Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1)CCC>O1CCOCC1.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>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:32]4[N:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: Brc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: c1ccc(COc2ccc(Nc3ncnc4ccc(-c5ncccn5)cc34)cc2)cc1
Yield: 40.3 %

Procedure:
The (4-benzyloxy-phenyl)-(6-bromoquinazolin-4-yl)amine (200 mg, 0.49 mmol), 2-(tributylstannyl)pyrimidine (200 mg, 0.54 mmol) and bis(triphenylphosphine)palladium(II) chloride (catalytic) were dissolved in dioxan (3 ml) and heated at reflux under nitrogen for 27 hr (Procedure B). The solvent was removed from the cooled reaction under vacuum, and the residue was purified by flash column chromatography (silica gel, eluting with an ethyl acetate/iso-hexane gradient). The resulting oily solid was triturated with iso-hexane/ethyl acetate to give the product (80 mg, 40%) as a pale yellow solid; δH [2H6]-DMSO 10.30 (1H, b, NH), 9.61 (1H, s, 5-H), 9.07 (2H, d, pyrimidine 4-H, pyrimidine 6-H), 8.86 (1H, d, 7-H), 8.51 (1H, s, 2-H), 7.93 (1H, d, 8-H), 7.78 (2H, d, 2′-H, 6′-H), 7.65-7.36 (6H, m, 5×Ph-H, pyrimidine 5-H), 7.11 (2H, d, 3′-H, 5′-H), 5.18 (2H, s, CH2); m/z 406 (M+1)+.
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[NH:9][C@H:8]([C:10]([NH:12][C@H:13]([C:23](=[O:31])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][S:19]C(=O)C)=[O:11])[CH2:7][CH2:6][CH2:5]1.O>CCO>[SH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]([NH:12][C:10]([C@@H:8]1[CH2:7][CH2:6][CH2:5][C:4](=[O:3])[NH:9]1)=[O:11])[C:23](=[O:31])[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)SCCCCC[C@H](NC(=O)[C@@H]1CCCC(=O)N1)C(=O)Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C1CCC[C@@H](C(=O)N[C@@H](CCCCCS)C(=O)Nc2ccccc2)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 2N solution of NaOH (7.0 mmol) was added to a solution of thioacetic acid S—{(S)-6-[((S)-6-oxo-piperidine-2-carbonyl)-amino]-6-phenylcarbamoyl-hexyl}ester (0.95 mmol) in EtOH (13 ml). The reaction mixture was stirred at RT overnight and then poured into water and extracted with AcOEt, washed with water, brine and finally dried over Na2SO4. Removal of the solvent under reduced pressure led to the desired adduct, which was purified through HPLC.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][CH:10]1[C:14]2([CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:13][N:12]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][CH:10]2[C:14]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:13][N:12]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11]2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(N)C2(CCCC2)C1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(Nc2ccnc(Cl)n2)C2(CCCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
To a solution of 2,4-dichloropyrimidine (600 mg, 4.03 mmol) and tert-butyl 4-amino-2-azaspiro[4.4]nonane-2-carboxylate (1.07 g, 4.43 mmol) in EtOH (20 mL) was added Et3N (815.6 mg, 8.06 mmol). After addition, the reaction mixture was stirred at rt overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1 to 1/1) to give the product as a white solid (528 mg, 37.2%).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]=1.[Li:13]CCCC>CCCCCC>[CH3:1][N:2]([CH3:12])[C:3]1([Li:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: CN(C)C1=CCc2ccccc21
Reactant: [Li]CCCC
Solvent: CCCCCC
Product: [Li]C1(N(C)C)C=Cc2ccccc21
Reaction time: 8 h
Yield: 90.7 %

Procedure:
In the drybox 3.8 g (23.9 mmol) of N,N-dimethyl-1H-inden-3-amine was combined with 100 mL of hexane. To this solution 15 mL (23.9 mmol) of n-BuLi (1.6 M) was added dropwise. Upon complete addition of the n-BuLi the solution was stirred overnight. The resulting precipitate was collected via filtration, washed with hexane and dried under reduced pressure to give 3.58 g of product. Yield 91 percent.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([C:15]([OH:17])=O)[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1>CCOC(C)=O>[CH:1]1([CH2:7][NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[O:17])[CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(NCC2CCCCC2)ncn1
Reactant: Nc1ccc(O)cc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(O)cc1)c1cc(NCC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[(cyclohexylmethyl)amino]pyrimidine-4-carboxylic acid (Intermediate 6) and 4-amino-phenol (Aldrich), the title compound was obtained as a white solid after trituration in EtOAc.
Reaction SMILES: C(O[C:4](=O)[NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC>C1COCC1>[CH3:4][NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)NC1CCCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN[C@H]1CCCc2ccccc21
Temperature: 75 °C
Reaction time: 2 h

Procedure:
(1,2,3,4-Tetrahydro-naphthalen-1-yl)-carbamic acid ethyl ester (5.0 g, 22.8 mmol) is added slowly under nitrogen to a suspension of LiAlH4 (2.6 g, 68 mmol) in THF (50 mL). The resulting mixture is heated at 75° C. with stirring for 2 hours. On cooling, Na2SO4.10H2O (15.0 g) and ether (100 mL) are added to the mixture. The resulting mixture is stirred at room temperature for 1 hour, filtered through celite, and concentrated in vacuo. 1 N HCl (20 mL) and ether (20 ML) are added to the residue. The organic layer is separated and discarded. The aqueous layer is basified with 1 N NaOH and extracted with CH2Cl2 (2×25 mL). The combined extract is washed with water (2×), dried (Na2SO4) and concentrated to give (S)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine as an oil. [α]RT=−10.6 (0.02, EtOH). 1H NMR (CDCl3) 7.30 (m, 1H), 7.06-7.20 (m, 3H), 3.66 (t, 1H), 2.78 (m, 2H), 2.50 (s, 3H), 1.70-2.00 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([Br:17])[CH:11]=2)=O)=[N:4][S:5][N:6]=1.COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:27]2)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:7](=[S:27])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([Br:17])[CH:11]=2)=[N:4][S:5][N:6]=1
Reactant: Nc1nsnc1C(=O)Nc1ccc(F)c(Br)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Nc1nsnc1C(=S)Nc1ccc(F)c(Br)c1
Yield: 55.7 %

Procedure:
A solution of 4-amino-N-(3-bromo-4-fluorophenyl)-1,2,5-thiadiazole-3-carboxamide (225 mg, 0.7 mmol) and 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (570 mg, 1.4 mmol) in toluene (6.8 mL) was stirred at 95° C. for 16 h. The reaction mixture was diluted with ethyl acetate (50 mL) and the insoluble salts were filtered. The filtrate was concentrated to a crude residue which was purified on silica gel to give the desired product (130 mg, 55%). LCMS for C9H7BrFN4S2 (M+H)+: m/z=332.8, 334.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([CH2:19][C:20]#[CH:21])([CH2:16][C:17]#[CH:18])[C:13](O)=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:23][OH:24]>>[OH:24][NH:23][C:13](=[O:14])[C:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH2:19][C:20]#[CH:21])[CH2:16][C:17]#[CH:18]
Reactant: C#CCC(CC#C)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1
Reactant: NO
Agent: Cl
Product: C#CCC(CC#C)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1
Yield: 85 %

Procedure:
2-(4-Methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from (4-methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid (0.25 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.22 g of the product was isolated. Yield 85%; white solid; mp 156° C.; MS: 321.9 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ2.00-2.13 (m, 2H), 3.00-3.30 (m, 4H), 3.90(s, 3H), 7.01 (d, J=9.0 Hz, 2H), 7.82 (d, J=9.0 Hz, 2H), 8.76 (brs, 1H), 10.65 (brs, 1H); IR (KBr, cm−1): 3392s, 3293s, 3271m, 2955m, 1650s, 1594s;
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:13]=3[CH:28]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].N[C@H:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:31][OH:32]>C1(Cl)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[O:16][C:12]3[CH:11]=[CH:10][C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:1]5[O:32][CH2:31][C@@H:30]([C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)[N:2]=5)[CH:4]=4)=[CH:28][C:13]=3[C:14]=2[C:24]([NH:26][CH3:27])=[O:25])=[CH:18][CH:19]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C#N)c3)cc12
Reactant: N[C@@H](CO)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C4=N[C@H](c5ccccc5)CO4)c3)cc12
Yield: 13.2 %

Procedure:
Zinc chloride (8 mg, 0.054 mmol) was added to a stirring solution of 5-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (40 mg, 0.108 mmol) and (R)-2-amino-2-phenylethanol (148 mg, 1.080 mmol) in PhCl (3 mL) at rt. It was subjected to two interations of microwave irradiation at 200° C. for 1 hr. The material was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (7 mg, 13%). 1H NMR (500 MHz, CD3OD) δ ppm 8.33 (1 H, s), 7.94-8.00 (4 H, m), 7.91 (1 H, d, J=7.94 Hz), 7.64-7.73 (2 H, m), 7.61 (1 H, t, J=7.78 Hz), 7.32-7.42 (6 H, m), 7.26 (2 H, t, J=8.55 Hz), 5.45 (1 H, t, J=9.16 Hz), 4.94 (1H, t, J=9.31 Hz), 4.36 (1 H, t, J=8.24 Hz), 2.97 (3 H, s). LC-MS retention time 1.75 min; m/z (MH+): 491. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% MeOH/95% H2O/10 mM ammonium bicarbonate, Solvent B=95% MeOH/5% H2O/10 mM ammonium bicarbonate, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Phenomenex Gemini C-18, 4.6×150 mm, 3 μm, Rt=18.32 min, purity=97%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 μm, Rt=18.11 min, purity=97%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:20]([O:22]C)=[O:21])[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CC(C)=O.CO>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:20]([OH:22])=[O:21])[NH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2c(OCc3ccccc3)cc(OC)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Product: COc1cc(OCc2ccccc2)c2cc(C(=O)O)[nH]c2c1

Procedure:
0.11 g of methyl 4-benzyloxy-6-methoxy-1H-indole-2-carboxylate is dissolved in 3 ml of acetone and 2 ml of methanol. 6 ml of 1N sodium hydroxide are then added. This mixture is left to react for 4 hours at room temperature. The medium is concentrated on a rotary evaporator and diluted with 20 ml of water. The resulting mixture is acidified to pH=2 with concentrated hydrochloric acid. A light brown solid is obtained. The recovered mass is 700 mg, which corresponds to a yield of 67%.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:11](=O)[CH2:10][CH2:9][N:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH2:7]1)=[O:5])[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO.CCOC(C)=O>[CH2:1]([O:3][C:4]([CH:6]1[CH:11]([NH2:29])[CH2:10][CH2:9][N:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CCOC(=O)C1CN(c2ccc(OC)c(OC)c2)CCC1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)C1CN(c2ccc(OC)c(OC)c2)CCC1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.1 %

Procedure:
A suspension of rac-1-(3,4-dimethoxy-phenyl)-4-oxo-piperidine-3-carboxylic acid ethyl ester (640 mg) and ammonium acetate (3 g) in 10 ml methanol was stirred 18 h at RT., then sodium cyanoborohydride (2 g) was added. After 18 h at RT, the mixture was diluted with AcOEt, washed twice with water and brine. The organic layers were dried over MgSO4, filtered, evaporated and chromatographied (silica gel, AcOEt/heptane, 1/1) to give the title compound (450 mg, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:15](=[N:17][OH:18])[CH3:16])[CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[CH3:19][C:20](OC(C)=O)=[O:21]>>[C:20]([O:18]/[N:17]=[C:15](/[C:10]1[CH:9]=[C:8]([C:5]2([C:3]([O:2][CH3:1])=[O:4])[CH2:7][CH2:6]2)[CH:13]=[CH:12][C:11]=1[OH:14])\[CH3:16])(=[O:21])[CH3:19]
Reactant: COC(=O)C1(c2ccc(O)c(C(C)=NO)c2)CC1
Reactant: CC(=O)OC(C)=O
Product: COC(=O)C1(c2ccc(O)c(/C(C)=N/OC(C)=O)c2)CC1
Yield: 99 %

Procedure:
The solution of 1-[4-hydroxy-3-(1-hydroxyimino-ethyl)-phenyl]-cyclopropanecarboxylic methyl ester (10.0 g, 40.1 mmol) in Ac2O (250 mL) was heated at 45° C. for 4 h. The Ac2O was removed by evaporation under vacuum before water (100 mL) and EtOAc (100 mL) were added. The organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL×2). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give (E)-methyl 1-(3-(1-(acetoxyimino)ethyl)-4-hydroxyphenyl)cyclopropanecarboxylate (10.5 g, 99%), which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][C@H:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:11][CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.O.[Pd]>[C:1]([O:5][C:6]([NH:8][NH:9][C@H:10]([C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:11][CH2:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC[C@H](NNC(=O)OC(C)(C)C)C(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CCC[C@H](NNC(=O)OC(C)(C)C)C(C)(C)C
Reaction time: 4.5 h
Yield: 92.9 %

Procedure:
(S)—N′-(1-tert-Butyl-but-3-enyl)-hydrazinecarboxylic acid tert-butyl ester (2.34 g, 9.65 mmoles) was dissolved in methanol (50 mL) in a Parr bottle. 10% Pd/C (70 mg) was added as a slurry in water (1.6 mL), and the mixture was shaken on a Parr hydrogenator for 4.5 h with a starting pressure of 55 psi. The pressure decrease was monitored as a measure of the reaction progress, indicating that the reaction was likely complete after 30 minutes. The catalyst was allowed to substantially settle, and the supernatant was removed with a pipette, passed through a 0.45 micron syringe filter, and analyzed by TLC. Solvent was removed in vacuo to yield 2.19 g (92.7%) of (S)—N′-(1-tert-butyl-butyl)-hydrazinecarboxylic acid tert-butyl ester as a faintly pale yellow oil. Rf=0.48 (5:1 hexanes:ethyl acetate, 12 visualization), 1H NMR (400 MHz, CDCl3) □ 6.0 (br, 1H), 4.0 (br, 1H), 2.5 (d, 1H), 1.5 (s, 9H), 1.1 (m, 2H), 1.6 (br, 2H), 0.94 (s, 9H), 0.94 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]([OH:16])[CH2:13][C:14]#[CH:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:16][CH2:12][CH2:13][C:14]#[CH:15])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: C#CCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCCOc1ccc(Br)cc1[N+](=O)[O-]
Yield: 71.4 %

Procedure:
A mixture of 4-bromo-1-fluoro-2-nitrobenzene (20.0 g, 90 mmol), 3-butyn-1-ol (7.0 g, 99.8 mmol) and potassium carbonate (13.8 g, 99.8 mmol) in dry DMF (20 mL) was heated with 4 Å molecular sieves for 43 h. The mixture was cooled, diluted with water to approximately 500 mL and extracted three times with ethyl acetate. The combined organic extracts were washed with water and then brine, dried and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 5 to 10% ethyl acetate in cyclohexane) to give 4-Bromo-1-but-3-ynyloxy-2-nitro-benzene as a yellow solid (17.35 g, 71%). NMR showed an impurity (19%) which was not removed at this stage. LCMS: RT=4.41 min, [M+Na]+=292/294.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:14]=1[CH:15]=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[CH:15][C:14]3[CH:17]=[C:18]([C:21]([F:22])([F:24])[F:23])[CH:19]=[CH:20][C:13]=3[Cl:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Cl
Product: O=C1Nc2cc(Cl)ccc2C1=Cc1cc(C(F)(F)F)ccc1Cl

Procedure:
In a manner similar to the methods described in Examples 1a and 1b, 6-chloro-1,3-dihydro-indol-2-one (Aldrich) reacted with 2-chloro-5-trifluoromethyl-benzaldehyde (Aldrich) to give 6-chloro-3-[1-(2-chloro-5-trifluoromethyl-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole, which was subsequently reacted with di-tert-butyl-dicarbonate and DMAP and directly used for the next step.
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH:23]1([CH2:26][NH:27][C:28](=[O:45])[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:30]=2)[CH2:25][CH2:24]1>>[CH:23]1([CH2:26][NH:27][C:28]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[C:33]([C:2]3[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=4)=[O:7])=[CH:4][N:3]=3)[CH:34]=2)=[O:45])[CH2:25][CH2:24]1
Reactant: Cc1ccc(C(=O)NCC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CS(=O)(=O)Nc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Product: Cc1ccc(C(=O)NCC2CC2)cc1-c1ccc(C(=O)NCc2cccc(NS(C)(=O)=O)c2)cn1

Procedure:
6-(5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl)-N-(3-methylsulphonylaminobenzyl)-nicotinamide was prepared from 6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and N-cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 10) using General Method B. LCMS: retention time 2.88 min, MH+ 493. NMR: δH [2H6]-DMSO 9.34, (1H, t), 9.16, (1H, d), 8.96, (1H, b), 8.62, (1H, t), 8.35, (1H, dd), 7.94, (1H, s), 7.85, (1H, d), 7.75, (1H, d), 7.43, (1H, d), 7.31, (1H, t), 7.21, (1H, s), 7.11, (2H, m), 4.52, (2H, d), 3.14, (2H, t), 2.99, (3H, s), 2.39, (3H, s), 1.03, (1H, m), 0.43, (2H, m), 0.23, (2H, m).
Reaction SMILES: [C:1]([N:3]=[C:4](OCC)[CH2:5][CH3:6])#[N:2].[C:10]([C:12]1[CH:25]=[CH:24][C:15]2[O:16][C:17]([CH3:23])([CH3:22])[C@@H:18]([OH:21])[C@H:19]([NH2:20])[C:14]=2[CH:13]=1)#[N:11]>C(OCC)(=O)C>[C:10]([C:12]1[CH:25]=[CH:24][C:15]2[O:16][C:17]([CH3:23])([CH3:22])[C@@H:18]([OH:21])[C@H:19]([NH:20][C:4](=[N:3][C:1]#[N:2])[CH2:5][CH3:6])[C:14]=2[CH:13]=1)#[N:11]
Reactant: CCOC(CC)=NC#N
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Solvent: CCOC(C)=O
Product: CCC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Reaction time: 2 h

Procedure:
To 1.39 g of ethyl N-cyanopropionimidate, 2.17 g of 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-amino-2H-benzo[b]pyran-3-ol was added, and the mixture was reacted under stirring at a temperature of from 100° to 120° C. for 2 hours. The reaction mixture was cooled, then dissolved in 100 ml of ethyl acetate, washed twice with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate Then, ethyl acetate was distilled off under reduced pressure The residual oily substance was purified by silica gel column chromatography to obtain 1.48 g of the above identified compound in the form of crystals.
Reaction SMILES: FC(F)C1N(C)C=C(O)C(=O)C=1.F[CH:14](F)[C:15]1[N:20](C)[C:19]([CH:22]([OH:27])[C:23]([F:26])([F:25])[F:24])=[C:18]([OH:28])[C:17](=[O:29])[CH:16]=1.C(O)C(N)(CO)CO.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>CC#N>[OH:28][C:18]1[C:17](=[O:29])[CH:16]=[C:15]([CH3:14])[NH:20][C:19]=1[CH:22]([OH:27])[C:23]([F:26])([F:24])[F:25]
Reactant: Cn1c(C(F)F)cc(=O)c(O)c1C(O)C(F)(F)F
Agent: Cn1cc(O)c(=O)cc1C(F)F
Agent: NC(CO)(CO)CO
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Solvent: CC#N
Product: Cc1cc(=O)c(O)c(C(O)C(F)(F)F)[nH]1

Procedure:
Proceeding in a similar manner as A, 2-difluoromethyl-5-hydroxy-1-methyl-1H-pyridin-4-one was converted to 6-difluoromethyl-3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one. 1H NMR (DMSO-d6+1 drop of D2O) ppm: 7.12 (t, J=52.8 Hz, 1H), 6.56 (s, 1H), 5.83 (b, 1H), 3.79 (s, 3H). 19F NMR (DMSO-d6+1 drop of D2O) ppm: −73.3 (3F), −117.8 (2F). MS (m/z) 274.1 [M+1]+. HPLC conditions: Column: XTerra MS C18 5 μm 4.6×250 mm. Mobile phase: A=the aqueous phase: 4 mM Tris, 2 mM EDTA, pH 7.4; B=the organic phase: CH3CN. The gradient program: B %: 0 min. 5%, 15 min. 55%, 25 min. 55%, 25.05 min. 5%, 30 min. 5%. Flow rate=1 ml/min.; injection volume=5 μL; wavelength: 220, 254, 280, 450 nm. Retention time of 2-Difluoromethyl-5-hydroxy-1-methyl-1H-pyridin-4-one=6.7 min. Retention time of 6-difluoromethyl-3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one=11.4 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[N+:10]([O-])([OH:12])=[O:11]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([Cl:8])=[CH:4][C:3]=1[OH:9]
Reactant: O=[N+]([O-])O
Reactant: Oc1cc(Cl)ccc1Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Cl)c(O)cc1Cl
Temperature: 0 °C
Yield: 31 %

Procedure:
2,5-dichlorophenol (72 g, 440 mmol) were slurried in 100 ml dichloromethane which resulted in an endothermic reaction. To this mixture were slowly added 30 ml (480 mmol) concentrated nitric acid. The reaction was allowed to reach and maintain reflux. The mixture was stirred until it reached ambient temperature and all materials remained in solution. 50 g of ice were added and solids precipitated. The mixture was filtered cold and washed with 25 ml dichloromethane, 50 ml dichloromethane, then twice with 25 ml dichloromethane to yield 28.4 g of 2,5-dichloro-4-nitrophenol.