NH:2]([S:1]([Cl:13])(=[O:5])=[O:3])[S:7]([Cl:6])(=[O:10])=[O:8]
Reactant: NS(=O)(=O)O
Reactant: O=S(=O)(O)Cl
Reactant: O=S(Cl)Cl
Product: O=S(=O)(Cl)NS(=O)(=O)Cl

Procedure:
The reaction of sulphamic acid with chlorosulphonic acid and thionyl chloride gives HN(SO2Cl)2. This reaction also provides by-products including sulphur dioxide, sulphuric acid and hydrochloric acid. Sulphur dioxide is generated from the reaction of thionyl chloride with sulphamic acid. Thus generation of sulphur dioxide indicates continuation of the reaction. Thus the heating is continued until generation of sulphur dioxide is ceased.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[C:11]1[C:12](=[O:18])[CH2:13][CH:14](OC)[CH:15]=1)([O:3][CH3:4])=[O:2].[SH:19][CH2:20][CH2:21][OH:22].C[O-].[Na+]>CO>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[C:11]1[C:12](=[O:18])[CH2:13][CH:14]([S:19][CH2:20][CH2:21][OH:22])[CH:15]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)CCCC/C=C\C1=CC(OC)CC1=O
Reactant: OCCS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCC/C=C\C1=CC(SCCO)CC1=O
Reaction time: 0.83 h

Procedure:
To a stirred solution of 7.57 g (30 mmols) of 2-(6-carbomethoxy-2-cis-hexenyl)-4-methoxycyclopent-2-en-1-one (Example 283) and 2.46 g (31.5 mmols) of β-mercaptoethanol in 150 ml of methanol is added 15 ml of N/10 sodium methoxide in methanol solution. After 50 minutes at room temperature the solution is acidified with 0.27 ml of gl. acetic acid and partitioned with ether-brine. The ether extract is washed with brine, dried over magnesium sulfate, and concentrated. The residue is subjected to column chromatography on silica-gel to provide an oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.C([Li])CCC.[CH3:12][N:13]1[C:17]([CH:18]=[O:19])=[CH:16][N:15]=[CH:14]1>C1COCC1>[CH3:1][N:2]1[C:6]([CH:18]([C:17]2[N:13]([CH3:12])[CH:14]=[N:15][CH:16]=2)[OH:19])=[CH:5][N:4]=[N:3]1
Reactant: Cn1ccnn1
Reactant: Cn1cncc1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cncc1C(O)c1cnnn1C
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-methyl-1H-1,2,3-triazole (1.47 g, 17.7 mmol, PCT Int. Appl. 2008098104) in 20 mL THF was cooled to −40° C. in a dry-ice/acetonitrile bath. n-Butyllithium (1.6 M in hexane, 10.2 mL, 16.3 mmol) was added dropwise via syringe and the mixture was stirred at −40° C. for 30 minutes. A solution of 1-methyl-1H-imidazole-5-carbaldehyde (1.50 g, 13.6 mmol) in 10 mL THF was then added and the mixture was stirred for 5 minutes, then was transferred to an ice/water bath. After 1 hour, the mixture was quenched by addition of saturated aqueous NH4Cl, diluted with water, and extracted twice with EtOAc. The aqueous phase, which contained the title compound, was then concentrated. The residue was purified by flash column chromatography (silica gel, gradient 3-10% MeOH-DCM) to afford the title compound as a light yellow foam.