Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:21]([Cl:22])=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([F:23])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N=C=NCCCN(C)C)C.[N:35]1([S:41]([NH2:44])(=[O:43])=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]12([CH2:11][O:12][C:13]3[C:21]([Cl:22])=[CH:20][C:16]([C:17]([NH:44][S:41]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)(=[O:43])=[O:42])=[O:18])=[C:15]([F:23])[CH:14]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: NS(=O)(=O)N1CCOCC1
Reactant: O=C(O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NS(=O)(=O)N1CCOCC1)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.5 %

Procedure:
To a mixture of 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoic acid (0.17 g, 0.50 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.22 g, 1.15 mmol) and 4-dimethylaminopyridine (0.14 g, 1.15 mmol) in anhydrous dichloromethane (10 mL) was added morpholine-4-sulfonamide (0.17 g, 1.0 mmol) at ambient temperature. The resulting mixture was stirred at ambient temperature for 16 h. The mixture was quenched with hydrochloride acid (1N, 30 mL) followed by extraction with ethyl acetate (100 mL). The organic layer was washed with water (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo, the residue was purified by silica gel column chromatography using 10-60% gradient ethyl acetate (containing 0.2% acetic acid) in hexanes to afford the title compound as an off-white solid (0.05 g, 20%): 1H NMR (300 MHz, DMSO-d6) δ 7.88 (s, 1H), 6.88 (s, 1H), 4.06 (d, J=6.8 Hz, 2H), 3.39 (s, 3H), 2.50-2.42 (m, 1H), 2.12-2.05 (m, 1H), 1.98-1.94 (m, 1H), 1.90-1.68 (m, 4H), 1.50-1.41 (m, 2H), 1.22 (s, 3H), 0.87 (s, 3H); MS (ES−) m/z 397.2, 399.2 (M−1); MS (ES+) m/z 399.1, 401.1 (M+1);
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@H:10]([C:25]([N:27]2[CH2:31][CH2:30][S:29][CH2:28]2)=[O:26])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:18]([O:17][C:15](=[O:16])[NH:14][C@H:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[C:25]([N:27]1[CH2:31][CH2:30][S:29][CH2:28]1)=[O:26])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](C(=O)N2CCSC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@H]1CCNC[C@H]1C(=O)N1CCSC1)OCc1ccccc1
Temperature: 25 °C
Yield: 102.9 %

Procedure:
(3R, 4S)-4-Benzyloxycarbonylamino-3-(thiazolidine-3-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester (325 mg) was dissolved in abs. DCM (12 ml) and TFA (0.44 ml) was added dropwise. The resulting mixture was then allowed to stir at RT over night and was then evaporated. The residue was transferred into ice/brine, basified to pH 10 with 2N NaOH and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and evaporated to give a residue that was purified by flash chromatography to give the desired product as a white foam (260 mg). MS (ESI): 350.1 MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][C:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>CN1C(=O)CCC1>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:2]2[CH:7]=[C:6]([N:8]3[CH:12]=[N:11][C:10]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[N:9]3)[CH:5]=[CH:4][N:3]=2)=[CH:24][CH:23]=1
Reactant: Clc1cc(-n2cnc(Nc3ccccc3)n2)ccn1
Reactant: COc1ccc(CN)cc1
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2cc(-n3cnc(Nc4ccccc4)n3)ccn2)cc1
Reaction time: 0.25 h

Procedure:
[1 g, 3.68 mMol] of [1-(2-Chloro-pyridin-4-yl)-1H-[1,2,4]triazol-3-yl]-phenyl-amine was dissolved in 14 mL of NMP with [2.4 mL, 2.52 g, 18.4 mMol] of p-methoxybenzylamine and heated 250 C. for 15 min (MW, 150 W). The solvent was removed in vacuo (Kugel-Rohr style) and the residue was treated with MTBE. The ether was decanted away from the dark residue and was replaced with fresh MTBE and mass broken up with vigorous stirring. The ether was again decanted away and replaced with methanol and vigorously stirred for 1 hour. The tan solid was isolated via suction filtration and washed sequentially with methanol and MTBE. The resulting powder was boiled in hot acetonitrile for several minutes, allowed to cool, isolated via suction filtration, and washed with more acetonitrile and finally MTBE. Yield: 0.5g (38.5%). 1H NMR 500 MHz (DMSO-d6) ∂ 3.7(s, 3H), 4.45(d, 2H), 6.85(m, 3H), 6.93(s, 1H), 6.98(d, 1H), 0.3(m, 5H), 7.64(d, 2H), 8.05(d, 1H), 9.1(s, 1H), 9.5(s ex, H). LC/MS [M+H+]=373.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)(=[O:14])C.Cl([O-])=O.[Na+]>>[O:14]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Product: CCOC(=O)C(=O)C(=O)OCC

Procedure:
A reaction was performed similarly to Example 1 using 0.25 g (0.0016 mole) diethyl malonate, 0.95 mL (0.0166 mole) acetic acid, 1.71 g (0.0047 mole) of 25% sodium chlorite aqueous solution, and GC analysis was performed to give 88.1% GC total area value of diethyl ketomalonate.
Reaction SMILES: C(O[C:4](OCC)(OCC)[CH2:5][CH3:6])C.Cl.N1C=CC=CC=1.[NH2:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([C:30]=1[NH:31][CH2:32][C:33]1([OH:39])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[CH:28][CH:27]=[CH:26][CH:25]=2>C1(C)C=CC=CC=1>[CH2:5]([C:6]1[N:31]([CH2:32][C:33]2([OH:39])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[C:30]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:23]=[CH:22][C:21]=2[N:20]=1)[CH3:4]
Reactant: CCOC(CC)(OCC)OCC
Reactant: Nc1cnc2ccccc2c1NCC1(O)CCOCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCc1nc2cnc3ccccc3c2n1CC1(O)CCOCC1

Procedure:
Triethylorthopropionate (2.4 mL, 12.0 mmol) and pyridine hydrochloride (60 mg, 0.5 mmol) were added to a suspension of 4-[(3-aminoquinolin-4-ylamino)methyl]tetrahydropyran-4-ol (10.0 mmol) in toluene (50 mL). The reaction mixture was heated at reflux for 2.5 hours and then concentrated under reduced pressure. The residue was triturated with acetonitrile and the filtered to provide 4-[(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-ol as a tan solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:15]([C:17]4[C:25]5[C:20](=[CH:21][C:22]([C:26]6[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=6)=[CH:23][CH:24]=5)[N:19]([CH2:33][CH2:34][NH:35]C(OC(C)(C)C)=O)[CH:18]=4)=[O:16])=[C:10]3[CH2:9][S:8]2)[CH:2]=1.[ClH:43].O1CCOCC1>C(Cl)Cl>[ClH:43].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:15]([C:17]4[C:25]5[C:20](=[CH:21][C:22]([C:26]6[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=6)=[CH:23][CH:24]=5)[N:19]([CH2:33][CH2:34][NH2:35])[CH:18]=4)=[O:16])=[C:10]3[CH2:9][S:8]2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)NCCn1cc(C(=O)c2ccn3c2CSC3c2cccnc2)c2ccc(-c3ccc(F)cc3)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCCn1cc(C(=O)c2ccn3c2CSC3c2cccnc2)c2ccc(-c3ccc(F)cc3)cc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-(pyridin-3-yl)-7-[1-(2-tert-butoxycarbonylaminoethyl)-6-(4-fluorophenyl)indol-3-ylcarbonyl]-1H,3H-pyrrolo[1,2-c]thiazole (104 mg), prepared as in Example 57, in CH2Cl2 at 0° C. was treated with 4N HCl/dioxane (1 mL). The reaction mixture was stirred for 15 min at 0° C. and then concentrated in vacuo. The resulting solid was azeotroped three times with CH2Cl2 to give 3-(Pyridin-3-yl)-7-[1-(2-aminoethyl)-6-(4-fluorophenyl)indol-3-ylcarbonyl]-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (115 mg), 1H NMR (D3COD, 300 MHz) δ3.48-3.60 (m, 3H), 3.64-3.75 (m, 4H), 4.53 (d, 1H, J=15 Hz) 4.68-4.77 (m, 3H), 6.76 (d, 1H, J=3 Hz), 6.9 (d, 1H, J=1.5 Hz), 7.55 (dd, 1H, J=1.5 9 Hz), 7.75 (dd, 2H, J=6, 8 Hz), 7.83 (s, 1H), 8.13 (dd, 1H, J=6, 8 Hz), 8.30 (s, 1H), 8.35 (d, 1H, J=9 Hz), 8.49 (d, 1H, J=9 Hz), 8.87 (d, 2H, J=7 Hz), MS (DCI/NH3) m/e 483 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:34])[CH2:15][CH:16]([C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[CH:24][C:23]=1[O:32][CH3:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:4])([CH3:3])[CH3:2].[C:35](OC(=O)C)(=[O:37])[CH3:36]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:35](=[O:37])[CH3:36])=[CH:7][C:6]=1[NH:13][C:14](=[O:34])[CH2:15][CH:16]([C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[CH:24][C:23]=1[O:32][CH3:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(CN)ccc1C(C)(C)C)c1cc(OC)c(OC)cc1OC
Reactant: CC(=O)OC(C)=O
Product: CCCCCC(CC(=O)Nc1cc(CNC(C)=O)ccc1C(C)(C)C)c1cc(OC)c(OC)cc1OC

Procedure:
Following a similar procedure to that described in Example 144, but using N-(2-t-butyl-5-aminomethylphenyl)-3-(2,4,5-trimethoxyphenyl)octanamide prepared as described in Preparation 72B) and acetic anhydride, the title compound was obtained as a colorless foam-like substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([C@@H:28]3[CH2:32][CH2:31][CH2:30][C@H:29]3[C:33]([O:35]CCCC)=[O:34])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([C@@H:28]3[CH2:32][CH2:31][CH2:30][C@H:29]3[C:33]([OH:35])=[O:34])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: CCCCOC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(OC)cc4s3)c(F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2nc(Nc3ccc(-c4ccc(C(=O)[C@@H]5CCC[C@H]5C(=O)O)cc4)cc3F)sc2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a solution of butyl (1R,2R)-2-({3′-fluoro-4′-[(6-methoxy-1,3-benzothiazol-2-yl)-amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylate in methanol (8 mL) was added 1 N aqueous sodium hydroxide (6.15 mL), and the mixture was stirred at 50° C. overnight. The solvent was then removed by rotary evaporation. Water (5 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The aqueous layer was then treated with 1 N aqueous HCl to adjust the acidity to pH 2, and then extracted with ethyl acetate. The organic phase was evaporated under reduced pressure, and the residue was purified by flash chromatography (Biotage Flash 40S, 6:1 EtOAc/hexane) to afford (1R,2R)-2-({3′-fluoro-4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid (129 mg, 30%, 89% ee). LC-MS ret. time 3.56 min, m/z 491.3 (MH+); 1H NMR (300 MHz, DMSO-d6) δ 1.58-1.84 (m, 4H), 1.96-2.01 (m, 1H), 2.14-2.17 (m, 1H). 3.22 (q, 1H), 3.77 (s, 3H), 4.02-4.10 (q, 1H), 6.94 (dd, 1H), 7.46 (d, 1H), 7.53 (d, 1H), 7.65-7.76 (m, 2H), 7.86 (d, 2H), 8.04 (d, 2H), 8.72 (t, 1H), 10.33 (br s, 1H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[F:26][C:27]1[CH:35]=[C:34]2[C:30]([C:31]([Sn](CCCC)(CCCC)CCCC)=[N:32][N:33]2[CH3:36])=[CH:29][CH:28]=1>CN(C=O)C.[Cu]I.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:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:31]3[C:30]4[C:34](=[CH:35][C:27]([F:26])=[CH:28][CH:29]=4)[N:33]([CH3:36])[N:32]=3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(F)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Temperature: 90 °C
Yield: 5.4 %

Procedure:
2-Bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (80 mg, 0.187 mmol) and 6-fluoro-1-methyl-3-(tributylstannyl)-1H-indazole (0.1 g, 0.228 mmol) were dissolved in DMF (3 mL). The reaction mixture was evacuated and filled with nitrogen. Copper(I) iodide (6.71 mg, 0.0749 mmol) and tetrakis(triphenylphosphine)palladium (0) (10.8 mg, 0.00936 mmol) were added. The reaction mixture was heated at 90° C. for 2 h. The mixture was cooled and partitioned between ethyl acetate and water, the organic phase washed with brine, then dried over magnesium sulfate. The crude compound was purified by chromatography using 25% ethyl acetate/hexanes to obtain 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (5 mg, 38%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([NH:15][CH:16]1[CH2:22][S:21][CH:20]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)[CH2:19][N:18]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[C:17]1=[O:36])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4]([CH:6]([NH:15][CH:16]1[CH2:22][S:21][CH:20]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)[CH2:19][N:18]([CH2:28][C:29]([OH:31])=[O:30])[C:17]1=[O:36])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccco2)CN(CC(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccco2)CN(CC(=O)O)C1=O

Procedure:
Following the procedure described in Example 43, 270 mg of isomer B of t-butyl α-[6-(1-ethoxycarbonyl-3-phenylpropylamino)-2-(2-furyl)-5-oxoperhydro-1,4-thiazepin-4-yl]acetate [prepared as described in Example 56(g)] were de-t-butylated using trifluoroacetic acid, to afford 180 mg of the title compound as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:8][C:7](=[O:9])[CH:6]([C:5]1[CH:11]=[CH:12][C:2]([Cl:1])=[CH:3][CH:4]=1)[OH:10]
Reactant: O=C(O)C(O)c1ccc(Cl)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(O)c1ccc(Cl)cc1

Procedure:
To a stirred solution of 4-chloromandelic acid (10.7 g, 57.3 mmol) in methanol was added sulfuric acid (3.3 mL, 63.1 mmol). The reaction mixture was refluxed for 6 hours. The reaction mixture was concentrated, neutralized with sat. sodium carbonate solution, extracted with ether, washed with brine, dried, and concentrated. Purification by silica gel chromatography (40% ethyl acetate in hexanes) yielded 10.3 g of (4-chlorophenyl)hydroxyacetic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1[Cl:14].S(Cl)(Cl)=O.[CH3:19]O>>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]([O:13][CH3:19])=[O:12])[C:3]=1[Cl:14]
Reactant: Nc1nc(C2CC2)nc(C(=O)O)c1Cl
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1nc(C2CC2)nc(N)c1Cl
Temperature: 60 °C

Procedure:
To a solution of 6-amino-5-chloro-2-cyclopropyl-4-pyrimidinecarboxylic acid (i.e. the product of Step D1 or D2 of Example 2) (8.5 g, 40 mmol) in methanol (120 mL) was added dropwise with cooling thionyl chloride (15 mL, 200 mmol). The mixture was heated at 60° C. for 24 h. The mixture was concentrated to 25% of the original volume and diluted with water (100 mL). Phenolphthalein pH indicator was added, and 10% aqueous sodium hydroxide was added dropwise with cooling at 10-20° C. to bring the pH to 8-10. The solid was isolated by filtration, washed with water and dried in a vacuum oven at 50-60° C. to afford the title product (7.3 g), a compound of the present invention.
Reaction SMILES: [N:1]1([C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[CH:20](N(C)C)[N:21]([CH3:23])[CH3:22])(C)(C)C>>[CH3:20][N:21]([CH3:23])[CH:22]=[C:10]1[CH2:11][CH2:12][CH2:13][CH:8]([C:6]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:7])[C:9]1=[O:14]
Reactant: O=C1CCCCC1C(=O)N1CCCC1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=C1CCCC(C(=O)N2CCCC2)C1=O

Procedure:
2-(Pyrrolidine-1-carbonyl)-cyclohexanone (56 mg, 0.29 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (58 mg) as a yellow oil which was used directly in the next step. MS ISP (m/e): 251.3 (100) [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:12]=[CH:13][CH:14]=2)=[C:4]([N+:19]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[NH2:19][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[S:8][C:9]1[CH:10]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)Nc1cccc(Sc2ccc(C)cc2[N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Product: CC(=O)Nc1cccc(Sc2ccc(C)cc2N)c1
Yield: 20 %

Procedure:
The product from Example 71b was reduced with SnCl2 following the procedure from Example 1f providing the title compound (120 mg, 20%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][CH:4]=1.[C:15](Cl)(=[O:18])[CH2:16][CH3:17].[Cl-].[Al+3].[Cl-].[Cl-].O>ClC(Cl)C>[CH3:14][O:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:15](=[O:18])[CH2:16][CH3:17]
Reactant: COc1ccc(OC)c2ccccc12
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O
Product: CCC(=O)c1cc(OC)c2ccccc2c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.5 %

Procedure:
To a cold solution (ice bath) of 1,4-dimethoxy-naphthalene (5 g, 26.6 mmol) in dichloroethane (100 mL) was added propionyl chloride (2.7 g, 29.3 mmol) followed by aluminum chloride (3.9 g, 29.3 mmol). After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 4 hr. Water (200 mL) was added and the organic material was extracted with dichloromethane (200 mL). The organic extracts were dried (MgSO4) and concentrated to give a residue which was purified by flash chromatography (silica gel, ethyl acetate/hexane: 1/9) to give an oil (1.4 g): 1H NMR (DMSO-d6) δ 1.16 (t, 3H, CH3), 3.13 (q, 2H, CH2), 3.87 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 7.02 (s, 1H, Ar—H), 7.67 (m, 2H, Ar—H), 8.10 (d, 2H, Ar—H); MS 245 (M+1).
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[C:9]1([CH3:16])[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CN=C1.O>CN(C=O)C>[CH3:1][C:2]([Si:5]([CH3:7])([CH3:6])[O:15][C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:16])([CH3:4])[CH3:3]
Reactant: Cc1ccccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Add TBDMSCl (4.6 g, 30.5 mmol) to a solution of o-cresol (3 g, 28 mmol) and imidazole (2.08 g, 30.5 mmol) in 25 ml of dry DMF and stir at room temperature. After 7 h, pour the reaction into H2O and extract with hexane twice. Combine the organic layers, wash with H2O, dry over Na2SO4, filter and concentrate under reduced pressure to give a residue. Purify the residue by column chromatography on silica gel eluting with hexane to afford pure (1,1-dimethylethyl)dimethyl(2-methylphenoxy)silane as colourless oil. Add AIBN (330 mg, 1.98 mmol) to a solution of NBS (3.87 g, 21.76 mmol) and (1,1-dimethylethyl)dimethyl(2-methylphenoxy)silane (4.4 g, 19.78 mmol) in 100 ml of CCl4 and stir at reflux for 6 h. Concentrate the solvent under reduced pressure, add hexane and filter the solid. Wash the hexane with a saturated aqueous solution of NaHCO3 and H2O. Dry the organic phase over Na2SO4, filter and concentrate under reduced pressure to obtain [2-(bromomethyl)phenoxy](1,1-dimethylethyl)dimethylsilane as colourless oil.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])=[N:5][CH:4]=1)=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[N:5][CH:4]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)CNc1ncc(C=O)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=Cc1cnc(NCC(=O)O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 181.2 %

Procedure:
To a magnetically stirred solution of material from Example 2 (2.19 g, 9.04 mmol) in CH2Cl2 (50 mL) is added TFA (25 mL, 324 mmol). The resulting solution is allowed to stir at room temperature for 8 h and then evaporated to dryness under a gentle stream of N2 over 18 h. The resulting tan residue is dissolved in CH2Cl2, sonicated briefly and the solvent is removed in vacuo to give 3.05 g (96%) the title compound as a tan solid as a •1.3 TFA salt by weight. LC/MS (Condition A): ret. T=0.82 min, (M+H)+ 187.00. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.67 (1 H, s), 9.11 (1 H, br. s.), 8.05 (1 H, s), 4.12 (2 H, d, J=5.19 Hz).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[N:8]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1.[NH2:21][C:22]1[N:27]=[CH:26][C:25]([N:28]2[C:32](=[O:33])[CH2:31][C:30]3([CH2:39][CH:38]4[N:40]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:35]([CH2:36][CH2:37]4)[CH2:34]3)[CH2:29]2)=[CH:24][CH:23]=1>>[CH:16]1([N:8]2[C:6]3[N:7]=[C:2]([NH:21][C:22]4[N:27]=[CH:26][C:25]([N:28]5[C:32](=[O:33])[CH2:31][C:30]6([CH2:34][CH:35]7[N:40]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:38]([CH2:37][CH2:36]7)[CH2:39]6)[CH2:29]5)=[CH:24][CH:23]=4)[N:3]=[CH:4][C:5]=3[CH:10]=[C:9]2[C:11](=[O:12])[N:13]([CH3:15])[CH3:14])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC1(CC(=O)N(c3ccc(N)nc3)C1)C2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC5(CC4=O)CC4CCC(C5)N4C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1
Yield: 72.3 %

Procedure:
Following general N—C coupling procedure 1, 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (162 mg, 0.55 mmole) was combined with tert-Butyl 1′-(6-aminopyridin-3-yl)-5′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,3′-pyrrolidine]-8-carboxylate (150 mg, 0.55 mmole) which gave tert-butyl 1′-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-5′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,3′-pyrrolidine]-8-carboxylate (250 mg) in 86% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.76 (s, 1H), 8.56-8.49 (m, 1H), 8.41 (s, 1H), 8.08-7.99 (m, 2H), 6.49 (s, 1H), 4.88-4.77 (m, 1H), 4.31 (s, 2H), 3.62-3.49 (m, 2H), 3.14 (s, 6H), 2.82 (s, 2H), 2.65-2.51 (m, 2H), 2.16-1.53 (m, 14H), 1.49 (s, 9H)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)=[CH:4][CH:3]=1.[Mg].[CH3:17][CH:18]([CH3:36])[CH2:19][CH2:20][Si@H:21]1[CH2:26][CH2:25][C@H:24]([CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH:32](Br)[CH2:31][CH2:30]2)[CH2:23][CH2:22]1>[Cu]Cl.C1COCC1>[CH3:17][CH:18]([CH3:36])[CH2:19][CH2:20][Si@H:21]1[CH2:22][CH2:23][C@H:24]([CH2:27][CH2:28][C@H:29]2[CH2:30][CH2:31][C@H:32]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=4)=[CH:4][CH:3]=3)[CH2:33][CH2:34]2)[CH2:25][CH2:26]1
Reactant: CC(C)CC[Si@H]1CC[C@H](CCC2CCC(Br)CC2)CC1
Reactant: Fc1ccc(-c2ccc(Br)cc2)cc1F
Agent: Cl[Cu]
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)CC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(F)c(F)c4)cc3)CC2)CC1

Procedure:
26.9 g (0.1 mol) of 4-bromo-3',4'-difluorobiphenyl was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of copper (I) chloride and 85.9 g (0.1 mol) of 4-(2-(trans-4-(3-methylbutyl)-4-silacyclohexyl)ethyl)cyclohexyl bromide. After a conventional after treatment, 4-(trans-4-(2-(trans-4-(3-methylbutyl)-4-silacyclohexyl)ethyl)cyclohexyl)-3',4'-difluorobiphenyl was obtained. The silacyclohexane rings of the product were a mixture of trans isomers and cis isomers. They were separated by means of chromatography to obtain 34.2 g (yield 73.0%) of the trans isomer.