Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C[CH2:11][C:12]1[C:13]([C:44](O)=[O:45])=[C:14]([N:29]([CH2:35][C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=2[F:43])[C:30](OCC)=[O:31])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][O:27][CH3:28])=[O:25])=[CH:19][CH:18]=1)C)C1C=CC=CC=1.[NH2:47][C:48]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][N:49]=1>>[CH2:35]([N:29]([CH2:11][C:12]1[C:13]2[C:44](=[O:45])[N:47]([C:48]3[CH:53]=[CH:52][C:51]([F:54])=[CH:50][N:49]=3)[C:30](=[O:31])[N:29]([CH2:35][C:36]3[C:37]([F:43])=[CH:38][CH:39]=[CH:40][C:41]=3[F:42])[C:14]=2[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][O:27][CH3:28])=[O:25])=[CH:19][CH:18]=1)[CH3:14])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)N(Cc1c(F)cccc1F)c1sc(-c2ccc(NC(=O)NOC)cc2)c(CCN(C)Cc2ccccc2)c1C(=O)O
Reactant: Nc1ccc(F)cn1
Product: CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(-c2ccc(F)cn2)c(=O)n3Cc2c(F)cccc2F)cc1
Yield: 63.1 %

Procedure:
The similar reaction as described in Example 5 by using 4-(N-benzyl-N-methylaminoethyl)-2-(N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylic acid (10.0 g, 15.65 mmol) and 2-amino-5-fluoropyridine (3.51 g, 31.30 mmol) gave N-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-3-(5-fluoropyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea (3.39 g, 32%) as white solids. The similar reaction as described in Reference Example 18 by using the compound (1.0 g, 1.46 mmol) gave the title compound (560 mg, 64%) as white solids.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=3[OH:21])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:22]12(C3C=C(C=CC=3O)C=O)CC3CC(CC(C3)[CH2:23]1)[CH2:29]2>>[C:1]12([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=3[O:21][CH:22]([CH3:29])[CH3:23])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: COC(=O)c1ccc(C23CC4CC(CC(C4)C2)C3)c(O)c1
Reactant: O=Cc1ccc(O)c(C23CC4CC(CC(C4)C2)C3)c1
Product: COC(=O)c1ccc(C23CC4CC(CC(C4)C2)C3)c(OC(C)C)c1
Yield: 75.4 %

Procedure:
When methyl 4-(1-admantyl)-3-hydroxybenzoate was substituted for 3-(1-admantyl)-4-hydroxybenzaldehyde in Example 60, Step A, the identical process afforded the title compound (0.95 g, 75.4%) as a colourless solid. 1H-NMR (CDCl3) 1.39 (d, 6H, J=6 Hz); 1.75 (5, 6H); 2.05 (s, 3H); 2.11 (s, 6H); 3.87 (s, 3H); 4.69-4.71 (m, 1H); 7.24 (d, 1H, J=8.1 Hz); 7.47 (b, 1H); 7.51 (dd, 1H, J=1.55, 8.09 Hz).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].CS(O[CH2:38][C:39]([F:42])([F:41])[F:40])(=O)=O>CN(C)C=O>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH2:38][C:39]([F:42])([F:41])[F:40])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Reactant: CS(=O)(=O)OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3CC(F)(F)F)CC1
Yield: 74 %

Procedure:
The title compound was synthesized in analogy to example 51, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate in N,N-dimethylformamide, to give the desired product as a colorless foam (74%).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[N:23]([CH3:28])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])=[CH:15][CH:14]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:29](OCC)=[O:30].[O-]CC.[Na+].Cl>C(O)C>[OH:30][CH:29]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[N:23]([CH3:28])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])=[CH:15][CH:14]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4)cc2)n(C)n1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)n(C)n1
Temperature: 78 °C
Yield: 93.9 %

Procedure:
2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [4-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (1.345 g, 3.59 mmol) and ethyl formate (0.862 mL, 10.77 mmol) were dissolved in anhydrous ethanol (7.19 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (6.70 mL, 17.9 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (1.358 g, 3.37 mmol, 94%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=2)[C:3]=1[NH2:4].[CH2:23]([N:30]=[C:31]=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C1C=CC=CC=1>C1COCC1>[CH2:23]([NH:30][C:31]([NH:4][C:3]1[C:5]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:16][CH:17]=2)=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[F:1])=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CC(C)(C)Cc1ccc(CCc2cc(F)cc(F)c2N)cc1
Reactant: CCCCCCCN=C=O
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCCCCCCNC(=O)Nc1c(F)cc(F)cc1CCc1ccc(CC(C)(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of the product from step (d) (4.5 g) in THF (50 ml) was stirred at room temperature and heptyl isocyanate (5.5 g containing 36 mole % benzene, prepared by the method described in Organic Syntheses, Collective Volume 3, p. 846) and N,N-dimethylaminopyridine (750 mg) were added. The mixture was stirred at room temperature for ca 60 hours, then evaporated under reduced pressure to give an oil which was flash chromatographed through a silica column using ether/hexane (2:1 v/v). The eluate was evaporated under reduced pressure and the residue crystallised from hexane and triturated with methanol to give 4.5 g of material. The latter was flash chromatographed through a silica column using ether/hexane (2:1 v/v) and then freeze-dried from dioxan to give 5.3 g of the desired product, mp 105°-107° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][CH:15]=1.C(N(CC)CC)C>C(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH:13]=[CH:14][CH:15]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cccc(Nc2cc(Cl)ncn2)c1
Temperature: 80 °C

Procedure:
4,6-Dichloropyrimidine (1.5 g, 10 mmol), tert-butyl 3-aminophenylcarbamate (2.1 g, 10 mmol) and triethylamine (2.2 g, 20 mmol) were mixed in ethanol (20 mL), heated at 80° C. for 16 hr. The reaction mixture was cooled to RT and solvent was removed in vacuo. The gummy crude product was mixed with 20 mL of DCM and was stirred at RT to give an off-white solid, which was filtered and dried under vacuum (1.6 g, 5 mmol). MS (m/z): MH+=321, 323.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]=C)[C:5]#[N:6].[O:12]=[O+][O-].[BH4-].[Na+].O>CO>[OH:12][CH2:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[CH3:1]
Reactant: C=Cc1ccc(C#N)cc1C
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cc(C#N)ccc1CO
Temperature: -70 °C
Yield: 90 %

Procedure:
3-Methyl-4-vinylbenzonitrile (0.40 g; 2.8 mmol; from step (i) above) was dissolved in 50 mL of methanol and cooled to −70° C. Ozone (2 eq.) was bubbled through, and then 0.20 g (5.3 mmol) of sodium borohydride and 5 mL of water were added and the cooling bath was removed. After 4 h the methanol was evaporated and the residue was partitioned between 1M HCl and ether. The aqueous layer was extracted twice with ether and the combined organic phase was washed with water, dried (Na2SO4) and evaporated to yield 0.37 g (90%) of the desired product, which was used in the next step without further purification.
Reaction SMILES: [ClH:1].[CH:2]1([NH:8][NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:10][C:11]([CH3:18])([CH3:17])[C:12](=O)[CH2:13][C:14]#[N:15]>C(O)C>[ClH:1].[C:11]([C:12]1[CH:13]=[C:14]([NH2:15])[N:8]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[N:9]=1)([CH3:18])([CH3:17])[CH3:10]
Reactant: NNC1CCCCC1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(C2CCCCC2)n1
Temperature: 25 °C
Yield: 38.9 %

Procedure:
A stirred solution of cyclohexylhydrazine hydrochloride (1.5 g, 9.96 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.5 g, 11.98 mmol) in ethanol (5 mL) was refluxed for 15 h. After cooling to rt, the reaction mixture was concentrated under reduced pressure and the obtained crude product was recrystallized from a mixture of diethyl ether and petroleum ether to afford 3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-amine hydrochloride (1.0 g, 39%) as colorless solid. 1H NMR (400 MHz, DMSO-d6) δ13.24 (brs, 1H), 7.02 (brs, 2H), 5.52 (s, 1H), 4.30 (m, 1H), 1.63-1.98 (m, 7H), 1.10-1.40 (m, 12H); LC-MS (ESI) m/z 222 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:6]=2[CH:17]=1.[C:18]1([CH3:32])[CH:23]=[CH:22][C:21]([N:24]2[C:28](B(O)O)=[CH:27][CH:26]=[N:25]2)=[CH:20][CH:19]=1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[C:6]3[CH:17]=[C:2]([C:28]4[N:24]([C:21]5[CH:22]=[CH:23][C:18]([CH3:32])=[CH:19][CH:20]=5)[N:25]=[CH:26][CH:27]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[CH:11][CH:12]=1
Reactant: Fc1ccc(-n2cnc3ccc(Br)cc32)cc1
Reactant: Cc1ccc(-n2nccc2B(O)O)cc1
Product: Cc1ccc(-n2nccc2-c2ccc3ncn(-c4ccc(F)cc4)c3c2)cc1

Procedure:
The title compound, light brown foam (78 mg, 61%), MS (ISP) m/z=369.2 [(M+H)+], was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-fluoro-phenyl)-1H-benzo[d]imidazole (intermediate G) (100 mg, 344 μmol) and 1-p-tolyl-1H-pyrazol-5-ylboronic acid (intermediate B) (90.2 mg, 447 μmol).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].[CH3:23][N:24](C)C=O>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.[C-]#N.[Zn+2].[C-]#N>[CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:23]#[N:24])[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(=O)N1c2ccc(C#N)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
A solution of 1-methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Example 4) (355 mg, 0.962 mmol) in N,N-dimethylformamide (DMF) (5 mL) at room temperature was degassed over 30 min under house vacuum and quenched several times with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.1 mmol) and zinc(II) cyanide (153 mg, 1.3 mmol) were then added and the resulting yellow mixture was stirred under nitrogen at 100° C. for 5 h then cooled to room temperature. The insoluble were filtered off, rinsed with AcOEt then destroyed with bleach. The organic phase was washed with water. The aqueous phase was extracted with AcOEt. The combined organic phases were washed twice with water then brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using a 10 G silica cartridge (gradient: 13 to 63% AcOEt in Hexanes) gave 1-methylethyl[(2S,4R)-1-acetyl-6-cyano-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (238 mg, 0.755 mmol, 78% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=2)=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[B-](F)(F)(F)[F:31].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[Cl:1][C:2]1[C:3]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=2)=[C:4]([F:31])[C:5]([N:8]2[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: F[B-](F)(F)F
Reactant: Cc1cnc(-c2cc(N3CCC(NC(=O)OC(C)(C)C)CC3)ncc2Cl)c(C)c1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: Cc1cnc(-c2c(Cl)cnc(N3CCC(NC(=O)OC(C)(C)C)CC3)c2F)c(C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
A cooled (0° C.), stirred suspension of tert-butyl (1-(5′-chloro-3,5-dimethyl-[2,4′-bipyridin]-2′-yl)piperidin-4-yl)carbamate (550 mg, 1.32 mmol) in acetonitrile (13 mL) was treated with Selectfluor® (827 mg, 2.24 mmol) portionwise. A light yellow solution was obtained and stirring was continued for 2 h. LC-MS showed the reaction was ˜70% complete. The reaction was quenched with water at this point to avoid more by-product formation. EtOAc was added and layers were separated. The aqueous layer was extracted with EtOAc (2×). The organic extract was dried over sodium sulfate and concentrated to give the crude product, which was purified on ISCO separation system with a 12-gram column using 0-40% EtOAc in heptane to afford 164 mg (29%) of white foam: LRMS (M+H)+: 435.1; 1H NMR (400 MHz, CDCl3) δ 1.43-1.50 (m, 11 H), 2.03 (d, J=12.13 Hz, 2 H), 2.14 (s, 3 H), 2.39 (s, 3 H), 2.90-3.12 (m, 2 H), 3.69 (br. s., 1 H), 3.87-4.08 (m, 2 H), 4.48 (br. s., 1 H), 7.46 (s, 1 H), 8.09 (s, 1 H), 8.40 (s, 1 H).
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH2:20]([S:27](Cl)(=[O:29])=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][S:27]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:29])=[O:28])=[CH:10][CH:11]=1
Reactant: NCc1ccc(OC(F)F)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(Cc1ccccc1)NCc1ccc(OC(F)F)cc1
Reaction time: 3 h
Yield: 92.2 %

Procedure:
4-(Difluoromethoxy)benzyl amine (1.73 g, 9.97 mmol) was dissolved in THF (10 mL). It was cooled in an ice-bath. Under nitrogen atmosphere, triethylamine (1.46 mL, 10.46 mmol) was added and then benzylsulfonyl chloride (1.9 g, 9.97 mmol) in THF (10 mL) was dropped in. The cooling bath was removed after the addition. The mixture was stirred for 3 h and then evaporated to dryness. DCM (50 mL) was added to the residue. It was then washed with 1% HCl (15 mL), water (50 mL×3) and brine, dried (MgSO4) and evaporated to give the title compound (3.01 g. 92%) as a solid; 1H NMR (400 MHz, CDCl3): δ 7.32-7.40 (m, 5H), 7.26 (d, 2H), 7.09 (d, 2H), 6.49 (t, 1H), 4.36 (bt, 1H), 4.24 (s, 2H), 4.10 (d, 2H); Mass Spectrum: M−H+ 326.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:4]=1.Cl.O.[NH:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.Cl>>[ClH:1].[CH3:2][C:3]1[CH:4]=[C:5]([C:11]([F:14])([F:13])[F:12])[C:6]2[NH:9][C:20]3[CH2:21][CH2:22][NH:17][CH2:18][C:19]=3[C:7]=2[CH:8]=1
Reactant: O=C1CCNCC1
Reactant: Cc1ccc(NN)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Product: Cc1cc(C(F)(F)F)c2[nH]c3c(c2c1)CNCC3

Procedure:
A microwave-compatible sealable tube was charged with (4-methyl-2-trifluoromethyl-phenyl)-hydrazine hydrochloride (434 mg, 1.6 mmol), 4-piperidone monohydrate hydrochloride (300 mg, 1.6 mmol), and 2-PrOH (3 mL). The reaction was saturated with HCl gas and the tube was sealed. The reaction mixture was subjected to microwave irradiation at 120° C. for 12 min. The solids were filtered and washed with ether to provide crude 8-methyl-6-trifluoromethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride. The resulting crude product was dissolved in THF (12 mL) and H2O (3 mL), then Na2CO3 (184 mg, 1.7 mmol) and Boc2O (374 mg, 1.7 mmol) were added consecutively. After 2 h, EtOAc (25 mL) and water (10 mL) were added. The aqueous layer was extracted with EtOAc (25 mL) and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 1–2.5% MeOH/CH2Cl2) to provide 8-methyl-6-trifluoromethyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (200 mg, 29%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:32])[CH2:14][CH:15]([NH:24][C:25](=[O:31])[C@@H:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].N1C=CC=CC=1.[C:39](Cl)(=[O:41])[CH3:40]>O1CCCC1>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13](=[O:32])[CH2:14][CH:15]([NH:24][C:25](=[O:31])[C@@H:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:39](=[O:41])[CH3:40])=[CH:19][CH:18]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C(=O)CC(Cc2ccc(N)cc2)NC(=O)[C@@H]2CCCN2)cc(OC)c1OC
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cc(C(=O)CC(Cc2ccc(NC(C)=O)cc2)NC(=O)[C@@H]2CCCN2)cc(OC)c1OC
Temperature: 22 °C
Yield: 62.9 %

Procedure:
In an oven-dried round bottomed flask was added L-proline, 1-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl] 2-(4-aminophenyl)ethylamide (100 mg, 0.23 mmol), and tetrahydrofuran (5 mL). The solution was stirred at 22° C., and treated with pyridine (0.037 mL, 0.45 mmol, 2.0 eq) followed by acetyl chloride (0.024 mL, 0.34 mmol, 1.5 eq). The reaction mixture was allowed to stir for one hour. The solvent was removed in vacuo and the residue partitioned between EtOAc (50 mL) and sat. NaHCO3 (50 mL). The organic layer was washed with sat. aq. NaCl, dried (MgSO4) and concentrated to an oil. The oil was purified by flash chromatography to provide 70 mg of L-proline, 1-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl] 2-(4-(N-acetyl)aminophenyl)ethylamide as a foam.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[OH2:4].[C:5]([C:8]1[CH:16]=[C:15]([CH3:17])[C:14]([CH3:18])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])(=O)[CH3:6]>O>[OH2:3].[CH3:6][C:5]1[C:8]2[C:9](=[CH:13][C:14]([CH3:18])=[C:15]([CH3:17])[CH:16]=2)[C:10](=[O:11])[O:12][C:2]=1[C:1]([OH:4])=[O:3]
Reactant: CCO
Reactant: CC(=O)c1cc(C)c(C)cc1C(=O)O
Solvent: O
Product: Cc1cc2c(C)c(C(=O)O)oc(=O)c2cc1C

Procedure:
4,6,7- Trimethylisocoumarin -3- carboxylic acid monohydrate, mp. (EtOH-H2O) 241°, (Found: C, 62.27; H, 5.74. C13H12O4. H2O requires C, 62.39; H, 5.64) was prepared from 2- acetyl -4, 5- dimethyl benzoic acid by an analogous procedure to that described in Example 2.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:20][CH2:21][O:22][CH:23]([CH3:25])[CH3:24])[C:13](OC(C)(C)C)=[O:14])=[CH:7][CH:6]=1)C.FC(F)(F)C(O)=O.[CH2:34](Cl)[Cl:35]>>[CH:23]([O:22][CH2:21][CH2:20][N:12]([CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:3])=[O:26])=[CH:6][CH:7]=1)[C:13](=[O:14])[CH2:34][Cl:35])([CH3:25])[CH3:24]
Reactant: ClCCl
Reactant: CCOC(=O)c1ccc(CN(CCOC(C)C)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OCCN(Cc1ccc(C(=O)O)cc1)C(=O)CCl
Reaction time: 8 h

Procedure:
7.1 g of the crude 4-[N-(2-isopropoxyethyl)-N-tert-butoxycarbonylaminomethyl]benzoic acid ethyl ester are dissolved in 70 ml of methylene chloride, and 40 ml of trifluoroacetic acid are added. The clear solution is left to stand overnight at room temperature and then concentrated by evaporation. The residue is taken up in methylene chloride, washed with aqueous ammonia solution (pH>9) and concentrated by evaporation. The oily/crystalline residue is dissolved in 50 ml of ethanol, and 50 ml of 2N sodium hydroxide solution are added. After stirring for 2 hours at 60°-65°, the solution is concentrated by evaporation and the residue is adjusted to pH 1 with water and 2N hydrochloric acid. The solution immediately becomes extremely cloudy and after about 5 minutes a precipitate forms. The mixture is concentrated by evaporation and the residue is heated briefly with 100 ml of ethanol. The solution is dried with magnesium sulfate, filtered over Hyflo and concentrated by evaporation. The crude crystalline material is suspended in 80 ml of tetrahydrofuran, and 3.2 g of chloroacetyl chloride are added. The suspension is stirred at room temperature for 14 hours, then concentrated to dryness by evaporation. The residue is dissolved in methylene chloride, washed with diluted hydrochloric acid, dried and concentrated by evaporation. Sticky, sparingly soluble crystals are obtained corresponding to 4-[N-(2-isopropoxyethyl)-N-chloroacetylaminomethyl]-benzoic acid.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:18]3[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=3)=[N:9][C:10]3[N:11]([N:13]=[CH:14][C:15]=3[CH:16]=[CH2:17])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1.C(O)C.[Pd]>[CH2:16]([C:15]1[CH:14]=[N:13][N:11]2[CH:12]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]([C:18]3[CH:19]=[CH:20][C:21]([CH:22]=[O:23])=[CH:24][CH:25]=3)=[N:9][C:10]=12)[CH3:17]
Reactant: C=Cc1cnn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc12
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1cnn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
275 mg 4-(6-phenyl-3-vinylpyrazolo[1,5-a]pyrimidin-5-yl)benzaldehyde is dissolved in 10 ml THF and 10 ml ethanol. Pd/C (10% w/w) is added and stirred under H2-atmosphere at room temperature for 1.5 h. The mixture is filtrated over kieselgur. The filtrate is concentrated and the residue is purified by chromatography on silica gel (dichloromethane/ethyl acetate) to yield the desired compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([NH:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([I:25])[CH:20]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1.O>COCCOC>[Si:1]([O:8][CH2:9][C@H:10]([NH:17][C:18](=[S:36])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([I:25])[CH:20]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](NC(=O)c1cccc(I)c1)c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@H](NC(=S)c1cccc(I)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
To a solution of N-(1-tert-butyldimethylsilyloxy-2(R)-phenylethan-2-yl)-3-iodobenzamide (13.1 g, 27.2 mmol) in 1,2-dimethoxyethane (80 ml) was added Lawesson's reagent (8.2 g, 20 mmol). The reaction mixture was stirred at ambient temperature for 1 h and then at 60° C. for 2 hours, cooled and poured into water (100 ml). The mixture was extracted with CH2 Cl2 (2×50 ml), washed with brine (100 ml), dried (MgSO4) and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel eluting with ethyl acetate/hexane (=1:7) to afford N-(1-tert-butyldimethylsilyloxy-2(R)-phenyl-ethan-2-yl)-3-iodobenzthiamide (4.99 g, 50%) as a yellow liquid.