Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].O1CCOCC1.[CH3:8][N:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[C:16]3[C:33](=[CH:34][CH:35]=2)[O:32][C:19]2([CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[CH2:18][C:17]3=[O:36])[CH:11]=[N:10]1>CCOCC>[ClH:1].[CH3:8][N:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[C:16]3[C:33](=[CH:34][CH:35]=2)[O:32][C:19]2([CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)[CH2:18][C:17]3=[O:36])[CH:11]=[N:10]1
Reactant: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)OC(C)(C)C)CC2)O3)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4 N hydrogen chloride/dioxane solution was added to tert-butyl 6-(1-methyl-1H-pyrazol-4-yl)-4-oxo-spiro[chroman-2,4′-piperidine]-1′-carboxylate (1.0 g), and stirred overnight at room temperature. Ether was added to the reaction liquid, the solid was taken out through filtration, washed with ether, and dried under reduced pressure to obtain the intended product as a white solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]3[CH2:32][CH2:31][NH:30][CH2:29][C:23]=3[N:24]=[C:25]([S:27][CH3:28])[N:26]=2)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].Cl[C:34]1[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][N:35]=1>O1CCOCC1.C(N(CC)C(=O)C)C>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]3[CH2:32][CH2:31][N:30]([C:34]4[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][N:35]=4)[CH2:29][C:23]=3[N:24]=[C:25]([S:27][CH3:28])[N:26]=2)=[CH:16][CH:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: Clc1cccnc1Cl
Reactant: CSc1nc2c(c(Nc3ccc(C(C)(C)C)cc3)n1)CCNC2
Agent: CCN(CC)C(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc2c(c(Nc3ccc(C(C)(C)C)cc3)n1)CCN(c1ncccc1Cl)C2
Yield: 25 %

Procedure:
The solution of diisopropylethylamine (235 mg, 1.82 mmol), N-(4-tert-butylphenyl)-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine (300 mg, 0.91 mmol) and 2,3-dichloropyridine (270 mg, 1.82 mmol) in dioxane (5 mL) and N,N-diethylacetamide (0.5 mL) was irradiated in microwave at 180° C. for 10 hr. Solvent was removed in vacuo and residue was dissolved in ethyl acetate, washed with water and brine and dried over sodium sulfate and purified by column chromatography, product was obtained as a beige solid (100 mg).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH:5]([C:10]1[CH:11]=[C:12]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[K+]>CCO>[CH3:25][S:22]([N:18]1[CH2:19][CH2:20][CH2:21][CH:16]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:36])=[O:3])[CH:11]=[C:12]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:34])([F:33])[F:35])=[CH:30][CH:31]=3)[CH:13]=2)[CH2:17]1)(=[O:23])=[O:24]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(S(C)(=O)=O)C2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(S(C)(=O)=O)C2)c1
Temperature: 78 °C

Procedure:
To a solution of compound 39a, 2-[5-(1-Methanesulfonyl-piperidin-3-yl)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid ethyl ester (70.0 mg, 0.133 mmol) in EtOH (6.5 ml) was added 2M KOH (0.027 ml, 0.53 mmol). The reaction was heated to 78° C. for 3 hours, cooled to room temperature, and concentrated in vacuo. Purification via Gilson HPLC, gave the product as a white lyophilate. (53.4 mg, 81%) 1H NMR (300 MHz, MeOD) δ ppm 0.85 (dd, J=6.59, 1.70 Hz, 6 H) 1.42 (dt, J=13.28, 6.74 Hz, 1 H) 1.56-1.71 (m, 3 H) 1.79-1.87 (m, 1 H) 1.92 (dd, J=13.56, 7.16 Hz, 2 H) 2.69-2.85 (m, 5 H) 3.19-3.23 (m, 2 H) 3.61-3.72 (m, 3 H) 7.23 (s, 1 H) 7.42 (d, J=1.51 Hz, 2 H) 7.62-7.74 (m, 4 H) Calcd for C25H30F3NO4S (M+H) 497.57, Found 498.3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([NH2:30])=[N:12][C:13](S(C)(=O)=O)=[N:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CCO>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([NH2:30])=[N:12][CH:13]=[N:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1nc(N)c(C#Cc2ccc(N)nc2)c(-c2cccc(C(F)(F)F)c2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(C#Cc2c(N)ncnc2-c2cccc(C(F)(F)F)c2)cn1

Procedure:
To a solution of 60 mg (0.080 mmol) 5-(6-amino-pyridin-3-ylethynyl)-2-methanesulfonyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-ylamine (B-10) and 15.7 mg (0.42 mmol) sodiumborohydride in 1 mL EtOH is stirred at 80° C. for 60 minutes. The title compound is purified from the crude reaction mixture by RP-HPLC (ACN/H2O gradient). Yield: 1.4 mg (5%).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:23]=[CH:22][C:9]([O:10][CH2:11][CH2:12][C@@H:13]2[CH2:15][C@@H:14]2[CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:8][C:7]=1[F:24])(=[O:5])=[O:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[N:31]#[C:32]Br>C(Cl)(Cl)Cl>[CH2:1]([S:3]([C:6]1[CH:23]=[CH:22][C:9]([O:10][CH2:11][CH2:12][C@@H:13]2[CH2:15][C@@H:14]2[CH:16]2[CH2:21][CH2:20][N:19]([C:32]#[N:31])[CH2:18][CH2:17]2)=[CH:8][C:7]=1[F:24])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCNCC2)cc1F
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C#N)CC2)cc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-((1R,2S)-2-{2-[4-(ethylsulfonyl)-3-fluorophenoxy]ethyl}cyclopropyl)piperidine (Step C, Example 111; 150 mg, 0.428 mmol) and potassium carbonate (244 mg, 1.77 mmol) were stirred in chloroform (7 mL). Cyanogen bromide (61 mg, 0.58 mmol) was added. The mixture was stirred at RT for 15 min and refluxed overnight. The mixture was cooled to RT, mixed with silica gel (5 g), and concentrated to dryness under reduced pressure. The residue was loaded on a silica gel column (15 g of silica gel) and eluted with dichloromethane/methanol (97.5:2.5, 1 L to provide the title compound as an white solid. MS (Multimode) m/z 381 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O:33][C:34]([C@H:36]1[CH2:41][CH2:40][C@H:39]([C:42](O)=[O:43])[CH2:38][CH2:37]1)=[O:35])C1C=CC=CC=1.C(C1C=C(NC(C2C=CC(N3CCN(C([C@H]4CCC[C@@H]4C(O)=O)=O)CC3)=NC=2)=O)C=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:42]([CH:39]4[CH2:38][CH2:37][CH:36]([C:34]([OH:35])=[O:33])[CH2:41][CH2:40]4)=[O:43])[CH2:21][CH2:20]3)=[CH:17][CH:18]=2)=[O:25])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCNCC3)cc2)c1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(C(=O)[C@H]4CCC[C@@H]4C(=O)O)CC3)nc2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCN(C(=O)C4CCC(C(=O)O)CC4)CC3)cc2)c1

Procedure:
4-{4-[4-(3-tert-Butyl-phenylcarbamoyl)-phenyl]-piperidine-1-carbonyl}-cyclohexanecarboxylic acid was prepared from N-(3-tert-butyl-phenyl)-4-piperidin-4-yl-benzamide and trans-1,4-cyclohexane dicarboxylic acid monobenzyl ester in a manner similar to the one described in the synthesis of (1S,2S)-2-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-cyclopentanecarboxylic acid above. LCMS calcd for C30H38N2O4 (m/e) 490, obsd 491 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH:19]1[CH2:21][CH2:20]1.Cl>CN(C=O)C.CCOC(C)=O>[CH:19]1([CH2:18][O:10][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[OH:1])[CH2:21][CH2:20]1
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: BrCC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCC2CC2)c(O)c1
Temperature: 50 °C
Yield: 53.2 %

Procedure:
A mixture of 3,4-dihydroxybenzaldehyde (0.5 g, 3.62 mmol), K2CO3 (0.550 g, 3.98 mmol) and (bromomethyl)cyclopropane (0.386 ml, 3.98 mmol) in DMF (12 ml) was heated to 50° C. overnight. The reaction mixture was portioned between EtOAc and HCl 1N. The organic phase was washed several times with brine and dried over Na2SO4; the solvent was removed; and the crude was purified by flash chromatography on silica gel cartridge (petroleum ether:EtOAc=90:10 to 85:15) to give 4-(cyclopropylmethoxy)-3-hydroxybenzaldehyde (0.370 g, 1.925 mmol, 53.2% yield, MS/ESI+ 193.0 [MH]+).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]2[N:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:3]1=[O:17].[H-].[Na+].[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23]Cl.CCOCC>C1(C)C(C)=CC=CC=1.O>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3](=[O:17])[C:4]2[CH:16]=[CH:15][CH:14]=[N:13][C:5]1=2
Reactant: CN1C(=O)c2cccnc2Nc2ccccc21
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: CN(C)CCN1c2ccccc2N(C)C(=O)c2cccnc21
Yield: 59.1 %

Procedure:
9.0 gm of 6,11-dihydro-6-methyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one were dissolved in 200 ml of hot absolute xylene, 2.1 gm of 50% sodium hydride in mineral oil were added to the solution, and the mixture was refluxed for 2 hours. Then, 5.3 gm of 2-dimethylamino-ethyl chloride were added dropwise, and the mixture was refluxed for 16 hours more. The cooled reaction mixture was shaken with a mixture of ether and water, and the organic phase was separated and extracted with dilute acetic acid. Then the acidic aqueous layer was made alkaline with concentrated ammonia, and the precipitated oil was extracted with ether. After evaporation of the ether extract, the residue was distilled, yielding 7.0 gm (59% of theory) of 11-(2'-dimethylamino-ethyl)-6,11-dihydro-6-methyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, b.p. 163°-164° C. at 0.01 mm Hg.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:7][CH2:6][C:5]2=[CH:8][C:9]([NH:11][C:12]3[C:13](=[O:28])[N:14]([CH3:27])[CH:15]=[C:16](B4OC(C)(C)C(C)(C)O4)[CH:17]=3)=[N:10][N:4]2[CH2:3]1.Cl[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([N:37]2[N:48]=[CH:47][C:46]3[C:45]4[CH2:44][C:43]([CH3:50])([CH3:49])[CH2:42][C:41]=4[S:40][C:39]=3[C:38]2=[O:51])[C:32]=1[CH:52]=[O:53].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>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].C(#N)C.O>[CH3:29][C:2]1([CH3:1])[O:7][CH2:6][C:5]2=[CH:8][C:9]([NH:11][C:12]3[C:13](=[O:28])[N:14]([CH3:27])[CH:15]=[C:16]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]([N:37]5[N:48]=[CH:47][C:46]6[C:45]7[CH2:44][C:43]([CH3:49])([CH3:50])[CH2:42][C:41]=7[S:40][C:39]=6[C:38]5=[O:51])[C:32]=4[CH:52]=[O:53])[CH:17]=3)=[N:10][N:4]2[CH2:3]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2cc3n(n2)CC(C)(C)OC3)c1=O
Reactant: CC1(C)Cc2sc3c(=O)n(-c4nccc(Cl)c4C=O)ncc3c2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: Cn1cc(-c2ccnc(-n3ncc4c5c(sc4c3=O)CC(C)(C)C5)c2C=O)cc(Nc2cc3n(n2)CC(C)(C)OC3)c1=O
Temperature: 95 °C
Yield: 33.5 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 335b (240 mg, 0.60 mmol), 4-chloro-2-{4,4-dimethyl-9-oxo-7-thia-10,11-diazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),11-trien-10-yl}pyridine-3-carbaldehyde 282i (107.7 mg, 0.30 mmol), Pd(dppf)Cl2 (24.5 mg, 0.030 mmol), K3PO4 (127.2 mg, 0.60 mmol), sodium acetate (49.2 mg, 0.60 mmol), water (0.5 mL), and acetonitrile (10 mL). After three cycles of vacuum/nitrogen flush, the mixture was heated at 95° C. for 1 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 335c as a brown solid (60 mg, 22%, two steps). MS-ESI: [M+H]+ 598.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19]C3C=CC(CC(OC)=O)=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:31].[Na+]>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[C:17][C:5]3[CH:6]=[CH:7][C:2]([C:1]([OH:8])=[O:31])=[CH:3][CH:4]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Using General Procedure I; a solution of methyl {4-[4-(1-benzyloxycyclopropyl)-phenylethynyl]-phenyl}-acetate (Compound 76, 45.0 mg, 0.11 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 35.0 mg (81%) of the title compound as a pale-yellow solid.
Reaction SMILES: [C:1]([NH:10][C@H:11]([C@H:14]([OH:20])/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH3:19])[CH2:12][OH:13])(=[O:9])[CH2:2]CCCCCC.N[C@H]([C@H](O)/C=C/CCC)CO.C(Cl)(=O)C>>[C:1]([NH:10][C@H:11]([C@H:14]([OH:20])/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH3:19])[CH2:12][OH:13])(=[O:9])[CH3:2]
Reactant: CCC/C=C/[C@@H](O)[C@H](CO)NC(=O)CCCCCCC
Agent: CCC/C=C/[C@@H](O)[C@@H](N)CO
Solvent: CC(=O)Cl
Product: CCC/C=C/[C@@H](O)[C@H](CO)NC(C)=O

Procedure:
Compound (7) is prepared analogously to the process described for (6) by using 117.9 mg (0.75 mMol) of compound (5) and 58.1 mg (0.74 mg) acetyl chloride.
Reaction SMILES: C(OC(=O)NC1C=CC=C([CH2:14][N:15]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:40])[C@@H:22]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31](Cl)[CH:30]=3)[CH2:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:16]2)C=1)(C)(C)C.C(Cl)(=O)C(Cl)=O.NC1C=CN([CH2:54][C:55](C)([OH:57])[CH3:56])N=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:24]1([CH2:23][C@H:22]([C:29]2[CH:30]=[CH:31][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][CH:34]=2)[C:21]([NH:20][C:17]2[CH:18]=[CH:19][N:15]([CH2:14][C:55]([OH:57])([CH3:56])[CH3:54])[N:16]=2)=[O:40])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A solution of 3-cyclopentyl-2-(R)-(4-methanesulfonyl-phenyl)-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 3, 60 mg, 0.20 mmol) was dissolved in methylene chloride (10 mL) and N,N-dimethylformamide (one drop) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 117 μL, 0.23 mmol) which produced gas evolution and it was then stirred at 0° C. for 15 minutes and 1 h at 25° C. After this time, the reaction was concentrated in vacuo to ⅙ of the original volume. In a separate flask a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 34 mg, 0.22 mmol), 2,6-lutidine (35 μL, 0.30 mmol) and methylene chloride (5 mL) was cooled to 0° C. in an ice bath. To this solution was added the solution of the prepared acid chloride diluted with another portion of methylene chloride (2 mL) dropwise. After addition was complete, the reaction was then allowed to warm to 25° C. and stirred for 16 hours. After this time the reaction was diluted with methylene chloride (10 mL) and washed with a saturated aqueous sodium bicarbonate solution (1×10 mL) and a 1 N aqueous hydrochloric acid solution (1×10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification an AnaLogix Intelliflash system (4 g column, 20% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(R)-(4-methanesulfonyl-phenyl)-propionamide (65 mg, 75%) as a white foam: [α]30589=−20.0° (c=0.13, methylene chloride); ES-HRMS m/e calcd for C22H31N3O4S (M+H)+ 434.2108, observed 434.2108; H1-NMR (300 MHz, DMSO-d6) δ ppm 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.10 (m, 2 H, CH2), 1.35-1.80 (m, 8H, 4×CH2), 2.08 (m, 1H, CH), 3.18 (s, 3H, SO2CH3), 3.86 (s, 2H, NCH2), 3.93 (m, 1H, ArCHCO), 4.65 (s, 1H, OH), 6.45 (d, J=2.1 Hz, 1H, Ar), 7.50 (d, J=2.1 Hz, 1H, Ar), 7.64 (d, J=8.2 Hz, 2H, Ar), 7.88 (d, J=8.2 Hz, 2H, Ar), 10.78 (s, 1H, NH).
Reaction SMILES: [CH3:1][C:2]([C:4]([O:6][CH2:7][CH2:8][OH:9])=[O:5])=[CH2:3].N1C=CC=CC=1.[C:16](Cl)(=[O:21])[O:17][CH:18]([Cl:20])[CH3:19]>CCOCC>[CH3:3][C:2]([C:4]([O:6][CH2:7][CH2:8][OH:9])=[O:5])=[CH2:1].[C:16](=[O:21])([O-:5])[O:17][CH:18]([Cl:20])[CH3:19]
Reactant: CC(Cl)OC(=O)Cl
Agent: C=C(C)C(=O)OCCO
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(Cl)OC(=O)[O-]
Reaction time: 0.5 h
Yield: 173.5 %

Procedure:
To 24 mL of HEMA (200 mmol) in 1000 mL of dry ether was added 16.8 mL (213 mmol) of pyridine at 4-10° C., under argon. To this solution was added 21.3 mL (200 mmol) of 1-chloroethyl chlorocarbonate, drop wise with stirring over 0.5 hour. After stirring for 0.5 hour at 4-10° C., the heavy precipitate was removed by filtration and the filtrate was concentrated to an oil in vacuo, yielding 44 g (100%) of HEMA-1-chloroethyl carbonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:26][C:27]2[CH:32]=[C:31](C)[CH:30]=[CH:29][N:28]=2)=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15]3)=[CH:10][CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][NH:14][CH2:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1ccnc(COc2ccc(Cl)cc2-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1ccc(OCc2ccccn2)c(-c2ccc3c(c2)CNCC3)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cooled solution of, 1,1-dimethylethyl 7-(5-chloro-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate, (0.28 g) in DCM (1 ml) was added TFA (1 ml) and this was stirred at room temperature overnight. The reaction mixture was dissolved in water and backwashed with ethyl acetate. The aqueous layer was neutralised with aqueous sodium bicarbonate and extracted with ethyl acetate. The organics were dried over sodium sulphate and concentrated in vacuo to yield the title compound, 0.12 g
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:3].[C:18](Cl)(=[O:22])[CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>>[C:18]([O:17][C@H:14]1[CH2:15][CH2:16][C@H:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=2)[CH2:12][CH2:13]1)(=[O:22])[CH2:19][CH2:20][CH3:21]
Reactant: CCCC(=O)Cl
Reactant: CN(C)Cc1ccc([C@H]2CC[C@H](O)CC2)cc1
Solvent: CCN(CC)CC
Product: CCCC(=O)O[C@H]1CC[C@H](c2ccc(CN(C)C)cc2)CC1

Procedure:
from trans-4-(4-dimethylaminomethylphenyl)-cyclohexanol and butyric acid chloride/triethylamine. Colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:18])[C:11]3[N:12]([C:14](I)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:18])[C:11]3[N:12]([C:14]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(-c2ccc(Cl)cc2)cn2c(I)cnc12
Product: Cc1cc(-c2ccc(Cl)cc2)cn2c(C#C[Si](C)(C)C)cnc12
Yield: 79.7 %

Procedure:
Prepared from 6-(4-chloro-phenyl)-3-iodo-8-methyl-imidazo[1,2-a]pyridine (example C.21 step 2) (3.686 g, 10 mmol) and trimethylsilylacetylene (2.8 mL, 20 mmol) as described in example C.20 step 4. Obtained the title compound as a yellow foam (2.70 g, 80%). MS (ISP) 339.1 [(M+H)+], 341 [(M+2+H)+].
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[N:19](S(C4C=CC(C)=CC=4)(=O)=O)[C:18]=3[CH:17]=[C:16]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH:15]=1)[CH2:5][CH2:6][O:7]2.[OH-].[Na+]>O1CCCC1.CO>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[NH:19][C:18]=3[CH:17]=[C:16]([C:34]([N:36]([CH3:37])[CH3:38])=[O:35])[CH:15]=1)[CH2:5][CH2:6][O:7]2
Reactant: Cc1ccc(S(=O)(=O)n2c(C)nc3c(OC4CCOc5cc(F)cc(F)c54)cc(C(=O)N(C)C)cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)N(C)C)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.9 %

Procedure:
To a solution of 4-[(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-N,N,2-trimethyl-1-[(4-methylphenyl)-sulfonyl]-1H-benzi midazole-6-carboxamide (280 mg, crude, STEP 8) in tetrahydrofuran (8 mL) and methanol (4 mL) was added sodium hydroxide (165 mg, 4.1 mmol) at room temperature. After stirring at room temperature for 1 hour, the mixture was quenched with saturated sodium dihydrogenphosphate aqueous solution, and extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and concentrated in vacuum. The residue was purified by column chromatography on silica gel (gradient elution from dichloromethane only to ethyl acetate:methanol 10:1) to afford the title compound as a white solid (74 mg, 65% for 2 steps).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[C:45]([CH2:47][O:48][CH:49]3[CH2:54][CH2:53][CH2:52][CH2:51][O:50]3)[N:44]=[C:43]([CH3:55])[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[C:45]([CH2:47][O:48][CH:49]3[CH2:54][CH2:53][CH2:52][CH2:51][O:50]3)[N:44]=[C:43]([CH3:55])[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(COC2CCCCO2)n1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cc(COC2CCCCO2)n1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (374 mg, 1.0 mmol) and (RS)-3-{3-[2-methyl-6-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-3-oxo-propionic acid tert-butyl ester (Example K64) (426 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (500 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH2:13])=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[B-](F)(F)(F)[F:15].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([F:15])[C:8]([NH2:13])=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc2ccnc(Cl)c2cc1Cl
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CN(C)C=O
Product: Nc1c(Cl)cc2c(Cl)nccc2c1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 35.2 %

Procedure:
To a solution of 2.62 g (12.3 mmol) of 1,7-dichloro-isoquinolin-6-ylamine in DMF (130 mL) was added 5.5 g (15.5 mmol) of Selectfluor® as a solid in one portion. The mixture was stirred at room temperature for 15 h. The mixture was poured over ice and stirred until all of the ice had melted during which time a solid precipitated from solution. The brown solid was collected by filtration, washed with water and dried on the filter pad to provide 1.0 g (60% by 1H-NMR, 21%) of 1,7-dichloro-5-fluoro-isoquinolin-6-ylamine. MS calc. for C9H5Cl2FN2 [M]+: 231.05. Found: 231.68.