Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[S:2].[C:13]([O:17][C:18](=[O:32])[N:19]([CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)[CH2:20][CH3:21])([CH3:16])([CH3:15])[CH3:14]>CN(C)C=O>[C:13]([O:17][C:18](=[O:32])[N:19]([CH2:20][CH3:21])[CH2:22][CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]=[C:1]=[S:2])=[CH:29][CH:30]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CCN(CCOc1ccc(N)cc1)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CCN(CCOc1ccc(N=C=S)cc1)C(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 1.5 h
Yield: 59.8 %

Procedure:
Thiocarbonyldiimidazole (438 mg, 2.46 mmol) (Aldrich) was dissolved in dimethylformamide (10 mL) and the solution was cooled to −15° C. A solution [2-(4-amino-phenoxy)-ethyl]-ethyl-carbamic acid tert-butyl ester (750 mg, 2.35 mmol) (from step C above) in dimethylformamide (25 mL) was added dropwise, stirred at room temperature for 90 minutes and poured into ice/water. After stirring 30 minutes the precipitate was filtered off, washed with water, and dried under high vacuum to give 453 mg (53%) of ethyl-[2-(4-isothiocyanato-phenoxy)-ethyl]-carbamic acid tert-butyl ester. Mass spectrum (ES) MH+=323.
Reaction SMILES: I[C:2]1[C:3]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[N:4][CH:5]=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[O:15][N:14]=[C:13]([C:16]([F:19])([F:18])[F:17])[N:12]=1)=[O:8].C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:41]2[CH2:42][CH2:43][O:44][CH2:45][CH:46]=2)O1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:44]1[CH2:43][CH:42]=[C:41]([C:2]2[C:3]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[N:4][CH:5]=[C:6]([CH:20]=2)[C:7]([NH:9][CH2:10][C:11]2[O:15][N:14]=[C:13]([C:16]([F:19])([F:18])[F:17])[N:12]=2)=[O:8])[CH2:46][CH2:45]1
Reactant: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(I)c1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(C2=CCOCC2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
5-Iodo-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide (49.6 mg, 100 μmol), potassium carbonate (39.5 mg, 286 μmol) and PdCl2(dppf) (3.89 mg, 4.76 μmol) were combined to give a light red solid. To this solid was added a solution of 3,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-pyran, (CAN 287944-16-5, 0.02 g, 95.2 μmol) in degassed DMF (2 mL). The reaction mixture was stirred at 80° C. overnight, after cooling extracted with i-propyl acetate (2×75 mL) and washed with water (1×10 mL) to pH 7. The organic layers were combined, dried with Na2SO4 and concentrated in vacuo to give a brown oil. The crude material was purified by flash chromatography (silica gel, 10 g, 0% to 10% i-propyl acetate in n-heptane) followed by preparative TLC (silica gel, 1.0 mm, 1:1 n-heptane/i-propyl acetate) to give the title compound (4 mg, 9%) as light brown solid; MS (ESI) 453.1 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([NH2:10])([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[N+:20]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1[C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33])([O-:22])=[O:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N+:20]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1[C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:10][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:9])[CH3:8])=[O:33])([O-:22])=[O:21]
Reactant: CC(C)(N)c1ccccc1
Reactant: O=C(O)c1cccc(-c2ccncc2[N+](=O)[O-])c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)c1cccc(-c2ccncc2[N+](=O)[O-])c1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution containing 2-phenylpropan-2-amine (5.5 g, 40.4 mmol), diisopropylethylamine (18.8 mL, 108 mmol), 3-(3-nitropyridin-4-yl)benzoic acid (8.8 g, 27.0 mmol) and DMF (180 mL) was added HATU (15.4 g, 40.4 mmol) in one portion. The solution was maintained at room temperature for 1 h then concentrated. Purification on silica gel (50-100% ethyl acetate/hexanes, 60 min. gradient) afforded 3-(3-nitropyridin-4-yl)-N-(2-phenylpropan-2-yl)benzamide as a dark yellow, fluffy solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 9.21 (s, 1H), 8.93 (d, J=5.02 Hz, 1H), 8.51 (s, 1H), 7.97 (dt, J=7.03, 1.76 Hz, 1H), 7.92 (s, 1H), 7.73 (d, J=5.02 Hz, 1H), 7.52-7.61 (m, 2H), 7.34-7.41 (m, 2H), 7.27 (t, J=7.65 Hz, 2H), 7.16 (t, J=7.28 Hz, 1H), 1.64-1.72 (m, 6H). LCMS: retention time: 2.060 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10u, C18, 3.0×50 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 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 mM where solvent A was 10% methanol/90% H2O/10 mM TFA and solvent B was 10% H2O/90% methanol/10 in M TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 362 (MH+).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH:6]([CH2:8][NH2:9])[NH:5][CH:4]([CH2:10][NH2:11])[CH2:3]1.[Li+].[OH-].Br[CH2:15][C:16]([OH:18])=[O:17].Br>O>[C:16]([OH:18])(=[O:17])[CH3:15].[C:16]([OH:18])(=[O:17])[CH3:15].[C:16]([OH:18])(=[O:17])[CH3:15].[C:16]([OH:18])(=[O:17])[CH3:15].[C:16]([OH:18])(=[O:17])[CH3:15].[OH:1][CH:2]1[CH2:7][CH:6]([CH2:8][NH2:9])[NH:5][CH:4]([CH2:10][NH2:11])[CH2:3]1
Reactant: O=C(O)CBr
Agent: Br
Agent: NCC1CC(O)CC(CN)N1
Agent: [Li+]
Solvent: O
Product: CC(=O)O
Temperature: 85 °C

Procedure:
4-Hydroxy-2,6-piperidinedimethaneamine (10 mmol) is dissolved in water (10 ml). The pH is adjusted to 10 with 4M LiOH, and a solution of bromoacetic acid (55 mmol) and LiOH (55 mmol) in water (10 ml) is gradually added to the stirred mixture at ambient temperature. The temperature is gradually increased to 85° C. during 4 hours while the pH is kept in the alkaline range (8 to 10) with aqueous LiOH. The solution is allowed to cool to ambient temperature, neutralised with conc. hydrobromic acid, loaded on a strong cation exchanger (AG 5Wx4) and eluted with 6M aqueous ammonia. After evaporation down, the crude product is dissolved in water and lyophilised to yield the title compound.
Reaction SMILES: [C:1]([N:5]1[C:28]2[C:27](=[O:29])[CH2:26][C:10]3([CH2:15][CH2:14][N:13](C(OCC4C=CC=CC=4)=O)[CH2:12][CH2:11]3)[CH2:9][C:8]=2[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CC1CC=CCC=1.Cl>C(O)C.[Pd].C(OCC)(=O)C.O1CCOCC1>[C:1]([N:5]1[C:28]2[C:27](=[O:29])[CH2:26][C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH2:9][C:8]=2[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc2c1C(=O)CC1(CCN(C(=O)OCc3ccccc3)CC1)C2
Agent: [Pd]
Agent: CC1=CCC=CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)(C)n1ncc2c1C(=O)CC1(CCNCC1)C2
Temperature: 25 °C
Yield: 110.2 %

Procedure:
A solution of benzyl 1-tert-butyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-carboxylate (46.6 g, 118 mmol) in ethanol (730 mL) was added to 10% palladium on carbon (9.4 g). To this mixture was added 1-methyl-1,4-cyclohexadiene (90 mL, 769 mmol). The reaction was stirred at reflux for 2 hours. The reaction was cooled to room temperature and filtered through Celite®. The filtrate was concentrated in vacuo to give a gray solid. The solid was dissolved in ethyl acetate (150 mL) and to this solution was added 4 M hydrochloric acid in 1,4-dioxane (35 mL). The resulting precipitate was collected by filtration and dried under vacuum to afford the title compound (34 g, 97%) as a white solid. +ESI (M+H) 262.5; 1H NMR (400 MHz, CD3OD, δ): 7.34 (s, 1 H) 3.12-3.25 (m, 4 H) 2.90 (s, 2 H) 2.66 (s, 2 H) 1.67-1.85 (m, 4 H) 1.62 (s, 9 H).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:9][N:8]=[C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[C:13]3([CH3:22])[S:20][CH3:21])[CH2:6][S:5]1.[C:23](Cl)(=[O:25])[CH3:24].C(OC(=O)C)C>CN(C=O)C>[C:23]([N:15]1[C:16]2[C:12](=[CH:11][C:10]([C:7]3[CH2:6][S:5][C:4](=[O:3])[NH:9][N:8]=3)=[CH:18][CH:17]=2)[C:13]([CH3:22])([S:20][CH3:21])[C:14]1=[O:19])(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: CSC1(C)C(=O)Nc2ccc(C3=NNC(=O)SC3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSC1(C)C(=O)N(C(C)=O)c2ccc(C3=NNC(=O)SC3)cc21
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
0.131 g sodium hydride from a 55% dispersion in mineral oil was added during 0.5 hr to a solution of 0.921 g of 1,3-dihydro-5-(3,6-dihydro-2-oxo-2H-1,3,4-thiadiazin-5-yl)-3-methyl-3-methylthio-2H-indol-2-one (compound of Example 1) in 25 ml DMF at 5° C. The mixture was stirred for 0.5 hr at 5° C. then 0.5 hr at 20° C. and cooled at 5° C. 0.215 ml of acetyl chloride in 1 ml DMF was added dropwise under stirring. The mixture was stirred for 0.5 hr at 5° C. then 1.5 hrs at 20° C. 250 ml ethylacetate was added and the corresponding organic solution was washed with water, dried and evaporated to dryness. The residual oil was purified by chromatography on silica (methylene chloride-ethylacetate: 9/1) to yield 0.4 g of white crystalline compound.
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][S:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:21]([C:31]([F:34])([F:33])[F:32])[CH:20]=2)=[CH:13][CH:12]=1)(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:34][C:31]([F:32])([F:33])[C:21]1[CH:20]=[C:19]([S:18][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([CH2:10][NH:9][CH2:8][CH2:7][C:6]([OH:35])=[O:5])=[CH:12][CH:13]=2)[CH:24]=[CH:23][C:22]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)CCNCc1ccc(CSc2ccc(-c3ccccc3)c(C(F)(F)F)c2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCNCc1ccc(CSc2ccc(-c3ccccc3)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[4-(2-trifluoromethyl-biphenyl-4-ylsulfanylmethyl)-benzylamino]-propionic acid tert-butyl ester (24 mg, 0.0478 mmol, 1 eq.) in DCM (2 mL) is added triethylsilane (0.038 mL, 0.2392 mmol, 5 eq.) followed by TFA (2 mL). The mixture is stirred at room temperature for 2 h. After concentration, the crude product is purified by preparative RP LC-MS to give 3-[4-(2-Trifluoromethyl-biphenyl-4-ylsulfanylmethyl)-benzylamino]-propionic acid: 1H NMR (CD3OD, 400 MHz) δ7.66 (s, 1H), 7.60 (d, 1H), 7.55–7.38 (m, 7H), 7.28–7.21 (m, 3H), 4.33 (s, 2H), 4.18 (s, 2H), 3.26 (t, 2H), 2.72 (t, 2H); MS (ES+): (446.1, M+1)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[NH:41]1[CH2:45][CH2:44][C@@H:43]([OH:46])[CH2:42]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:34]=[CH:35][C:36]([CH2:39][N:41]4[CH2:45][CH2:44][C@@H:43]([OH:46])[CH2:42]4)=[CH:37][CH:38]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: O[C@@H]1CCNC1
Reactant: COc1cc(-c2nn(-c3ccc(C=O)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: COc1cc(-c2nn(-c3ccc(CN4CC[C@@H](O)C4)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.3 %

Procedure:
A mixture of N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide (Intermediate 2) (0.075 g, 0.14 mmol), (R)-(+)-3-pyrrolidinol (0.024 g, 0.27 mmol), and sodium triacetoxyborohydride (0.087 g, 0.41 mmol) in dichloroethane (1.4 mL) was shaken at room temperature for 3 days. Additional portions of (R)-(+)-3-pyrrolidinol (0.1 mL), and sodium triacetoxyborohydride (0.084 g, 0.40 mmol) were added and the reaction mixture was shaken for 16 h. 1N NaOH (1 mL) was added and the precipitate was collected by filtration and combined with the residue obtained from extraction of the water layer with one portion of dichloromethane (20 mL). The crude mixture was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 20-80% acetonitrile—0.05 M ammonium acetate over 25 min, 21 mL/min). The appropriate fraction was collected, concentrated, and lyophilized to afford N1-{4-[4-amino-1-(4-{[(3R)-3-hydroxytetrahydro-1H-1-pyrrolyl]methyl}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide as a white solid (0.034 g, 0.055 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.93 (1H, s), 8.34-8.37 (2H, m), 8.15-8.19 (2H, m), 7.98-8.01 (1H, m), 7.85 (1H, d, J=10.4 Hz), 7.75 (1H, d, J=8.0 Hz), 7.48-7.54 (2H, m), 7.44 (1H, s), 7.40 (1H, d, J=8.4 Hz), 4.70 (1H, bs), 4.22 (1H, s), 3.96 (3H, s), 3.63 (2H, s), 2.49-2.72 (3H, m), 2.13-2.41 (1H, m), 1.91-2.06 (1H, m), and 1.53-1.61 (1H, m); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile—0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 10.53 min. MS: MH+ 622.2.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]5)=[N:26][CH:27]=4)[CH:20]=3)[N:15]([S:41]([C:44]3[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[CH:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl.CCOCC>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:27]=[N:26][C:25]([N:28]5[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]5)=[CH:24][CH:23]=4)[CH:20]=3)[N:15]([S:41]([C:44]3[CH:45]=[CH:46][C:47]([CH3:48])=[CH:49][CH:50]=3)(=[O:42])=[O:43])[CH:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Agent: Cl
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccccc4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Yield: 70.7 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(5-(3-(1-benzyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylate (100 mg, 0.144 mmol) was deprotected in HCl in ether (8 ml) to afford 60 mg (66.1% yield) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[CH3:12].[NH2:13][CH2:14][C:15]([O-:17])=[O:16].[Na+:18]>CN(C=O)C.O>[Na+:18].[Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([NH:13][CH2:14][C:15]([O-:17])=[O:16])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1Cl
Reactant: NCC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(NCC(=O)[O-])c([N+](=O)[O-])cc1Cl
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-chloro-5-fluoro-4-nitrotoluene (0.605 g, 3.19 mmol, as prepared above) in DMF (3.0 mL) at 70° C., was added dropwise, a solution of sodium glycinate (0.310 g, 3.19 mmol, Aldrich, used as received) in water (3.0 mL). The resulting suspension was stirred overnight at 70° C. The suspension was cooled to room temperature and the resulting red solid was filtered, washed with chloroform (10 mL) and dried under vacuum to give 0.360 g (46%) pure (1H NMR) title compound as a red powder; 1H NMR (DMSO-d6): δ 2.276 (s, 3H), 3.431 (d, 2H, J=4.2 Hz), 6.848 (s, 1H), 7.963 (s, 1H), 8.773 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:15]([Si:17]([CH3:20])([CH3:19])[CH3:18])#[CH:16].O>C(OCC)(=O)C.[Cu]I.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>[CH3:18][Si:17]([C:15]#[C:16][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)([CH3:20])[CH3:19]
Reactant: Brc1cccnc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccnc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A flask was charged with 3-bromopyridine (1.22 mL, 12.66 mmol) and triethylamine (40 mL) and sparged with nitrogen for 15 min. To this was added ethynyltrimethylsilane (1.97 mL, 13.92 mmol) and the reaction purged 15 min longer. To this was added copper(I) iodide (0.121 g, 0.633 mmol), and Pd(PPh3)2Cl2 (0.444 g, 0.633 mmol). The reaction was stirred at room temperature for 72 h. The reaction was diluted with ethyl acetate (60 mL) and poured into water. The black heterogeneous emulsion was filtered through a plug of celite and the layers separated. The organics were washed with brine, dried over magnesium sulfate, and concentrated. Column chromatography (5%-->15% EtOAc/Hex) gave 1.70 g (77%) as a dark oil. 1H-NMR (CDCl3, 500 MHz) δ 8.71 (m, 1H), 8.55 (dd, J=4.9, 1.5, 1H), 7.76 (ddd, J=7.9, 1.8, 1.8, 1H), 7.26 (ddd, J=7.9, 4.9, 0.6, 1H), 0.29 (s, 9H). 13C-NMR (CDCl3, 126 MHz) δ 152.8, 148.8, 138.9, 123.0, 120.4, 101.6, 98.3, −0.1. Mass spec.: 176.14 (MH)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O>[CH3:3][O:4][C:5](=[O:6])[CH2:7][CH:24]1[CH2:25][CH2:26][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 94 %

Procedure:
Sodium hydride (60% in mineral oil, 4.8 g, 120 mmol) was washed with hexanes and then suspended in N,N-dimethylformamide (100 mL). The mixture was cooled to 0° C. Trimethyl phosphonoacetate (17.0 mL, 111 mmol) was added to the mixture dropwise. The reaction was held at 0° C. for 45 minutes. A solution of N-tert-butoxycarbonyl-4-piperidone (18.5 g, 92.6 mmol) in N,N-dimethylformamide (25 mL) was added to the reaction mixture dropwise. The mixture was held at 0° C. for 1 h and then warmed to room temperature where it was held for 1 h. The reaction was quenched with 1 N hydrochloric acid. The mixture was extracted with diethyl ether (2×). Combined organic layers were washed with water (2×), then brine. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was dissolved in 1:1 ethyl acetate/methanol (60 mL). A catalytic amount of palladium (10% on charcoal) was added to the mixture. The reaction vessel was placed on a Parr apparatus, charged with 55 psi of hydrogen, and shaken at room temperature for 18 h. The reaction mixture was removed from the Parr apparatus and filtered. The filtrate was concentrated in vacuo to give the title compound as lightly colored oil in 94% yield. 1H NMR (300 MHz, CDCl3): δ 4.04 (d, J=10.25, 2H), 3.64 (s, 3H), 2.68 (t, J=14.44, 2H), 2.21 (d, J=6.95, 2H), 1.99-1.80 (m, 1H), 1.64 (d, J=13.54, 2H), 1.41 (s, 9H), 1.25-1.03 (m, 2H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][N:15](CCCC(N2C3C(=CC=CC=3)CCC2)=O)[CH2:14][CH2:13]1.ClC1C=C2C(=CC=1)NC=C2C1CCNCC1.ClC[CH2:51][CH2:52][C:53]([N:55]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH2:58][CH2:57][CH2:56]1)=[O:54]>>[ClH:2].[Cl:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]2[C:4]=1[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:13][CH2:14][N:15]([CH2:51][CH2:52][C:53]([N:55]2[CH2:56][CH2:57][C:58]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[CH2:64]2)=[O:54])[CH2:16][CH2:17]1
Reactant: O=C(CCCN1CCC(c2c[nH]c3ccc(Cl)cc23)CC1)N1CCCc2ccccc21
Reactant: O=C(CCCCl)N1CCCc2ccccc21
Agent: Cl
Agent: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Product: O=C(CCN1CCC(c2c[nH]c3c(Cl)cccc23)CC1)N1CCc2ccccc2C1

Procedure:
5-Chloro-3-{1-[4-(3,4-dihydro-2H-quinolin-1-yl)-4-oxobutan-1-yl]piperidin-4-yl}-1H-indole, hydrochloride from 5-chloro-3-(piperidin-4-yl)-1H-indole and 4-chloro-1-(3,4-dihydro-2H-quinolin-1-yl)butan-1-one. Mp 158-162° C. 1H NMR (DMSO-d6): 1.85-1.95 (m, 2H); 1.95-2.20 (m, 6H); 2.60-2.75 (m, 4H); 2.95-3.15 (m, 5H); 3.55 (d, 2H); 3.70 (t, 2H); 7.05-7.25 (m, 6H); 7.40 (d, 1H); 7.75 (s, 1H); 10.45 (broad s, 1H); 11.15 (s, 1H). MS m/z: 436 (MH+), 303.
Reaction SMILES: [OH-].[Na+].Cl[CH2:4][C@H:5]([OH:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14].S(O)(O)(=O)=O.[NH2:21][CH2:22][CH3:23].C1(C)C=CC=CC=1>O.CO>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][C@H:5]1[O:15][CH2:23][CH2:22][NH:21][CH2:4]1
Reactant: COc1ccccc1C[C@@H](O)CCl
Reactant: CCN
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccccc1C[C@@H]1CNCCO1
Temperature: 40 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
Powdered sodium hydroxide (7.2 g, 180 mmol) was dissolved in water (15 mL). The solution was allowed to cool to ambient temperature before addition of intermediate (a) (R)-1-chloro-3-(2-methoxyphenyl)-2-propanol(6.0 g, 30.0 mmol) in methanol (20 mL+2×5 mL washes) via dropping funnel. After stirring for 5 mins 2-aminoethane hydrogen sulfate (16.9 g, 120 mmol) was added in portions over 5 mins and the reaction mixture heated to 40° C. After 2 hrs, toluene (75 mL) and powdered sodium hydroxide (7.2 g, 180 mmol) were added and the reaction heated to 65° C. and stirred for 17 hrs. The mixture was cooled, diluted with water (300 mL) and extracted with toluene (2×150 mL). The combined organics were washed with water (slowly separating emulsion obtained) and brine, dried (Na2SO4) and concentrated under reduced pressure to afford the crude product as a pale yellow oil (5.21 g). Purification by column chromatography (silica: ethyl acetate/ethanol/triethylamine, 79/20/1 ratio) afforded intermediate (d), (R)-2-(2-methoxybenzyl)morpholine as a colorless oil (6.04 g, 50% yield).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]([F:31])=[C:24]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])[CH:25]=1)=O>CC(O)C>[F:31][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)=[CH:25][C:24]=1[N:26]([CH3:30])[C:27](=[O:29])[CH3:28]
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Reactant: CC(=O)N(C)c1cc(C(=O)C=CN(C)C)ccc1F
Solvent: CC(C)O
Product: CC(=O)N(C)c1cc(-c2ccnc3c(C(=O)c4cccs4)cnn23)ccc1F
Temperature: 5 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
A 300 L vessel was flushed with nitrogen. Acetic acid (40.0 L) was charged, and then 7.312 kg (37.84 moles) of (5-amino-1H-pyrazol-4-yl)-thiophen-2-yl-methanone and 10.000 kg (37.84 moles) of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-methyl-acetamide were added consecutively. The mixture was heated to 120° C. (±5° C.) with stirring. The reaction was controlled by HPLC until completion (<1% of each starting material), which typically occurs in 4 hours. The reaction mass was cooled to 60-70° C. 2-Propanol (80.0 L) was charged to reaction mixture, cooled to 40-45° C. and aged for at least 1 hour. The mixture was cooled over approximately 2.5 hours to 0-5° C. and aged for at least 2 hours. Solids were filtered and washed twice with 10.0 L of chilled 2-propanol. The solid product was dried under vacuum at 50° C. (±5° C.) to remove residual solvents (<0.5% w/w of acetic acid and <0.5% w/w of 2-propanol). N-{2-fluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide was obtained as a crystalline material (12.686 kg). Yield 85%. Purity ≧95%.