Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9](B(O)O)=[CH:10][C:3]=12.I[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(CCC)=CC(CCC)=CC=2CCC)CCCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:10][C:3]=12
Reactant: Ic1cccnc1
Reactant: C[Si](C)(C)CCOCn1c(B(O)O)cc2c(Cl)ccnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(CCC)c1
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: C[Si](C)(C)CCOCn1c(-c2cccnc2)cc2c(Cl)ccnc21
Yield: 52.3 %

Procedure:
Argon was bubbled through a mixture of 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-2-ylboronic acid (5.55 g, 17 mmol), 3-iodopyridine (6.97 g, 34 mmol), Pd(OAc)2, 2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (405 mg, 0.85 mmol), and K3PO4 (2 M in H2O, 34 mmol) in DME (50 mL) for 10 min and then heated at reflux overnight. The reaction mixture was diluted with EtOAc and washed with saturated aq. K2HPO4 solution. The title compound was purified by flash column chromatography (silica gel, 20% EtOAc/CH2Cl2) to afford the desired product (3.2 g, 52% yield) as an oil. LC/MS(ESI+) m/z 361 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].[CH:32]1(C2C(N[C@@H]3C4C(=CC=CC=4)C[C@@H]3O)=NC(CC)=C(C3C=CC(Cl)=CC=3Cl)N=2)CC1>>[CH:30]1([C:11]2[C:12]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[O:27][CH2:28][CH3:29])=[N:13][C:14]([CH2:15][CH3:16])=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=2)[CH2:32][CH2:31]1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(C2CC2)nc1-c1ccc(Cl)cc1Cl
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1C1CC1

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[3-cyclopropyl-5-(2,4-dichlorophenyl)-6-ethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.87–1.21, 1.58, 1.80–1.85, 2.51, 3.15–3.17, 3.46–3.56, 3.66–3.76, 4.40–4.45, 5.88, 6.04, 7.21–7.34, 7.47–7.50; MS (ESI+) for C26H27Cl2N3O m/z 469 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[NH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]([C:23]#[N:24])=[C:16]2[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Br:32])[CH:27]=1>C(Cl)Cl.O1CCCC1>[Br:32][C:28]1[CH:27]=[C:26]([NH:25][C:16]2[C:15]3[C:20](=[CH:21][CH:22]=[C:13]([NH:12][C:8](=[O:10])[CH3:9])[CH:14]=3)[N:19]=[CH:18][C:17]=2[C:23]#[N:24])[CH:31]=[CH:30][CH:29]=1
Reactant: CC(=O)Cl
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.1 %

Procedure:
Triethylamine (0.359 g, 3.55 mmol) and acetyl chloride (0.277 mg, 3.55 mmol) were added to an ice cold solution of 1.00 g (2.96 mmol) of 6-amino-4-[(3-bromophenyl)-amino]-3-quinolinecarbonitrile in 8 mL of methylene chloride and 6 mL of tetrahydrofuran under N2. After stirring overnight at 25° C., volatile material was removed, and the residue was slurried with water and collected. Recrystallization from ethanol gave 0.543 g of brown solid; mp 258-261° C.(dec).
Reaction SMILES: [OH-].[Na+].BrBr.Br[O-].[Na+].[OH:8][C@@H:9]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:25]2[C:24](=[O:30])[CH2:23][C@@:22]2([CH3:31])[C@H:15]3[CH2:16][C@@H:17]([CH3:32])[C@@H:18]2[C:19](=[O:21])C)[CH2:10]1.Br[O-].O.O.O.O.O.O.O.S([O-])([O-])=[O:43].[Na+].[Na+]>O.O1CCOCC1>[OH:8][C@@H:9]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:25]2[C:24](=[O:30])[CH2:23][C@@:22]2([CH3:31])[C@H:15]3[CH2:16][C@@H:17]([CH3:32])[C@@H:18]2[C:19]([OH:21])=[O:43])[CH2:10]1
Reactant: CC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@@]21C
Reactant: O=S([O-])[O-]
Agent: BrBr
Agent: [Na+]
Agent: [O-]Br
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1C[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]2(C)[C@H]1C(=O)O
Reaction time: 3 h
Yield: 99.5 %

Procedure:
A solution of sodium hydroxide (7.35g.) in water, (55 ml.) was stirred at -5° and bromine added slowly maintaining the temperature between -5° and 0°. Cold dioxan (45 ml.) was added and the pale yellow sodium hypobromite solution stirred at 0° until required. 3α-Hydroxy-16α-methyl-5α-pregnane-11, 20-dione (5.0g.) was dissolved in dioxan (200 ml.) and water (55 ml.). The hypobromite solution was added over 5 min. and the resulting mixture kept between 5° and 10° with stirring for 3 hr. Sodium sulphite heptahydrate (2.8g.) in water (15 ml.) was added and the solution refluxed for 15 min. The mixture was acidified and concentrated to incipient crystallisation before pouring into water (1 1.). Filtration afforded the title compound (3.85g.); m.p. 265°-268°.
Reaction SMILES: [NH2:1][C:2]1[N:17]=[CH:16][C:15](Br)=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[CH3:13])=[O:5].[N:19]1([C:24]2[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[N:20]1>>[NH2:1][C:2]1[N:17]=[CH:16][C:15]([C:27]2[CH:26]=[CH:25][C:24]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:29][CH:28]=2)=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[CH3:13])=[O:5]
Reactant: OB(O)c1ccc(-n2cccn2)cc1
Reactant: Cc1cnccc1NC(=O)c1cc(Br)cnc1N
Product: Cc1cnccc1NC(=O)c1cc(-c2ccc(-n3cccn3)cc2)cnc1N

Procedure:
Reaction of 2-amino-5-bromo-N-(3-methyl-pyridin-4-yl)-nicotinamide with [4-(1H-pyrazol-1-yl)phenyl]boronic acid gives the compound “A19”;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([F:19])[CH:13]=3)[CH:11]=1)[O:8][CH:7]([C:20]([F:23])([F:22])[F:21])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2.[OH-].[Na+:28]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([F:19])[CH:13]=3)[CH:11]=1)[O:8][CH:7]([C:20]([F:22])([F:23])[F:21])[C:6]([C:24]([O-:26])=[O:25])=[CH:5]2.[Na+:28]
Reactant: Cc1ccc(-c2cc(Cl)cc3c2OC(C(F)(F)F)C(C(=O)O)=C3)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2cc(Cl)cc3c2OC(C(F)(F)F)C(C(=O)[O-])=C3)cc1F

Procedure:
A solution of 52.0 mg (0.135 mmole) of 6-chloro-8-(3-fluoro-4-methylphenyl)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid in 2.0 mL of ethanol was treated with 1.334 mL of 0.1008N NaOH. The resultant mixture was lyophilized to provide a quantitative yield of a yellow solid: 1H NMR (CD3OD/400 MHz) 2.29 (d, 3H, J=1.6 Hz), 5.84 (q, 1H, J=7.2 Hz), 7.17-7.20 (m, 2H), 7.24-7.29 (m, 3H), 7.40 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[NH:10][C:11]1([CH3:25])[CH2:16][CH2:15][CH:14]([O:17][Si](C(C)(C)C)(C)C)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([O:8][C:9](=[O:26])[NH:10][C:11]1([CH3:25])[CH2:12][CH2:13][CH:14]([OH:17])[CH2:15][CH2:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(NC(=O)OCc2ccccc2)CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(NC(=O)OCc2ccccc2)CCC(O)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.2 %

Procedure:
To a solution of example 45D (341 mg, 0.91 mmol) in tetrahydrofuran (5 mL) was added tetrabutylammonium fluoride (1 M solution in THF, 2.0 mL, 2 mmol). The resulting brown solution was stirred at room temperature for 24 hours and then concentrated in vacuo and partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to afford a crude oil. The crude oil was purified by flash chromatography using a linear gradient of 80% hexane/20% ethyl acetate to 80% ethyl acetate/20% hexane to give the title compound (185 mg) as an inseparable mixture of diastereomers. MS (CI) m/z 264 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[NH:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:18]=1.O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:21])[CH2:9][N:8]=[C:7]([C:13]3[NH:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:18]=1
Reactant: O=C1CN=C(c2ccc[nH]2)c2cc(Cl)ccc2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Solvent: C1CCOC1
Product: S=C1CN=C(c2ccc[nH]2)c2cc(Cl)ccc2N1
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 159.6 %

Procedure:
10 g (38.5 mmol) of 7-chloro-1,3-dihydro-5-(1H-pyrrol-2-yl)-1,4-benzodiazepin-2-one were dissolved in anhydrous THF (400 ml) in a 1 litre round-bottom 3-neck flask equipped with a mechanical stirrer. The flask was then placed in the water bath of an ultrasonic apparatus. To the stirred reaction solution was added P4S10 (10 g; 22.5 mmol) and the reaction mixture was irradiated with ultrasound. The temperature was maintained at about 40° C. throughout the reaction. After 2.5 hours, an additional portion of P4S10 (10 g; 22.5 mmol) was added to the mixture and the reaction was continued for an additional 2 hours. The heterogeneous mixture was cooled to ambient temperature and filtered. After washing the solid by-product with several portions of CH2CL2, the filtrates were combined and approximately 80% of the solvent was removed in vacuo. The residual solution was basified with saturated sodium bicarbonate solution until a pH of about 8 was reached. The product which precipitated out was filtered. The filtrate was then extracted with CH2Cl2, followed by concentration in vacuo. The solids were combined and recrystallized in THF/Petroleum ether to give 9.9 g (94% yield) of 7-chloro-1,3-dihydro-5-(1H-pyrrol-2yl)-1,4-benzodiazepin-2-thione as a pale yellow powder having the following characteristics: m.p. 258°-260° C. dec.; IR (KBr) 3450, 3165 cm-1. Anal. Calcd. for C13H10C1N3S: C 56.62; H 3.66; N 15.24. Found: C 56.50; H 3.59; N 15.12.
Reaction SMILES: COC[CH2:4][C@@H:5]1[CH2:9][N:8]([C:10]2[CH:11]=[CH:12][C:13]3[O:14][CH2:15][C:16](=[O:20])[NH:17][C:18]=3[N:19]=2)[C:7](=[O:21])[CH2:6]1.[O:22]1CCCC1.Cl.C(=O)([O-])O.[Na+]>CO>[OH:22][CH2:4][C@@H:5]1[CH2:9][N:8]([C:10]2[CH:11]=[CH:12][C:13]3[O:14][CH2:15][C:16](=[O:20])[NH:17][C:18]=3[N:19]=2)[C:7](=[O:21])[CH2:6]1
Reactant: C1CCOC1
Reactant: COCC[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C1COc2ccc(N3C[C@@H](CO)CC3=O)nc2N1
Temperature: 60 °C
Yield: 93 %

Procedure:
To a solution of 6-{(4S)-4-[(methoxymethyl)methyl]-2-oxopyrrolidin-1-yl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (2.21 g, 7.20 mmol) in methanol (25 ml)/tetrahydrofuran (25 ml) was added 4N Hydrochloric acid (2.5 ml) at room temperature and the mixture was heated to 60° C. and stirred with heating for 16 hours. The reaction solution was poured into a saturated sodium hydrogen carbonate aqueous solution and extracted with a mixed solvent of chloroform/methanol (9:1) (3×). The organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. 1.76 g (93%) of a crude product of the title compound was obtained in the form of a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].CN(C)C=O>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: Oc1ccccc1Br
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccccc1Br
Yield: 46.7 %

Procedure:
2-Bromophenol (1.88 g), anhydrous potassium carbonate (1.51 g), (2-bromoethoxy)-(tert-butyl)dimethylsilane (2.61 g) and dimethylformamide (30 ml) were heated for 20 h at 90° C., cooled, poured into water (100 ml), extracted with ethyl acetate, the organic phase washed with water, brine, dried (MgSO4) and evaporated to dryness. The residue was purified by column chromatography eluting with 1:9 ether/isohexane to give the product as a crystalline solid (1.68 g).
Reaction SMILES: C1(S([CH2:9][C:10]2[CH:11]=[CH:12][N:13]3[C:18]=2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=4)=[C:22]([Cl:35])[CH:21]=2)=[N:16][CH:15]=[N:14]3)=O)C=CC=CC=1.[NH2:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>C(Cl)Cl>[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([CH2:9][C:10]2[CH:11]=[CH:12][N:13]3[C:18]=2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=4)=[C:22]([Cl:35])[CH:21]=2)=[N:16][CH:15]=[N:14]3)[CH2:39][CH2:38]1
Reactant: NC1CCNCC1
Reactant: O=S(Cc1ccn2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12)c1ccccc1
Solvent: ClCCl
Product: NC1CCN(Cc2ccn3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)CC1
Temperature: 135 °C
Yield: 41.6 %

Procedure:
A mixture of the sulfoxide 7B (100 mg, 0.20 mmol) and 4-aminopiperidine (0.6 gm, 6 mmol) was heated in a sealed tube at 135° C. for 4 hr. The reaction mixture was taken up in DCM, washed with water, and dried (Na2SO4). Removal of the solvent followed by radial chromatography (2 mm silica gel plate eluted with DCM containing 5% MeOH) afforded 7C (40 mg, 42%) as a foam. Analytical HPLC retention time=1.35 min. (YMC Xterra S7 C18, 3.0×50 mm column, 10–90% aqueous methanol over 2 minutes containing 0.1% TFA, 5 mL/min, monitoring at 220 nm) and a LC/MS M++1=481.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].C([O-])([O-])=[O:22].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH2:12])=[O:22])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:17]([F:18])([F:19])[F:20]
Reactant: N#Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of 4-[4-chloro-3-(trifluoromethyl)phenoxy]benzonitrile (Preparation 47, 48 g, 161 mmol) in DMSO (500 ml) was added K2CO3 (45 g, 323 mmol) followed by dropwise addition of a 30 wt % aqueous hydrogen peroxide solution (27 ml, 806 mmol) at 15° C. The reaction mixture was stirred for 1 hour at room temperature and the mixture was poured into water (500 ml) to afford a preciptate. The precipitated solid was collected by filtration, azeotroped with toluene, and dried over in vacuo to give 51 g of titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:11][S:12]([NH2:15])(=[O:14])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+].O>[Cu]I.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:15][S:12]([CH3:11])(=[O:14])=[O:13])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: COc1ncc(Br)cc1I
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncc(Br)cc1NS(C)(=O)=O
Temperature: 105 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
To a 20 mL scintillation vial, 5-bromo-3-iodo-2-methoxypyridine (Alfa Aesar, 2.02 g, 6.43 mmol), methanesulfonamide (Fluka, 0.645 g, 6.78 mmol), copper (I) iodide (Strem, 0.122 g, 0.643 mmol), cesium carbonate (Aldrich, 5.27 g, 16.1 mmol) and water (0.60 ml, 33.3 mmol) were mixed into DMF (6 mL). The reaction mixture was stirred at 105° C. for overnight. Then the mixture was heated in a microwave reactor (Biotage) at 120° C. for 30 min. The reaction mixture was partitioned between Tris-HCl buffer (1 M, pH 7.0) (20 mL) and EtOAc (20 mL). The aq phase was extracted with EtOAc (2×20 mL). The combined organic phases were washed with saturated aq NaCl (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (100 g, eluent: EtOAc in hexanes 0% to 50%) to afford N-(5-bromo-2-methoxypyridin-3-yl)methanesulfonamide (1.06 g, 59% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 7.97 (d, J=2.19 Hz, 1H) 7.90 (d, J=2.19 Hz, 1H) 6.72 (br. s., 1H) 4.00 (s, 3H) 3.04 (s, 3H). m/z (ESI, positive ion): 280.8, 282.8 [M+1, M+3].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][CH2:10][C:11]([C:13]2[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[Cl:19][C:16]1[N:15]=[CH:14][C:13]([CH:11]([OH:12])[CH2:10][CH2:9][CH:8]([C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[OH:20])=[CH:18][CH:17]=1
Reactant: O=C(CCC(=O)c1ccc(Cl)nc1)c1ccc(Cl)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(CCC(O)c1ccc(Cl)nc1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.2 %

Procedure:
The product from Example 207A (2.90 g, 9.38 mmol) and sodium borohydride (0.745 g, 19.70 mmol) were combined in ethanol (94 mL) at 0° C. The mixture was warmed to room temperature and stirred for 6 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate and 1M HCl. The organic layer was washed with water, brine, dried with sodium sulfate, filtered and evaporated to give the title compound (2.62 g, 89%).
Reaction SMILES: [O:1]1[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[O:4][CH2:3][CH2:2]1)[O:11][CH2:10][C:9]([CH:15]=[O:16])=[CH:8]3.[BH4-].[Na+].Cl>C(O)C>[O:1]1[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[O:4][CH2:3][CH2:2]1)[O:11][CH2:10][C:9]([CH2:15][OH:16])=[CH:8]3
Reactant: O=CC1=Cc2c(ccc3c2OCCO3)OC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCC1=Cc2c(ccc3c2OCCO3)OC1
Reaction time: 0.25 h

Procedure:
2.18 g (10 mmol) of the aldehyde obtained in Step C are dissolved in 25 ml of anhydrous ethanol and then 0.38 g (10 mmol) of sodium borohydride is added to the medium. After 15 minutes of stirring, the solvent is evaporated in vacuo; the residue obtained is then acidified with a 1N hydrochloric acid solution. The aqueous phase is extracted with dichloromethane; the organic phase is then dried over magnesium sulphate and then concentrated under reduced pressure. The crude product is passed over a silica column (eluant:petroleum ether/ethyl acetate:70/30 then 50/50) to yield the title alcohol in the form of a clear syrup.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.Cl[CH:20]([CH3:24])[C:21]([OH:23])=[O:22]>C1(C)C(C)=CC=CC=1>[Cl:3][C:4]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH:20]([CH3:24])[C:21]([OH:23])=[O:22])=[CH:11][CH:12]=1
Reactant: CC(Cl)C(=O)O
Reactant: Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CC(Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1)C(=O)O
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
208 parts of 50% sodium hydroxide solution are added portionwise at about 90° C. and at a reduced pressure of 270 mbar to a solution of 255 parts of 4-(2',4'-dichlorophenoxy)-phenol and 132 parts of 2-chloropropionic acid in 1,200 parts of xylene. By distilling off the water present in the reaction mixture, the reaction temperature is maintained at 90° C. The addition being complete, stirring is continued for 15 minutes at this temperature, subsequently the batch is brought to normal pressure. 400 Parts of water are then added, and stirring is continued for 10 minutes at 85° C. The batch is subsequently acidified at this temperature with 120 parts of phosphoric acid, and stirring is continued for 10 minutes. After elimination of the water phase via a separating funnel, xylene is distilled off under a pressure of 80 mbar, and the solids are dried at 60° C. and 250 mbar. 327 Parts of 2-[4'-(2,4-dichlorophenoxy)-phenoxy]-propionic acid are obtained. The content of pure final product is 99.5%, corresponding to a yield of 99.5% of theory. The residual amount of 4-(2',4'-dichlorophenoxy)-phenol is 0.3%.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.[NH2:23][NH:24][C:25](=O)[CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32].C[O-].[Na+]>CO>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[N:6]=[C:25]([CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][C:28]5=[O:32])[NH:24][N:23]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:21][CH:20]=1
Reactant: NNC(=O)CN1CCCC1=O
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C1CCCN1Cc1nc(-c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)n[nH]1
Yield: 34 %

Procedure:
A suspension of ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine hydrochloride (0.300 g, 0.94 mmol) and N-amino-2-(2-oxopyrrolidinyl)acetamide (0.442 g, 2.81 mmol) in 4 mL of anhydrous methanol was prepared. An excess of a commercial solution of sodium methoxide in methanol (0.643 mL, 4.37 M) was added. Upon adding the basic solution, the reaction mixture became clear then cloudy. After an hour, the temperature was raised to reflux temperature and was maintained for 48 hours. The reaction was then quenched with water, the pH adjusted to neutral and the crude product extracted with ethyl acetate. The title compound was purified by preparative HPLC (0.118 g, 34% yield): 1H NMR (CD3OD) δ 8.68 (s, 1H), 8.07–8.02 (m, 3H), 7.68 (d, 1H), 7.29 (t, 2H), 4.66 (s, 2H), 3.53 (t, 2H), 2.47 (t, 2H), 2.10 (quintet, 2H); ES-MS (m/z) 377 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[C:9]([N+:18]([O-:20])=[O:19])[CH:10]=[C:11]4[C:17]=3[C@H:14]([CH2:15]2)[CH2:13][NH:12]4)[CH2:5][C@H:4]([NH:21][C:22](=[O:28])[N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:3]1.F[B-](F)(F)F.[CH3:34][S+:35](C)SC.N>O1CCCC1>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[C:9]([N+:18]([O-:20])=[O:19])[CH:10]=[C:11]4[C:17]=3[C@H:14]([CH2:15]2)[CH2:13][N:12]4[S:35][CH3:34])[CH2:5][C@H:4]([NH:21][C:22](=[O:28])[N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:3]1
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc([N+](=O)[O-])cc4c3[C@@H](CN4)C[C@H]2N(C)C1
Reactant: CS[S+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: C1CCOC1
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc([N+](=O)[O-])cc4c3[C@H](C[C@H]2N(C)C1)CN4SC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.6 %

Procedure:
Under argon, 38 mg (0.1 mmol) of 3-(2,3β-dihydro-6-methyl-13-nitro-8α-ergolinyl)-1,1-diethylurea in 2 ml of absolute, freshly distilled tetrahydrofuran is combined with 47 mg (0.24 mmol) of dimethylmethylthiosulfonium fluoroborate, and the mixture is agitated for 20 minutes at room temperature. For working-up purposes, the batch is poured on 10 ml of ice and rendered alkaline with 25% strength ammonia solution. The organic phase is extracted repeatedly with methylene chloride. The extracts are dried over magnesium sulfate and concentrated. The crude product is purified over a preparative silica gel plate with methylene chloride/methanol 9:1 as the eluent, thus obtaining 28 mg of 3-(2,3β-dihydro-6-methyl-1-methylthio-13-nitro-8α-ergolinyl)-1,1-diethylurea.