Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:38]([O:55][CH2:56][CH2:57][N:58]1[CH2:63][CH2:62][N:61]([CH2:64][CH2:65][C@@H:66]([NH:75][C:76]2[CH:81]=[CH:80][C:79]([S:82]([NH2:85])(=[O:84])=[O:83])=[CH:78][C:77]=2[S:86]([C:89]([F:92])([F:91])[F:90])(=[O:88])=[O:87])[CH2:67][S:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH2:60][CH2:59]1)([C:51]([CH3:54])([CH3:53])[CH3:52])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C>[Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:85][S:82]([C:79]3[CH:80]=[CH:81][C:76]([NH:75][C@H:66]([CH2:65][CH2:64][N:61]4[CH2:62][CH2:63][N:58]([CH2:57][CH2:56][O:55][Si:38]([C:51]([CH3:52])([CH3:53])[CH3:54])([C:45]5[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=5)[C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[CH2:59][CH2:60]4)[CH2:67][S:68][C:69]4[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=4)=[C:77]([S:86]([C:89]([F:90])([F:92])[F:91])(=[O:87])=[O:88])[CH:78]=3)(=[O:83])=[O:84])=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](OCCN1CCN(CC[C@H](CSc2ccccc2)Nc2ccc(S(N)(=O)=O)cc2S(=O)(=O)C(F)(F)F)CC1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(N[C@H](CCN4CCN(CCO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)CC4)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.6 %

Procedure:
(R)-4-(4-((tert-butyldimethylsilyloxy)(4 ′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 13, 56.5 mg, 0.11 mmol), (R)-4-(4-(4-(2-(tert-butyldiphenylsilyloxy)ethyl)piperazin-1-yl)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 22, 80 mg, 0.1 mmol), DMAP (35.1 mg, 0.29 mmol), and EDC (36.7 mg, 0.19 mmol) were placed in a 50 ml flask and flushed with nitrogen. DCM (0.96 ml) was added, and the solution was stirred at room temperature overnight. The reaction mixture was diluted with DCM (40 ml) and washed with 1N sodium bisulfate (35 ml) followed by a saturated aq. sodium bicarbonate (40 ml). The organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure to give the title product (147 mg, yield: quantitative), that was used in the preparation of EXAMPLE 1 without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:14][CH2:13]1.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C>CC(N(C)C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:14][CH2:13]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COC(=O)CC1CCNCC1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: Cl
Solvent: CC(=O)N(C)C
Product: COC(=O)CC1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Reaction time: 2.5 h
Yield: 26.5 %

Procedure:
A mixture of 2-Chloro-5-nitropyridine (1.59 g, 10 mmol) and methyl piperidin-4-ylacetate hydrochloride (1.8 g, 10 mmol) (prepared as described in Patent Application WO 2000029407) in DMA (50 mL) was treated with 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (BEMP) (15 g of a 2.2 mmol/g loading on polystyrene support, 33 mmol). The resulting mixture was stirred for 2.5 h then filtered through diatomaceous earth. Volatile material was removed by evaporation to give the title compound (740 mg, 21%) as a solid; 1H NMR δ 1.08-1.28 (2H, m), 1.77 (2H, d), 1.99-2.12 (1H, m), 2.29 (2H, d), 3.07 (2H, t), 3.60 (3H, s), 4.51 (2H, d), 6.94 (1H, d), 8.13-8.25 (1H, m), 8.95 (d, 1H); MS m/e MH+ 280.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][CH:8]([NH:10][C:11]([C:13]2[C:14]([CH:19]([F:21])[F:20])=[N:15][N:16]([CH3:18])[CH:17]=2)=[O:12])[CH3:9])=[C:4]([Cl:22])[CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)(O)[O-].[Na+].C(COC)OC>O.C(OC(=O)C)C>[Cl:22][C:4]1[CH:3]=[C:2]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[S:6][C:5]=1[CH2:7][CH:8]([NH:10][C:11]([C:13]1[C:14]([CH:19]([F:21])[F:20])=[N:15][N:16]([CH3:18])[CH:17]=1)=[O:12])[CH3:9]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(Cc1sc(Br)cc1Cl)NC(=O)c1cn(C)nc1C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(Cc1sc(-c2ccc(F)cc2)cc1Cl)NC(=O)c1cn(C)nc1C(F)F

Procedure:
In a sulfonation flask a mixture containing of 207 mg (0.5 mmol) 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid[2-(5-bromo-3-chlorothiophen-2-yl)-1-methylethyl]amide, 90 mg (0.64 mmol) 4-fluorophenylboronic acid, 151 mg (1.8 mmol) sodiumbicarbonate, 36 mg (0.05 mmol) bistriphenylphosphine palladium dichloride, 10 ml dimethoxyethane and 5 ml of water is stirred at reflux for 6 hours. After cooling to ambient temperature ethylacetate and water is added and the organic layer separated and washed again twice with water. After drying (sodium sulphate) and distilling off the solvent in a water jet vacuum, the crude product is obtained. Purification is achieved by column chroma-tography over silicagel (eluent: ethylacetate/heptane 1:1). Yield: 180 mg (80% of theory) of a slightly brown oil (1H-NMR: 1.29/d/3H, 0.9/m/2H, 3.09/m/2H, 3.89/s/3H, 4.42/m/1H, 6.38/s (broad)/1H, 6.89/t/1H—CF2H, 7.05/m/2H, 7.48/m/2H, 7.89/s/1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[C:12]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13]1>[OH-].[OH-].[Pd+2]>[CH:12]1([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1CCCC1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: [Pd+2]
Agent: [OH-]
Product: CC(C)(C)OC(=O)NCCNC1CCCC1
Reaction time: 48 h

Procedure:
tert-Butyl 2-aminoethylcarbamate (3.0 g, 18.8 mmol) (Preparation 54) was dissolved in cyclopentanone (30 ml). Pearlman's Catalyst (0.1 g) was added and the reaction mixture was stirred under an atmosphere of hydrogen gas (414 kPa, 100 psi) for 48 hours. The catalyst was filtered off through Arbocel (Trade Mark) and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (95:5:0.5 by volume) increasing in polarity to dichloromethane:methanol:0.88 concentrated aqueous ammonia (90:10:1 by volume). The solvent was removed under reduced pressure to give the title compound (1.5 g) as an oil.
Reaction SMILES: [O-2].[Zn+2:2].[Zn].OO.[P:6](=[O:10])([OH:9])([OH:8])[OH:7]>O>[P:6]([O-:10])([O-:9])([O-:8])=[O:7].[Zn+2:2].[P:6]([O-:10])([O-:9])([O-:8])=[O:7].[Zn+2:2].[Zn+2:2]
Reactant: O=P(O)(O)O
Agent: OO
Agent: [O-2]
Agent: [Zn+2]
Solvent: O
Product: O=P([O-])([O-])[O-]
Yield: 109.3 %

Procedure:
Zinc-containing wastes resulting from the production of sodium formaldehydesulphoxylate (rongalite) in the amount of 440 g containing 405 g of zinc oxide and 21 g of metallic zinc are ground in a ball mill by the wet grinding method in the presence of 500 g of water, whereafter additional 1,000 g of water are added thereto along with a 30% aqueous solution of hydrogen peroxide in the amount of 71 g. Under continuous stirring the suspension is heated to a temperature of 70° C., whereafter 342 g of phosphoric acid as calculated for 100% H3PO4 are added thereto. After 30 minutes the suspension is filtered, the residue is washed and dried. There are obtained 700 g of zinc phosphate (the yield is equal to 98%).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[OH-].[Rh+3:6].[OH-].[OH-].[OH-]>>[N+:1]([O-:4])([O-:3])=[O:2].[Rh+3:6].[N+:1]([O-:4])([O-:3])=[O:2].[N+:1]([O-:4])([O-:3])=[O:2]
Reactant: O=[N+]([O-])O
Agent: [Rh+3]
Agent: [OH-]
Product: O=[N+]([O-])[O-]

Procedure:
Nitric acid is then added to the separated rhodium hydroxide to dissolve the hydroxide to form a rhodium nitrate solution.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[O:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[C:27](Cl)[CH:26]=[C:25]([Cl:30])[N:24]=2)[CH2:19][CH2:18]1>O1CCCC1>[Cl:30][C:25]1[N:24]=[C:23]([N:20]2[CH2:21][CH2:22][O:17][CH2:18][CH2:19]2)[N:28]=[C:27]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(Cl)nc(N3CCOCC3)n2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.5 %

Procedure:
To a solution of N-Boc-4-hydroxy piperidine (2.58 g, 12.81 mmol) in tetrahydrofuran at 0° C. under argon, was added sodium hydride (60%, 512 mg, 12.81 mmol). After stirring for 20 minutes, a solution of 2-morpholino-4,6-dichloropyrimidine (2.0 g, 8.54 mmol) in tetrahydrofuran (20 mL) was added through a syringe. The solution was stirred for 14 hours as the ice bath warmed to room temperature. At this time, the reaction mixture was quenched with water (2 mL), and was partitioned between EtOAc (350 mL) and Na2CO3(sat.) (75 mL). The organic layer was separated, washed with brine (50 mL), dried over Na2SO4, filtered, concentrated and the residue was purified by SiO2 chromatography (15-20% EtOAc in hexanes) to yield tert-butyl 4-(6-chloro-2-morpholinopyrimidin-4-yloxy)piperidine-1-carboxylate as a white solid (2.64 g, 77%). LCMS (m/z): 399.1 (MH+). 1H NMR (CDCl3): δ 6.00 (s, 1H), 5.18 (m, 1H), 3.74 (s, 8H), 3.64-3.74 (m, 2H), 3.28-3.38 (m, 2H), 1.86-1.96 (m, 2H), 1.68-1.78 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][C@@H:27]4[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]4[OH:33])=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][C@@H:27]4[CH2:32][CH2:31][N:30]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:29][C@H:28]4[OH:33])=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)N[C@@H]1CCNC[C@H]1O
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ccnc23)[C@H](O)C1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f10) and commercially propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[Br:29][C:30]1[CH:43]=[CH:42][CH:41]=[CH:40][C:31]=1[CH2:32][C:33]1[O:34][C:35]([CH3:39])=[C:36]([CH3:38])[CH:37]=1>CN(C)C=O.C(Cl)Cl>[Br:29][C:30]1[CH:43]=[CH:42][CH:41]=[CH:40][C:31]=1[CH2:32][C:33]1[O:34][C:35]([CH3:39])=[C:36]([CH3:38])[C:37]=1[C:7]([C:6]1[CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:13][CH3:14])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:9]
Reactant: Cc1cc(Cc2ccccc2Br)oc1C
Reactant: COc1c(C(C)C)cc(C(=O)O)cc1C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccccc3Br)oc(C)c2C)cc1C(C)C
Yield: 49.2 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 3,5-diisopropyl-p-anisic acid (0.983 g, 4.16 mmol, RN-117439-59-5), oxalyl chloride (0.398 mL, 4.56 mmol), N,N-dimethylformamide (2 drops), tin (IV) chloride (0.535 mL, 4.58 mmol) and 2-(2-bromo-benzyl)4,5-dimethyl-furan (1.10 g, 4.16 mmol) in CH2Cl2. Purification on Biotage KP-Sil eluting with 3% EtOAc/pet. ether gave 0.990 g (49%) of the title compound as a clear oil. 1H NMR (DMSO-d6) δ1.15 (d, 12 H), 1.84 (s, 3 H), 2.18 (s, 3 H), 3.27 (septet, 2 H), 3.73 (s, 3 H), 3.91 (s, 2 H), 7.12-7.16 (m, 2 H), 7.29 (t, 1 H, 7.44 (s, 2 H), 7.50 (d, 1 H).
Reaction SMILES: ClC1C2C(OCC)=CSC=2C=CC=1C(Cl)=O.[Cl:17][C:18]1[C:26]2[C:25]([O:27][CH2:28]C)=[C:24]([CH2:30]C)[S:23][C:22]=2[CH:21]=[CH:20][C:19]=1[C:32]([Cl:34])=[O:33]>>[Cl:17][C:18]1[C:26]2[C:25]([O:27][CH3:28])=[C:24]([CH3:30])[S:23][C:22]=2[CH:21]=[CH:20][C:19]=1[C:32]([Cl:34])=[O:33]
Reactant: CCOc1c(CC)sc2ccc(C(=O)Cl)c(Cl)c12
Agent: CCOc1csc2ccc(C(=O)Cl)c(Cl)c12
Product: COc1c(C)sc2ccc(C(=O)Cl)c(Cl)c12

Procedure:
A mixture of 4-chloro-3-ethoxybenzo[b]thiophene-5-carboxylic acid chloride and 4-chloro-3-ethoxy-2-ethylbenzo[b]thiophene-5-carboxylic acid chloride (prepared from the product of reference example 18).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([CH:12]([CH3:18])[C:13](OCC)=[O:14])[CH:11]=[CH:10][N:9]=[CH:8]1.[OH-].[Na+]>C1COCC1>[N:7]1([CH:12]([CH3:18])[CH2:13][OH:14])[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: CCOC(=O)C(C)n1ccnc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(CO)n1ccnc1
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 67.3 %

Procedure:
A suspension of 16.6 g (0.437 mol) of lithium aluminum hydride in 700 mL of THF was warmed to 40° C. and treated dropwise with 36.8 g (0.219 mol) of ethyl 2-(1H-1-imidazolyl)propanoate and the suspension allowed to stir at room temperature for 2.5 hours. The mixture was decomposed with dilute NaOH, filtered, and the solid washed with THF. The solvent was removed under reduced pressure and the residue distilled at 155-170° C./0.5 mm Hg. There was obtained 18.6 g (67% yield) of the product as an oil. The structure was confirmed by NMR and mass spectroscopy. MS m/z 127 (M+H+).
Reaction SMILES: ClC(OCC)=O.Cl.[Br:8][C:9]1[N:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][C@H:16]2[C:18]([OH:20])=O)=[CH:11][CH:10]=1.CCN(CC)CC.[N-:28]=[N+:29]=[N-:30].[Na+]>CC(C)=O.O>[Br:8][C:9]1[N:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][C@H:16]2[C:18]([N:28]=[N+:29]=[N-:30])=[O:20])=[CH:11][CH:10]=1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(Br)nc1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)[C@@H]1C[C@H]1c1ccc(Br)nc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
Ethyl chloroformate (5.8 mL, 62 mmol) was added to a solution of (trans)-2-(6-bromopyridin-3-yl)cyclopropanecarboxylic acid hydrochloride (Intermediate E, 5 g, 20.7 mmol) and Et3N (14.2 mL, 103.7 mmol) in Acetone (100 mL) at −5° C., then reaction mixture was stirred at −5° C. for 1 h, then a solution of NaN3 (2.7 g, 41.4 mmol) in water (10 mL) was added and stirred for 30 mins at RT. After completion the solvent was evaporated under vacuum. The crude residue was dissolved in ethyl acetate (200 mL), washed with water (80 mL), brine (80 mL), dried over anhydrous Na2SO4, filtered and evaporated to get (trans)-2-(6-bromopyridin-3-yl)cyclopropanecarbonyl azide (2.5 g, 45.5%) as a brown color gummy liquid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:23]=[C:22]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:21]=[CH:20][CH:19]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: OB(O)c1cccc(Cl)c1
Product: O=c1[nH]c2nccc(-c3cccc(Cl)c3)c2c2ccccc12
Yield: 13.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 153 using Compound 83 (50 mg, 0.22 mmol) and 3-chloro-phenylboronic acid (44 mg, 0.33 mmol) to provide 155 (9 mg, 14% yield) as a white solid. LC-MS (M+H=307, obsd.=307).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1.[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[N:15]1([CH2:2][C:3]2[N:4]=[N:5][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:7][CH:8]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: c1c[nH]cn1
Reactant: BrCc1ccc(-c2ccccc2)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc(-c2ccc(Cn3ccnc3)nn2)cc1

Procedure:
Synthesized using compound 65a (40 mg, 0.16 mmol), imidazole (44 mg, 0.64 mmol) and K2CO3 (111 mg, 0.80 mmol) in acetonitrile according to Method B. Crude product was purified by flash chromatography on silica-gel using ethyl acetate as eluent. After flash chromatography the solid was washed with ethyl acetate. Light orange solid. Yield: 22 mg, 58%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=5.58 (s, 2H), 7.08 (s, 1H), 7.17-7.26 (m, 2H), 7.55-7.61 (m, 3H), 7.72 (s, 1H), 7.88 (d, J=8.8 Hz, 1H), 8.09-8.14 (m, 2H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=50.9, 119.6, 125.1, 125.5, 127.4, 129.4, 130.7, 130.8, 135.8, 137.8, 157.2, 159.3; (ESI): m/z=236.91 [M+H]+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7](Cl)(=[O:9])[CH3:8]>[O-]S(C(F)(F)F)(=O)=O.[Ga+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)Cl
Reactant: c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Ga+3]
Product: CC(=O)c1ccccc1

Procedure:
Benzene (1 equivalent) was reacted with acetyl chloride (0.5 equivalents) in the presence of 0.25 equivalents of gallium triflate catalyst at 50°-60° C. for 1 hour giving 0.35 equivalents of acetophenone.
Reaction SMILES: CC1N=C(N2CCN(C3C=CC=CC=3)C2=O)SC=1C(OCC)=O.[F:24][C:25]1[CH:48]=[CH:47][C:28]([CH2:29][N:30]2[CH2:34][CH2:33][N:32]([C:35]3[S:36][C:37]([C:41]([O:43]CC)=[O:42])=[C:38]([CH3:40])[N:39]=3)[C:31]2=[O:46])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][N:30]2[CH2:34][CH2:33][N:32]([C:35]3[S:36][C:37]([C:41]([OH:43])=[O:42])=[C:38]([CH3:40])[N:39]=3)[C:31]2=[O:46])=[CH:47][CH:48]=1
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Yield: 97 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained in 97% yield: 1H NMR (300 MHz, DMSO-d6) δ 7.84-7.07 (m, 4H), 4.32 (s, 2H), 3.93 (t, J=8.1 Hz, 2H), 3.22 (t, J=8.1 Hz, 2H), 2.46 (s, 3H); MS (ES+) m/z 336.2 (M+1).
Reaction SMILES: CN(C=O)C.[NH:6]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:7]1.Br[C:18]1[N:23]=[C:22]([C:24]2[N:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3].O>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][N:6]([C:18]3[N:23]=[C:22]([C:24]4[N:25]=[CH:26][CH:27]=[CH:28][N:29]=4)[CH:21]=[CH:20][CH:19]=3)[N:7]=2)[CH:12]=1
Reactant: Brc1cccc(-c2ncccn2)n1
Reactant: c1cncc(-c2cc[nH]n2)c1
Agent: O=[Cu]
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: c1cnc(-c2cccc(-n3ccc(-c4cccnc4)n3)n2)nc1
Temperature: 90 °C
Reaction time: 60 h

Procedure:
10 ml of DMF were added to 515.5 mg (3.55 mmol) of 3-(1H-pyrazol-3-yl)pyridine (preparation cf. WO 94/29300 A1), 838.5 mg (3.55 mmol) of 2-(6-bromopyridin-2-yl)pyrimidine (WO 2010/006713), 28.2 mg (0.35 mmol) of copper(II) oxide, 2.31 g (7.10 mmol) of cesium carbonate and 276.3 mg (1.06 mmol) of iron(III) acetylacetonate, and the mixture was stirred at 90° C. for 60 hours. The entire reaction mixture was then cooled to room temperature, and water was added. The reaction mixture was then extracted with ethyl acetate. The organic phase was separated off, dried and concentrated under reduced pressure. The residue was purified by chromatography on silica gel. This gave 334 g (31.3% of theory) of 2-{6-[3-(pyridin-3-yl)-1H-pyrazol-1-yl]pyridin-2-yl}pyrimidine.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[N+:7]([C:10]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:11]=1[C:12](=[O:25])[C:13]1[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=1[C:19]2=[O:24])([O-])=O.[H][H]>[Pd].C(O)CCC>[NH2:7][C:10]1[C:11]2[C:12](=[O:25])[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19](=[O:24])[C:20]=2[CH:21]=[CH:22][CH:23]=1
Reactant: O=C1C2=C(CCCC2)C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 100 °C
Yield: 91.3 %

Procedure:
0.07 Gram of 5% palladium on carbon catalyst and 8 grams of crystal sodium carbonate were added to a mixture of 7.7 grams of 5-nitrotetrahydroanthraquinone and 320 grams of butanol. The resultant mixture was heated to 70° C. and hydrogen was fed for hydrogenation under normal pressure to have hydrogen absorbed in the starting 5-nitro compound in an amount of 2 mols per mol of the 5-nitro compound. The resultant solution was heated to 100° C. and subjected to filtration under hot conditions for separation of the catalyst therefrom, followed by distilling off butanol for condensation. The condensed solution was allowed to cool to precipitate crystals, which were then separated by filtration, washed with water and dried to obtain 6.1 grams of 1-aminoanthraquinone having a purity of 98.5%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=[C:10]([C:16]([O:18]CC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][C:3]=1[F:21].C1(OC2C=CC=CC=2)C=CC=CC=1>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[F:21])[NH:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]2=[O:18]
Reactant: CCOC(=O)C(=CNc1ccc(Br)c(F)c1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2cc(F)c(Br)cc2c1=O
Temperature: 70 °C
Yield: 63.7 %

Procedure:
A solution of diethyl 2-[[(4-bromo-3-fluorophenyl)amino]methylidene]propanedioate (90 g, 249.88 mmol) in diphenyl ether (600 mL, 3.79 mol) was stirred at 240° C. for 2.5 h. The mixture was allowed to cool to 70° C., the solids collected by filtration and dried in a vacuum oven to afford the desired material (50 g, 64%) as a white solid which was used without further purification. NMR Spectrum: 1H NMR (500 MHz, DMSO-d6, (100° C.)) δ 1.26-1.33 (3H, m), 4.25 (2H, q), 7.52 (1H, d), 8.37 (1H, d), 8.48 (1H, s), 12.05 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=314.
Reaction SMILES: [I:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](S(C)=O)[N:12]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]([CH:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)=[O:24])[CH3:21]>O1CCOCC1.CCO>[CH2:20]([O:22][C:23]([CH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:13]2[N:12]=[C:11]([N:7]3[C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([I:1])[C:10]=4[N:9]=[N:8]3)[CH:16]=[CH:15][N:14]=2)[CH2:27][CH2:26]1)=[O:24])[CH3:21]
Reactant: CCOC(=O)C1CCC(N)CC1
Reactant: CS(=O)c1nccc(-n2nnc3c(I)cccc32)n1
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)C1CCC(Nc2nccc(-n3nnc4c(I)cccc43)n2)CC1
Temperature: 110 °C
Reaction time: 4 h
Yield: 139.3 %

Procedure:
A mixture of 4-iodo-1-(2-methylsulfinyl-pyrimidin-4-yl)-1H-benzotriazole (2.0 g) and 4-amino-cyclohexanecarboxylic acid ethyl ester (1.8 g) in 1,4-dioxane (25 mL) was stirred at 110° C. for 4 h. The solvent was removed in vacuo to provide an oil, which was taken up in EtOH and heated in a water bath until a light orange solid formed. The solid was filtered, washed with Et2O, and dried to provide 4-[4-(4-(4-iodobenzotriazol-1-yl)-pyrimidin-2-ylamino]-cyclohexane-carboxylic acid ethyl ester (3.56 g, 93%) as a light orange powder.