Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](Br)=[CH:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2].[NH2:14][C:15]1[N:19]([CH3:20])[N:18]=[C:17]([CH3:21])[CH:16]=1>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([CH3:21])[CH:16]=2)=[CH:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C)ccc1Br
Reactant: Cc1cc(N)n(C)n1
Agent: [Pd]
Product: CCOC(=O)c1nc(C)ccc1Nc1cc(C)nn1C

Procedure:
The Pd catalyzed coupling of 3-Bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester and 5-Amino-1,3-dimethylpyrazole was performed in accordance with the general method of Example 78, step 3 to yield the title compound as a yellow-cristalline solid, MS (ISP): m/e=275.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1.[C:26](Cl)(=[O:28])[CH3:27].N1C=CC=CC=1>C(OCC)C>[C:26]([O:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])[C:4]([F:25])=[CH:3][C:2]=1[Cl:1])(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCCO)c(Cl)cc2F)c1=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)OCCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
using 3-[4-chloro-2-fluoro-5-(2-hydroxyethoxy)-phenyl]-1-methyl-6 -trifluoromethyl-2,4(1H,3H)-pyrimidinedione and acetyl chloride with pyridine in diethyl ether there is obtained 2-{2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H) -pyrimidinyl]-4-fluorophenoxy}-ethyl acetate, m.p. 88°-90° C.;
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][CH:12]1[CH2:17][CH:16]=[C:15]([C:18]2[N:19]=[C:20]([SH:23])[S:21][CH:22]=2)[CH2:14][N:13]1[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25].O(P(OC1C=CC=CC=1)O[C:39]1[C@H:45]([CH3:46])[C@H:44]2[N:41]([C:42](=[O:54])[C@@H:43]2[C@H:47]([O:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH3:48])[C:40]=1[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])C1C=CC=CC=1.C(#N)C>C1COCC1>[CH2:27]([O:26][C:24]([N:13]1[CH:12]([CH3:11])[CH2:17][CH:16]=[C:15]([C:18]2[N:19]=[C:20]([S:23][C:39]3[C@H:45]([CH3:46])[C@H:44]4[N:41]([C:42](=[O:54])[C@@H:43]4[C@H:47]([O:49][Si:50]([CH3:51])([CH3:52])[CH3:53])[CH3:48])[C:40]=3[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])[S:21][CH:22]=2)[CH2:14]1)=[O:25])[CH:28]=[CH2:29]
Reactant: C=CCOC(=O)N1CC(c2csc(S)n2)=CCC1C
Reactant: C=CCOC(=O)C1=C(OP(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC#N
Product: C=CCOC(=O)C1=C(Sc2nc(C3=CCC(C)N(C(=O)OCC=C)C3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71 %

Procedure:
A solution of lithium hexamethyldisilazide in THF (1M, 1.24 ml, 1.24 mmol) was added at 0° C. to a solution of allyl 2-methyl-5-(2-mercapto-1,3-thiazol-4-yl)-3,6-dihydro-1(2 H)-pyridinecarboxylate (368 mg, 1.24 mmol) in THF (2.4 ml) and the mixture was stirred for 10 minutes. To the reaction solution was added at 0° C. a solution of allyl (4R,5R,6S)-3-[(diphenoxyphosphino)oxy]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in acetonitrile (30%, 4.73 g, 2.5 mmol) and the solution was allowed to stand in a refrigerator for 13 hours. To the reaction solution was added ice water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue was purified with silica gel chromatography (hexane/ethyl acetate: 4/1→3/1) to give allyl (4R,5S,6S)-3-[(4-(1-[(allyloxy)carbonyl]-6-methyl-1,2,5,6-tetrahydro-3-pyridinyl}-1,3-thiazol-2-yl)sulfanyl]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (544 mg, 71%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]=[C:8]1[O:12][C:10](=[O:11])[CH2:9]1>O1CCCC1>[N:1]1([C:10](=[O:11])[CH2:9][C:8](=[O:12])[CH3:7])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N1CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
33 ml (0.38 mol) of morpholine were added dropwise at −5 to 0° C. to a solution of 30 g of diketene (0.36 mol) in 300 ml tetrahydrofuran. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 49.48 g (0.29 mol, 81% yield) of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:4]=1.[Cl:17][C:18]([Cl:24])([Cl:23])[C:19](=N)OC>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]2[N:7]=[C:19]([C:18]([Cl:24])([Cl:23])[Cl:17])[N:10]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]=2[CH:4]=1
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: COCCCCNc1cc(OC)ccc1N
Solvent: CC(=O)O
Product: COCCCCn1c(C(Cl)(Cl)Cl)nc2ccc(OC)cc21
Reaction time: 1.5 h

Procedure:
4-Methoxy-2-(4-methoxybutylamino)aniline (2.50 g) was dissolved in acetic acid (30 ml), methyl 2,2,2-trichloroethanimidate (1.62 ml) was added, and the mixture was stirred for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with diisopropyl ether, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the object product (1.75 g). MS (ESI+, m/e) 351 (M+1)
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:20][N:21]([C:34](=[O:37])[CH2:35][Cl:36])[C@@H:22]([C:30](=[O:33])[NH:31][CH3:32])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[NH2:7][C@H:8]([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[CH2:20][N:21]([C@H:22]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:30]([NH:31][CH3:32])=[O:33])[C:34](=[O:37])[CH2:35][Cl:36]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C[C@@H](Cc1ccc2ccccc2c1)NC(=O)OC(C)(C)C)C(=O)CCl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C[C@H](N)Cc1ccc2ccccc2c1)C(=O)CCl
Reaction time: 0.67 h
Yield: 151.5 %

Procedure:
((1R)-1-((N-Chloroacetyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)amino)methyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butyl ester (0.56 g, 1.04 mmol) was dissolved in a mixture of trifluoroacetic acid (4 ml) and methylene chloride (4 ml) and stirred for 40 min. The solvent was removed in vacuo and methylene chloride was added and removed in vacuo (3×10 ml) to afford 0.69 g of (2R)-2-(N-((2R)-2-amino-3-(2-naphthyl)propyl)-N-chloroacetylamino)-N-methyl-3-phenylpropionamide as a trifluoroacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]#[CH:18])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@H:12]([CH:14]1[CH2:16][CH2:15]1)[CH3:13])[CH2:7]2.C(=O)([O-])O.[K+].O.Cl[C:26](=[N:32][OH:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[O:33][N:32]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:18]=2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@H:12]([CH:14]1[CH2:16][CH2:15]1)[CH3:13])[CH2:7]2
Reactant: C#Cc1cc(Cl)c2c(c1)CN([C@@H](C)C1CC1)C2=O
Reactant: CCOC(=O)C(Cl)=NO
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(-c2cc(Cl)c3c(c2)CN([C@@H](C)C2CC2)C3=O)on1
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.2 %

Procedure:
7-chloro-2-((S)-1-cyclopropylethyl)-5-ethynylisoindolin-1-one (28.66 g, 110.35 mmol) and potassium hydrogen carbonate (110.0 g, 1103.45 mmol) were dissolved in a solution consisting of 1200 mL of ethyl acetate and 400 mL of water. To this solution was added ethyl 2-chloro-2-(hydroxyimino)acetate (66.9 g, 441.38 mmol). The ethyl 2-chloro-2-(hydroxyimino)acetate was added at room temperature as a solution in 160 mL of ethyl acetate via syringe pump at a rate of 5 mL/Hr. Following the addition of the ethyl 2-chloro-2 (hydroxyimino)acetate, the reaction was allowed to continue stirring at room temperature for an additional 12 hours. The ethyl acetate layer was extracted in a separatory funnel, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The material was purified by flash chromatography on silica gel eluting with a gradient of 0 to 25% ethyl acetate in hexane to afford the title compound as a white solid (17.05 g, 41.2%). 1H NMR (300 MHz, CDCl3) δ ppm 0.36-0.53 (m, 3H) 0.63-0.73 (m, 1H) 0.98-1.12 (m, 1H) 1.38 (d, 3H) 1.47 (t, 3H) 3.80 (dq, 1H) 4.43-4.65 (m, 4H) 7.05 (s, 1H) 7.83 (s, 2H). MS ESI, m/z=375 (M+H). HPLC Method B: 0.82 min
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1.O>N1C=CC=CC=1>[CH:28]1([C:31]([N:1]2[CH:5]=[CH:4][C:3]([C:6]3[CH:11]=[CH:10][C:9]([C:12]([N:14]4[C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=5[CH2:18][N:17]5[CH:25]=[CH:26][CH:27]=[C:16]5[CH2:15]4)=[O:13])=[CH:8][CH:7]=3)=[N:2]2)=[O:32])[CH2:30][CH2:29]1
Reactant: O=C(Cl)C1CC1
Reactant: O=C(c1ccc(-c2cc[nH]n2)cc1)N1Cc2cccn2Cc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: O=C(c1ccc(-c2ccn(C(=O)C3CC3)n2)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.8 %

Procedure:
To a solution of [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]-benzodiazepin-10-yl)-methanone (1.0 g) in dry pyridine (10 ml) was added cyclopropanecarbonyl chloride (0.44 g). After stirring at room temperature for 18 hours the reaction mixture was poured into water and the precipitate was collected by filtration. The crude product was dissolved in dichloromethane and dried over anhydrous sodium sulfate. This solution was filtered through a short column of hydrous sodium magnesium silicate, eluting with several additional volumes of dichloromethane. The eluant was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.88 g) was obtained as a crystalline solid, m.p. 197-199° C.
Reaction SMILES: N1CCCCC1.O=[CH:8][C:9]1[CH:17]=[CH:16][C:14]([OH:15])=[C:11]([O:12][CH3:13])[CH:10]=1.[CH3:18][O:19][C:20](=[O:24])[CH2:21][C:22]#[N:23]>C(O)C>[CH3:18][O:19][C:20](=[O:24])/[C:21](/[C:22]#[N:23])=[CH:8]/[C:9]1[CH:17]=[CH:16][C:14]([OH:15])=[C:11]([O:12][CH3:13])[CH:10]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: COC(=O)CC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: COC(=O)/C(C#N)=C/c1ccc(O)c(OC)c1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
0.2 ml of piperidine were added carefully to a solution of 4.6 g (30 mmol) of vanillin, 3.4 ml (30.3 mmol) of cyanoacetic acid methyl ester and 0.5 ml of ethanol held at 45° C. The product started to precipitate on cooling to room temperature. The cold reaction mixture was diluted with 8 ml of ethanol, filtered and washed with cold ethanol to give 6.5 g (93%) of 2-cyano-(E)-3-(4-hydroxy-3-methoxyphenyl)acrylic acid methyl ester in form of yellow crystals.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([NH2:16])[CH2:6][C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([NH:28][S:29]([C:32]2[C:33]3[N:34]=[CH:35][CH:36]=[N:37][C:38]=3[CH:39]=[CH:40][CH:41]=2)(=[O:31])=[O:30])[CH:20]=1>>[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([NH:16][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([Cl:18])=[CH:20][C:21]=1[NH:28][S:29]([C:32]1[C:33]2[N:34]=[CH:35][CH:36]=[N:37][C:38]=2[CH:39]=[CH:40][CH:41]=1)(=[O:31])=[O:30])[CH2:6][C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: COC(=O)[C@@H](N)Cc1csc2ccccc12
Agent: Cl
Product: COC(=O)[C@H](Cc1csc2ccccc12)NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
3-Benzo[b]thiophen-3-yl-2-(tert-butoxycarbonylamino)-propionic acid was treated as in EXAMPLE 2, Part A, to produce (S)-2-amino-3-benzo[b]thiophen-3-yl-propionic acid methyl ester hydrochloride as a white solid. This ester was coupled to 4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid as in EXAMPLE 1, Part C, to afford the title compound. HPLC: RT=10.33 min. MS (ESI−): mass calcd. for C27H21ClN4O5S2, 580.06; m/z found, 579/581 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.35 (s, 1H), 8.94 (d, J=1.8, 1H), 8.85 (d, J=1.8, 1H), 8.58 (dd, J=7.3, 1.4, 1H), 8.31 (dd, J=8.5, 1.3, 1H), 7.90-7.86 (m, 2H), 7.77 (d, J=2.0, 1H), 7.72-7.70 (m, 1H), 7.37-7.26 (m, 2H), 7.09 (s, 1H), 7.00 (d, J=8.4, 1H), 6.83 (dd, J=8.4, 2.0, 1H), 6.45 (d, J=7.1, 1H), 5.09-5.05 (m, 1H), 3.77 (s, 3H), 3.53 (dd, J=14.7, 5.8, 1H), 3.45 (dd, J=14.8, 5.2, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[S].[CH2:21](N)[CH2:22][NH2:23]>>[CH2:13]([O:12][C:8]1[C:9]([O:10][CH3:11])=[C:2]([C:3]([C:4]2[NH:23][CH2:22][CH2:21][N:5]=2)=[CH:6][CH:7]=1)[NH2:1])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1c(OCc2ccccc2)ccc(C#N)c1N
Reactant: NCCN
Agent: [S]
Product: COc1c(OCc2ccccc2)ccc(C2=NCCN2)c1N
Temperature: 100 °C

Procedure:
A mixture of 2-amino-4-(benzyloxy)-3-methoxybenzonitrile (144 g, 566 mmol) and sulfur (55 g, 1.7 mol) in ethylenediamine (800 mL) was degassed for 30 minutes then heated to 100° C. After 16 h the reaction mixture was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, diluted with a saturated sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.OB(O)[C:26]1[S:30][C:29]([C:31]([OH:33])=[O:32])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[NH2:23][C:9]1[N:8]=[CH:7][C:6]2[C:2]([C:26]3[S:30][C:29]([C:31]([OH:33])=[O:32])=[CH:28][CH:27]=3)=[CH:3][O:4][C:5]=2[C:10]=1[O:11][C@@H:12]([C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=1[Cl:22])[CH3:13]
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: O=C(O)c1ccc(B(O)O)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](Oc1c(N)ncc2c(-c3ccc(C(=O)O)s3)coc12)c1c(Cl)ccc(F)c1Cl

Procedure:
A mixture of 3-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridine-6-ylamine (100.0 mg, 0.238 mmol), 5-(dihydroxyboryl)thiophene-2-carboxylic acid (205 mg, 1.19 mmol), Pd(PPh3)4 (10.0 mg, 0.01 mmol), potassium carbonate (98.7 mg, 0.714 mmol) and 4:1 dioxane:water (4 mL) was heated in a microwave reactor at 100° C. for 6 h. The material was dry-loaded onto silica gel for column chromatography. The crude product was eluted with 20% MeOH/DCM. The fractions containing the product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.90 (d, J=6.8 Hz, 3H), 6.54 (q, J=6.9 Hz, 1H), 7.22 (t, J=8.6 Hz, 1H), 7.31 (d, J=3.8 Hz, 1H), 7.41 (dd, J=9.0, 4.9 Hz, 1H), 7.53 (d, J=3.8 Hz, 1H), 7.92 (s, 1H), 8.27 (s, 1H).
Reaction SMILES: [C:1]([N:5]1[CH2:9][C@@H:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[C@H:7]([C:18]([O:20]C)=[O:19])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[O-].[K+].[ClH:28]>C(OCC)C.CCOC(C)=O>[ClH:28].[C:1]([N:5]1[CH2:9][C@@H:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[C@H:7]([C:18]([OH:20])=[O:19])[CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1CN(C(C)(C)C)C[C@H]1c1ccc(F)cc1F
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)N1C[C@@H](C(=O)O)[C@H](c2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the methyl (3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylate enantiomer 79 (1.37 g, 4.61 mmol) and potassium trimethylsilanolate (0.68 g, 5.30 mmol) in diethyl ether (23 mL) was stirred at r.t. overnight. A saturated solution of hydrogen chloride in EtOAc was then added, the volatiles were evaporated to give 80, which was used without further purification in the preparation of Examples detailed below.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.[C:16]1([CH:22]2[CH2:26][CH2:25][NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]([N:24]1[CH2:25][CH2:26][CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23]1)=[O:15]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Reactant: c1ccc(C2CCNC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1C(=O)N1CCC(c2ccccc2)C1
Temperature: 25 °C

Procedure:
5-Methyl-3-phenylisooxazole-4-carboxylic acid (40 mg, 0.197 mmol), 3-phenyl-pyrrolidine (31.6 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H20N2O2: 332.1525, found 332.1539.
Reaction SMILES: CS(C)=O.[N+]([C:8]1[S:12][C:11]([C:13]#[N:14])=[CH:10][CH:9]=1)([O-])=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>O>[F:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:8]2[S:12][C:11]([C:13]#[N:14])=[CH:10][CH:9]=2)=[CH:18][CH:17]=1
Reactant: N#Cc1ccc([N+](=O)[O-])s1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(Oc2ccc(F)cc2)s1
Temperature: 60 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
To a dimethyl sulfoxide (100 mL) solution of 5-nitro-2-thiophene carbonitrile (5.00 g, 32.4 mmol) were added 4-fluorophenol (5.45 g, 48.6 mmol) and potassium carbonate (11.2 g, 81.0 mmol) under nitrogen atmosphere, which was stirred for 16 hours at 60° C. The reaction solution was cooled to room temperature and water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:10→1:5) to obtain the title compound (6.10 g, 85.9%).
Reaction SMILES: [N:1]1([C:7]2[N:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1.C(N(CC)CC)C>C(O)CCC>[S:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=3)[N:8]=2)[CH2:2][CH2:3]1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: Clc1nc2ccccc2s1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: COc1cc2nc(N3CCN(c4nc5ccccc5s4)CC3)nc(N)c2cc1OC

Procedure:
A suspension of 2-(1-piperazinyl)-4-amino-6,7-dimethoxyquinazoline (1.96 g), 2-chlorobenzthiazole (1.02 g), triethylamine (1.82 g) in butanol (100 ml) was refluxed for 72 hr and filtered. The precipitate was taken up in a solution of methanol and dimethyl sulfoxide, and 1 N sodium hydroxide was added until the mixture was alkaline. The precipitate was collected, washed with water, dried (1.3 g) and crystallized from methanol to give the title compound: mp 242°-245° C.; ir (nujol) 3460 and 3370 cm-1 : uv max (MeOH) 227 (ε=4130), 250 (ε=5280), 276 (ε=3649) and 340 nm (ε=690); nmr (DMSO-d6) δ 3.65 (m, 4H), 3.9 (m, 4H), 3.85 (s, 3H), 3.93 (s, 3H), 5.2 (s, 2H) and 7.2 (m, 6H); and Anal. Calcd for C21H22N6O2S.CH3OH: C, 58.14% H, 5.72% N, 18.50% and Found: C, 57.88% H, 5.90% N, 18.47%.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH3:7])[CH3:6].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[NH:22][CH:23]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([Cl:33])[CH:27]=3)[N:25]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[OH-].[K+]>CS(C)=O.C(Cl)Cl>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[N:22]([CH2:3][CH2:4][N:5]([CH3:7])[CH3:6])[CH:23]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([Cl:33])[CH:27]=3)[N:25]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(Cl)c3)c[nH]2)CC1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CN(C)CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
Add (2-chloro-ethyl)-dimethyl-amine hydrochloride (1.10 equiv; 579 μmol; 83 mg) in one portion to a mixture of 4-[4-(3-chloro-4-fluoro-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1 equiv; 526 μmol; 200 mg) and powdered KOH (2.5 equiv; 1.316 mmol; 73.8 mg) in DMSO (3 mL). Warm to 50° C. and stir for 2 h. Dilute with DCM, wash with water, brine, dry over MgSO4, filter, evaporate and purify on 40 g silica gel with 10% methanol/ACN to provide the title compound (194 mg; 0.43 mmol; 82%). MS (ES+): m/z=451 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].I[C:20]1[CH:30]=[CH:29][C:23]2[CH2:24][CH2:25][S:26](=[O:28])(=[O:27])[C:22]=2[CH:21]=1>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:30]=[CH:29][C:23]2[CH2:24][CH2:25][S:26](=[O:28])(=[O:27])[C:22]=2[CH:21]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S1(=O)CCc2ccc(I)cc21
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc2c(c1)S(=O)(=O)CC2

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 6-iodo-2,3-dihydro-1-benzothiophene 1,1-dioxide (Intermediate 234), the title compound was obtained as a beige solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8](OCC)=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[N:14]([CH3:17])[CH:15]=[CH:16][C:3]=12.CC(C[AlH]CC(C)C)C.O.[OH-].[Na+]>ClCCl>[I:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([CH3:13])[N:5]=[C:4]2[N:14]([CH3:17])[CH:15]=[CH:16][C:3]=12
Reactant: CCOC(=O)c1c(C)nc2c(ccn2C)c1I
Agent: CC(C)C[AlH]CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1nc2c(ccn2C)c(I)c1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A −78° C. solution of ethyl 4-iodo-1,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate in dichloromethane (DCM) (150 mL) was treated dropwise with DIBAL-H (128 mL, 128 mmol) and warmed to ambient temperature. After 30 min, the reaction mixture was cooled to 0° C. and treated sequentially with water (5.1 mL), 15% NaOH (5.1 mL) and finally water (12.8 mL) with a 10 minute delay in between each addition. The fine suspension was then filtered through a pad of celite and washed with ethyl acetate 3×. The filtrate was concentrated in vacuo to afford (4-iodo-1,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol (12.4 g, 41.0 mmol, 96% yield) as a yellow solid.