Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]([N:15]2[N:19]=[CH:18][C:17]3([CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:16]2)SC)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:24]([NH2:26])[CH3:25]>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]([N:15]2[N:19]=[CH:18][C:17]3([CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:16]2)[NH:26][CH2:24][CH3:25])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CSC(=NS(=O)(=O)c1ccc(N)cc1)N1CC2(C=N1)CCCC2
Reactant: CCN
Solvent: CO
Product: CCNC(=NS(=O)(=O)c1ccc(N)cc1)N1CC2(C=N1)CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of 4.05 g 4-amino-N-[(2,3-diaza-spiro[4.4]non-3-en-2-yl)-methylsulfanyl-methylene]-benzenesulfonamide in 30 mL MeOH was added 7.86 mL of a 70% aqueous solution of ethylamine. The mixture was stirred for 1 h. at room temperature and evaporated to dryness. The residue was dissolved in a minimal amount of DCM and triturated with MTBE. The precipitate was filtered off and dried in vacuo, and subsequently recrystallized from n-butyl acetate to give 2.40 g (67%) of 4-amino-N-[(2,3-diaza-spiro[4.4]non-3-en-2-yl)-ethylamino-methylene]-benzenesulfonamide as an off-white microcrystalline material after drying in vacuo at 80° C.; m.p. 141-142° C. 1H NMR (400 MHz, CDCl3) δ 1.14 (t, J=7.22 Hz, 3H), 1.47-1.89 (m, 8H), 3.35-3.57 (m, 2H), 3.79 (s, 2H), 4.02 (br.s., 2H), 6.65 (d, J=8.73 Hz, 2H), 6.78 (s, 1H), 6.91 (br. s., 1H), 7.70 (d, J=8.73 Hz, 2H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1B1OC(C)(C)C(C)(C)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:21]=[C:2]([C:30]3[CH:31]=[N:32][CH:33]=[CH:34][C:29]=3[CH3:28])[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[O:8])=[CH:11][CH:12]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: Cc1ccncc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1ccncc1-c1cc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cnc1N1CC[C@@H](O)C1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
(R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 171.1, 70 mg, 0.151 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (49.7 mg, 0.227 mmol), Pd(Ph3P)4 (17.48 mg, 0.015 mmol) and K3PO4 (96 mg, 0.454 mmol) were added to a vial, flushed with argon, treated with toluene (1 mL), and stirred at 110° C. for 2 h followed by 4 h at 130° C. Dioxane (1 mL) was added and the RM was stirred for an additional 3 days at 130° C. The RM was diluted with dioxane and filtered on a pad of Hyflo®, followed by Si-Thiol scavenger treatment. The solvent was evaporated off under reduced pressure and the crude product was purified by preparative SFC (Column Diol, from 20% to 25% in 6 min). The purified product was lyophilized in water/min. vol. MeCN to afford the title product as an off-white powder. UPLC-MS (Condition 3), tR=0.97 min, m/z=475.1/477.1 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 1.62-1.89 (m, 2H) 2.02/2.14 (s, 3H) 2.70-3.35 (m, 4H) 4.09-4.24 (m, 1H) 4.79-4.96 (m, 1H) 7.27-7.42 (m, J=8.66 Hz, 3H) 7.86 (d, J=7.91 Hz, 2H) 7.91-8.00 (m, 1H) 8.41-8.61 (m, 2H) 8.77 (br. s, 1H) 10.11-10.19 (m, 1H).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:12][C@H:13]1[CH2:18][CH2:17][C@H:16](O)[CH2:15][CH2:14]1>>[Cl:12][C@@H:13]1[CH2:18][CH2:17][C@H:16]([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:15][CH2:14]1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Reactant: O[C@H]1CC[C@H](Cl)CC1
Product: CCOC(=O)/C(=N\O[C@H]1CC[C@@H](Cl)CC1)C(C)=O

Procedure:
Ethyl (Z)-2-(hydroxyimino)-3-oxobutyrate (3.18 g) was treated with trans-4-chlorocyclohexanol as described in Example 4a, method 3 to give the title compound as a colourless oil (2.02 g). (Found: MH+, 276.0995. C12H19ClNO4 requires MH+, 276.1002; δH (CDCl3) 1.36 (3H, t, J 7H), 1.79, 1.96 and 2.09 (8H, 3m), 2.40 (3H, s), 4.11 (1H, qt, J 6 Hz), 4.38 (2H, q, J 7 Hz), and 4.41 (1H, qt, J 6 Hz). A small quantity of the trans-isomer was obtained from faster-eluting column fractions.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[CH2:14]1[CH2:20][CH:19](Cl)[C:17](=[O:18])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[O:1][CH:16]1[CH2:15][CH2:14][CH2:20][CH2:19][C:17]1=[O:18]
Reactant: O=C1CCCCC1Cl
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC)c(OC2CCCCC2=O)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 3-hydroxy-4-methoxybenzoate (2.47 g), α-chlorocyclohexanone (2.33 ml), potassium carbonate (3.76 g), and DMF (25 ml) was stirred at 90° C. for 2 hours. α-Chlorocyclohexanone (2.0 ml) was further added to the mixture, followed by stirring at 90° C. for one hour. After being allowed to stand for cooling, water was added to the mixture followed by extraction with ether. The organic layer was washed with a 1N aqueous solution of sodium hydroxide and then with a saturated saline, and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (silica gel, hexane:ethyl acetate=2:1) to give Compound IIm-a (3.16 g, 83%) as an oily substance.
Reaction SMILES: [CH2:1]([C:5]1[NH:14][C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH3:13])=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]2[C:32]#[N:33])=[CH:21][CH:20]=1>CS(C)=O>[CH2:1]([C:5]1[N:14]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]3[C:32]#[N:33])=[CH:23][CH:24]=2)[C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH3:13])=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)ccnc2[nH]1
Reactant: N#Cc1c(Cl)c(Cl)cn1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCc1nc2c(C)ccnc2n1Cc1ccc(-n2cc(Cl)c(Cl)c2C#N)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 41.5 %

Procedure:
To a solution of 2-butyl-7-methyl-3H-imidazo[4,5-b]-pyridine (568 mg) in dimethyl sulfoxide (7 ml) was added sodium hydride (132 mg, 60% oil dispersion) at ambient temperature. The mixture was stirred for 40 minutes at the same temperature. To the mixture was added dropwise a solution of 1-(4-bromomethylphenyl)-3,4-dichloropyrrole-2-carbonitrile (990 mg) in dimethyl sulfoxide (3 ml). The mixture was stirred for 2 hours at ambient temperature and ice water (30 ml) was added therein. The separated oil was extracted twice with ethyl acetate. The extracts were washed with water, dried, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluted by 50% ethyl acetate in n-hexane to give 2-butyl-3-[4-(2-cyano-3,4-dichloro-1-pyrrolyl)benzyl]-7-methyl-3H-imidazo[4,5-b]pyridine (546 mg) as an oil.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.C1(=O)O[CH2:14][CH2:13][O:12]1>>[O:2]1[C:3]2[CH:9]=[CH:8][C:7]([O:10][CH2:14][CH2:13][OH:12])=[CH:6][C:4]=2[O:5][CH2:1]1
Reactant: O=C1OCCO1
Reactant: Oc1ccc2c(c1)OCO2
Product: OCCOc1ccc2c(c1)OCO2
Yield: 99 %

Procedure:
The title compound was prepared according to the procedure of Example 114, Step 1 starting from sesamol (2.0 g, 14.5 mmol ) and ethylene carbonate (1.0 g, 11.4 mmol): solid; yield 99%. MS m/z 182 (M)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[C@H:20]3[C@H:24]([OH:25])[C@H:23]([OH:26])[C@@H:22]([CH2:27][OH:28])[O:21]3)=[C:13]([NH2:29])[N:12]=2)[CH:10]=1)=O)C.[CH3:30][NH2:31]>>[OH:25][C@@H:24]1[C@H:23]([OH:26])[C@@H:22]([CH2:27][OH:28])[O:21][C@H:20]1[N:17]1[CH:16]=[N:15][C:14]2[C:18]1=[N:19][C:11]([N:9]1[CH:10]=[C:6]([C:4]([NH:31][CH3:30])=[O:3])[CH:7]=[N:8]1)=[N:12][C:13]=2[NH2:29]
Reactant: CCOC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Reactant: CN
Product: CNC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Temperature: 65 °C

Procedure:
Compound 12 (0.05 mg, 0.12 mmol) was added to 4 mL methylamine (40% sol. In water). The mixture was heated at 65° C. for 24 h. After concentration in vacuo, the residue was purified using prep. TLC (10% MeOH:DCM). 1HNMR (CD3OD) 62.90 (s, 3H), 3.78 (m, 1H), 3.91 (m, 1H), 4.13 (d, 1H), 4.34 (d, 1H), 4.64 (m, 1H), 6.06 (d, 1H), 8.11 (s, 1H), 8.38 (s, 1H), 9.05 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:11][C:10]=2[C:27]([F:30])([F:29])[F:28])[CH:7]=1.[OH:31]OS([O-])=O.[K+]>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([C:19]3[CH:20]=[CH:21][C:22]([S:25]([CH3:26])=[O:31])=[CH:23][CH:24]=3)(=[O:17])=[O:18])=[CH:11][C:10]=2[C:27]([F:28])([F:30])[F:29])[CH:7]=1
Reactant: O=S([O-])OO
Reactant: CSc1ccc(S(=O)(=O)Nc2ccc(Oc3cncc(Cl)c3)c(C(F)(F)F)c2)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CS(=O)c1ccc(S(=O)(=O)Nc2ccc(Oc3cncc(Cl)c3)c(C(F)(F)F)c2)cc1
Reaction time: 5 h

Procedure:
To a solution of 2-(3-chloro-5-pyridyloxy)-5-(4-methylthiobenzenesulfonamido)benzotrifluoride (0.21 g) in acetone (5 mL) was added Oxone™ (0.136 g) in water (1 mL). After 5 hr, the reaction mixture is filtered, and the filtrate is diluted in methylene chloride and extracted with water. The solids from the organic extract were purified by silica chromatography. Trituration with hexane gave the title sulfoxide (0.144 g) as a white solid. mp 156-159° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20]CC)[CH2:16][CH2:15]3)[CH2:10][O:9]2)=[CH:4][C:3]=1[F:23].[C:24]([Cu])#[N:25]>CN1C(=O)CCC1>[C:24]([C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][CH2:12][C@H:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH3:20])[CH2:16][CH2:15]3)[CH2:10][O:9]2)=[CH:4][C:3]=1[F:23])#[N:25]
Reactant: N#C[Cu]
Reactant: CCC[C@H]1CC[C@H](C2COC(c3ccc(Br)c(F)c3)OC2)CC1
Solvent: CN1CCCC1=O
Product: C[C@H]1CC[C@H]([C@H]2CO[C@H](c3ccc(C#N)c(F)c3)OC2)CC1

Procedure:
In 40 cm3 of NMP, 6.2 g (0.016 mol) of 2-(4'-bromo-3'-fluorophenyl)-5-(trans-4'-propylcyclohexyl)-1,3-dioxane and 2.2 g (0.024 mol) of CuCN were refluxed with a mantle heater for 2 hours.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([C:19]2[NH:28][C:27](=O)[C:26]3[C:21](=[CH:22][C:23]([O:32][CH3:33])=[CH:24][C:25]=3[O:30][CH3:31])[N:20]=2)=[CH:14][C:13]=1[CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:37])=O>>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([C:19]2[N:28]=[C:27]([Cl:37])[C:26]3[C:21](=[CH:22][C:23]([O:32][CH3:33])=[CH:24][C:25]=3[O:30][CH3:31])[N:20]=2)=[CH:14][C:13]=1[CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCOCc4ccccc4)c(C)c3)nc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc(OC)c2c(Cl)nc(-c3cc(C)c(OCCOCc4ccccc4)c(C)c3)nc2c1

Procedure:
To a 100 mL round bottom flask was added 2-amino-4,6-dimethoxy-benzamide (318 mg, 1.6 mmol), 4-(2-benzyloxy-ethoxy)-3,5-dimethyl-benzaldehyde (461 mg, 1.6 mmol), p-toluenesulfonic acid monohydrate (32 mg, 0.16 mmol), sodium hydrogensulfite (318 mg, 1.8 mmol) and dimethylacetamide (5 mL). The mixture was stirred in a 150° C. oil bath under nitrogen overnight. Water (40 mL) and ether (30 mL) were added. The precipitate was filtered off, washed with water then ether, and air-dried. The intermediate 2-[4-(2-benzyloxyethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one was obtained as light brown/beige solid. Yield 474 mg (64%). 2-[4-(2-Benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (474 mg, 1.03 mmol) was stirred in phosphorus oxychloride (10 mL) at 100° C. for 4 h. Excess phosphorus oxychloride was removed under reduced pressure. Ice was added and the solid was collected. The solid was washed with water and ether, and air-dried. 2-[4-(2-benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-4-chloro-5,7-dimethoxy-quinazoline was obtained as a light brown solid (yield: 356 mg, 72%). 2-[4-(2-Benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-4-chloro-5,7-dimethoxy-quinazoline (192 mg, 0.4 mmol) was dissolved in a small amount of THF and 10% Pd/C (dry) (66 mg) was added. Anhydrous methanol (20 mL) and ammonium formate (955 mg) were added. The mixture was stirred in a 80° C. oil bath for 5 h. The mixture was filtered through Celite, washed with MeOH/DCM, purified by column chromatography to give 2-(4-(5,7-dimethoxyquinazolin-2-yl)-2,6-dimethylphenoxy)ethanol (36 mg, 25%) as an off-white solid. Selected data: MS (ES) m/z: 355.04; mp 169-170° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[N:17]=[CH:16][N:15]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=4[OH:28])[CH:13]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>CN(C=O)C>[CH:37]1([CH2:36][O:28][C:19]2[CH:20]=[C:21]([C:24]([F:25])([F:27])[F:26])[CH:22]=[CH:23][C:18]=2[C:14]2[N:15]=[CH:16][N:17]=[C:12]([O:11][C:8]3[CH:9]=[C:10]4[C:5]([CH:4]=[CH:3][CH:2]=[N:1]4)=[CH:6][CH:7]=3)[CH:13]=2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: BrCC1CCCCC1
Reactant: Oc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(Oc3ccc4cccnc4c3)ncn2)c(OCC2CCCCC2)c1
Temperature: 60 °C
Reaction time: 23 h

Procedure:
To a mixture of 2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenol, (Example 191), (50 mg, 0.13 mmol) and K2CO3 (54 mg, 0.39 mmol) in DMF (2.0 mL) was added (bromomethyl)cyclohexane (20 μL, 0.14 mmol, Aldrich). The reaction mixture was stirred at 60° C. for 23 h. The resulting mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography (gradient: 0% to 3.0% MeOH/CH2Cl2) to provide the title compound as a white amorphous solid. MS (ESI, pos. ion) nt/z: 480 (M+1).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>>[CH3:29][S:30]([O:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][C:12]2[N:13]=[C:9](/[CH:8]=[CH:7]/[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:10][CH:11]=2)=[CH:21][CH:20]=1)(=[O:32])=[O:31]
Reactant: OCCCCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCCCCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Yield: 97 %

Procedure:
In substantially the same manner as in Reference Example 12, 6-[4-[2-[(E)-2-phenylethenyl]-4-oxazolyl methoxy]phenyl]hexanol was allowed to react with methanesulfonyl chloride to give 6-[4-[2-[(E)-2-phenyl ethenyl]-4-oxazolylmethoxy]phenyl]hexyl methanesulfonate. The yield was 97%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 88-89° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][O:11][CH3:12])[C:4]=1[CH:13]([OH:18])[C:14]([CH3:17])([CH3:16])[CH3:15].C([Li])CCC.CCCCCC.CC1C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1>[C:14]([CH:13]1[C:4]2[C:3](=[CH:8][CH:7]=[CH:6][C:5]=2[O:9][CH2:10][O:11][CH3:12])[CH2:2][O:18]1)([CH3:15])([CH3:16])[CH3:17]
Reactant: COCOc1cccc(CO)c1C(O)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOc1cccc2c1C(C(C)(C)C)OC2
Reaction time: 0.08 h
Yield: 93.2 %

Procedure:
To a solution of 1-[2-(hydroxymethyl)-6-(methoxymethoxy)phenyl]-2,2-dimethyl-propan-1-ol (Intermediate 3, 300 mg, 1.18 mmol) in dry THF (5 mL) at OC butyllithium 1.6M solution in hexane (0.74 ml, 1.18 mmol) was slowly added and the reaction mixture was stirred for 5 minutes at the same temperature. 4-methylbenzenesulfonyl chloride (224.89 mg, 1.18 mmol) dissolved in THF (1 ml) was slowly added and the reaction mixture was stirred for 5 minutes at the same temperature. Butyllithium 1.6M solution in hexane (0.74 ml, 1.18 mmol) was slowly added and the reaction mixture was stirred for 30 minutes at at 0° C. The reaction was quenched with water (1 ml), diluted with brine (10 ml) and extracted with ethyl acetate (2×15 ml). The organic layer was dried (Na2SO4), filtered and evaporated and The residue was purified by flash chromatography (Biotage system) on silica gel using a SNAP 25 g as column and cyclohexane/ethyl acetate from 100:0 to 70:30 as eluent affording the title compound (260 mg) as colorless oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]2[N:9]([CH3:15])[C:10](=[O:14])[C:11]([CH3:13])([CH3:12])[C:6]2=[CH:5][CH:4]=1.Cl.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>>[CH3:15][N:9]1[C:7]2=[N:8][C:3]([NH:2][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[CH:4][CH:5]=[C:6]2[C:11]([CH3:12])([CH3:13])[C:10]1=[O:14]
Reactant: CN1C(=O)C(C)(C)c2ccc(N)nc21
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Product: CN1C(=O)C(C)(C)c2ccc(NC(=O)c3ccncc3)nc21

Procedure:
Prepared in analogy to example 2 from 6-amino-1,3,3-trimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one hydrochloride and isonicotinoyl chloride hydrochloride. The title compound was obtained as light yellow solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].Cl[C:10]1[N:11]=[N+:12]([O-:23])[C:13]2[C:22]3[CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=[CH:16][C:14]=2[N:15]=1>COCCOC>[CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH:6][C:10]1[N:11]=[N+:12]([O-:23])[C:13]2[C:22]3[CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=[CH:16][C:14]=2[N:15]=1)[CH3:2]
Reactant: [O-][n+]1nc(Cl)nc2ccc3c(c21)CCC3
Reactant: CCN(CC)CCN
Solvent: COCCOC
Product: CCN(CC)CCNc1nc2ccc3c(c2[n+]([O-])n1)CCC3
Yield: 89.9 %

Procedure:
N,N-Diethyl-1,2-ethanediamine (0.41 mL, 2.9 mmol) was added to a stirred solution of chloride 5 (215 mg, 1.0 mmol) in DME (30 mL) and the solution stirred at reflux temperature for 5 h. The solvent was evaporated and the residue was partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 8 (271 mg, 93%) as a pale yellow solid: mp (MeOH/EtOAc) 126-130° C.; 1H NMR δ 7.54 (d, J=8.4 Hz, 1H, H-6), 7.39 (d, J=8.4 Hz, 1H, H-5), 5.93 (br s, 1H, NH), 3.63 (br dd, J=7.5, 7.4 Hz, 2H, H-9), 3.52-3.57 (m, 2H, CH2N), 2.97 (br dd, J=7.8, 7.6 Hz, 2H, H-7), 2.74 (br t, J=6.0 Hz, 2H, CH2N), 2.63 (q, J=7.4 Hz, 4H, 2×CH2N), 2.16 (br p, J=7.6 Hz, 2H, H-8), 1.07 (t, J=7.1 Hz, 6H, 2×CH3); 13C NMR δ 158.4, 149.0, 142.0, 137.3, 132.2, 129.2, 124.6, 51.2, 46.6 (2), 38.5, 35.3, 32.8, 24.8, 11.5 (2). Anal. calcd for C16H23N5O.¼H2O: C, 62.8; H, 7.7; N, 22.9. Found: C, 63.0; H, 7.6; N, 22.9%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[F-].[Cs+]>O1CCOCC1>[C:10]1([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(Cl)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: COc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 52.7 %

Procedure:
A 100 mL of reactor equipped with magnetic stir bar was charged with 140 mg (0.15 mmol) of {[(t-Bu)2P(OH)]2PdCl}2 (from Experiment 7), 1.43 g (10.0 mmol) of 4-chloroanisole, 1.83 g (15.0 mmol) of PhB(OH)2 and 4.56 g (30.0 mmol) of CsF in 30.0 mL of 1,4-dioxane. The resulting mixture was refluxed for 8 h until the starting material was completely consumed as judged by GC. The reaction was cooled to room temperature, transferred to a separatory funnel, and diluted with 300 mL of diethyl ether and 100 mL of H2O. The layers were separated, and organic layer was washed with H2O (2×100 mL), brine (100 mL), and dried over mgSO4, filtered, and the ether and dioxane removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel using 2% EtOAc/hexane as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to give 0.97 g (53% yield) of 4-phenylanisole.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1)=O>>[CH3:36][S:33]([C:30]1[CH:31]=[CH:32][C:27]([C:25]2[N:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=3)[S:13][CH:24]=2)=[CH:28][CH:29]=1)(=[O:34])=[O:35]
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Product: CS(=O)(=O)c1ccc(-c2csc(-c3ccc(-c4ccccc4[N+](=O)[O-])c(C(=O)O)c3)n2)cc1
Yield: 11 %

Procedure:
4-[4-(4-Methanesulfonyl-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (33 mg, 11%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-bromo-1-[4-(methylsulfonyl)phenyl]-1-ethanone (available from TCI America) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 8.57 (d, J=8.3 Hz, 2H), 8.27-8.35 (m, 3H), 8.14 (d, J=7.8 Hz, 1H), 8.03 (d, J=8.1 Hz, 1H), 7.79 (t, J=8.4 Hz, 1H), 7.65 (t, J=7.6 Hz, 1H), 7.41-7.48 (m, 2H), 3.26 (s, 3H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.CCN(C(C)C)C(C)C.[C:16]1([C:22]2[N:26]3[C:27]4[C:32]([CH:33]=[CH:34][C:25]3=[N:24][N:23]=2)=[CH:31][C:30]([SH:35])=[CH:29][CH:28]=4)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:16]1([C:22]2[N:26]3[C:27]4[C:32]([CH:33]=[CH:34][C:25]3=[N:24][N:23]=2)=[CH:31][C:30]([S:35][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:29][CH:28]=4)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Brc1nccs1
Reactant: Sc1ccc2c(ccc3nnc(-c4ccccc4)n32)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(-c2nnc3ccc4cc(Sc5nccs5)ccc4n23)cc1
Temperature: 80 °C

Procedure:
To 2-Bromothiazole (0.27 mL, 3.0 mmol) in 1,4-dioxane (20 mL) was added iPr2NEt (0.96 mL, 5.5 mmol), and the reaction was degassed with N2 for 10 minutes. 10e (765 mg, 2.8 mmol) was added, followed by Pd2dba3 (63 mg, 0.07 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (81 mg, 0.14 mmol). The reaction was sealed and heated overnight at 80° C., and then cooled to room temperature and concentrated. The residue was diluted with EtOAc and water, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the crude material was purified by silica gel chromatography (60-100% EtOAc in hexanes) to give the desired product, 10f.