Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:24][C:25]1[CH:26]=[C:27]([C:31]2[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=2)[CH:28]=[N:29][CH:30]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=2)[CH2:24][C:25]2[CH:26]=[C:27]([C:31]3[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=3)[CH:28]=[N:29][CH:30]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)c(F)c2)CC1
Product: COc1cc(-c2cncc(CN(c3ccc(F)c(F)c3)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[(3,4-difluorophenyl)amino]piperidine (625 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][C:11]([C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1)=[O:12].[H-].[Na+].CI.[C:25](OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]([CH3:25])[C:11]([C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1)=[O:12]
Reactant: CCOC(C)=O
Reactant: COc1ccc(Cl)c(CC(=O)c2ccc(=O)n(C)c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc(Cl)c(C(C)C(=O)c2ccc(=O)n(C)c2)c1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-[2-(2-chloro-5-methoxy-phenyl)-acetyl]-1-methyl-1H-pyridin-2-one (9.35 g) in tetrahydrofuran (110 ml) was added sodium hydride (60% dispersion in mineral oil, 1.35 g) in three portions. The mixture was stirred at 40° C. for 1 h and then placed in an ice bath. Methyl iodide (5.01 g) was added dropwise. The mixture was stirred at 0° C. for 10 min and at room temperature for 2 h. Ethyl acetate was added and the mixture was washed with water and brine. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The residue was washed with cyclohexane, filtered and dried to give the title compound as an off-white solid (9.45 g). MS (m/e)=306.2 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]=[C:9]=[O:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.O>[F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]2[O:7][CH2:13][C:9](=[O:10])[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C=NC(=O)c1ccc(F)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: O
Solvent: ClCCl
Product: O=C1COC(c2ccc(F)cc2)=N1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 67.4 %

Procedure:
To a solution of 4-fluorobenzoyl isocyanate (1.2 g, 7.2 mmol) in DCM (25 mL) was added (trimethylsilyl)diazomethane (2.0 M in hexane, 4.3 mL, 8.6 mmol) at 0° C. The reaction mixture was stirred for 45 min at rt. The mixture was diluted with water and the separated aqueous phase was extracted with DCM (3×). The combined organic layers were dried over (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 100:0-80:20 DCM-methanol) to afford 870 mg of 2-(4-fluorophenyl)oxazol-4(5H)-one: LCMS (m/z): 180.0 (MH+), tR=0.39 min
Reaction SMILES: [CH3:1][S:2]([N:5]1[C@H:9]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=2[F:21])[CH2:8][C@@H:7]([SH:22])[CH2:6]1)(=[O:4])=[O:3].[NH:23]([C:40]([CH3:42])=[O:41])[C@H:24]([C:37]([OH:39])=[O:38])[CH2:25][S:26]SC1N=CC=CC=1[N+]([O-])=O>>[C:40]([NH:23][C@@H:24]([CH2:25][S:26][S:22][C@@H:7]1[CH2:8][C@@H:9]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=2[F:21])[N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6]1)[C:37]([OH:39])=[O:38])(=[O:41])[CH3:42]
Reactant: CS(=O)(=O)N1C[C@H](S)C[C@H]1COCc1cc(F)c(F)cc1F
Reactant: CC(=O)N[C@@H](CSSc1ncccc1[N+](=O)[O-])C(=O)O
Product: CC(=O)N[C@@H](CSS[C@@H]1C[C@@H](COCc2cc(F)c(F)cc2F)N(S(C)(=O)=O)C1)C(=O)O
Reaction time: 2 h
Yield: 93.3 %

Procedure:
(3R,5S)-1-Methanesulfonyl-5-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-3-thiol (100 mg, 0.28 mmol) and Ac-Cys(Npys)-OH (89 mg, 0.28 mmol) were dissolved in argon-degassed DMF (abs. 2 ml) and degassed 0.1 M phosphate buffer (pH 6.2, 2 ml) was added. The reaction mixture was magnetically stirred for 2 h under argon. Work-up as above (Example 22a) yielded (R)-2-acetylamino-3-[(3R,5S)-1-methanesulfonyl-5-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidin-3-yldisulfanyl]-propionic acid (135 mg), MS: 515 (MH−).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1>C1(C)C(C)=CC=CC=1>[OH:15][C:11]1[CH:10]=[C:9]([NH:8][C:4](=[O:5])/[CH:3]=[CH:2]\[C:1]([OH:6])=[O:7])[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cccc(O)c1
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1C
Product: O=C(O)/C=C\C(=O)Nc1cccc(O)c1
Temperature: 50 °C

Procedure:
A dry 3-liter 3-neck round bottom flask was fitted with a stirrer and thermocouple arrangement. The system was flushed with nitrogen and charged with 211 grams (2.15 moles) of maleic anhydride dissolved in 800 ml of xylene. The maleic anhydride was heated with stirring at 50° C. to form a solution. 3-aminophenol (220 g, 2.02 moles) was then slowly added neat to the solution with vigorous stirring over a period of about 5 minutes. The flask was again flushed with nitrogen and sealed under a nitrogen balloon. The flask was held at 50°-55° C. with vigorous stirring for 4 hours. At the end of 4 hours, the stirring was continued and the flask and contents were cooled with tap water/wet ice to 10° C. The bright yellow-colored slurry was readily poured out of the neck of the flask and vacuum filtered through a No. 4 filter paper to give a wet filter cake. The product was dried at a temperature below 50° C. in a draft hood. The yellow product was a powder melting at 115° C. Specific gravity was 1.210.
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:26][C:27]1[CH:44]=[CH:43][C:42]([C@H:45]2[C@H:50]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C@@H:49]([O:59][CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[C@H:48]([O:67][CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C@@H:47]([CH2:75][O:76][CH2:77][C:78]3[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=3)[O:46]2)=[CH:41][C:28]=1[CH2:29][C:30]1[CH:40]=[CH:39][C:33]([CH2:34][NH:35][CH:36]2[CH2:38][CH2:37]2)=[CH:32][CH:31]=1>C(Cl)Cl.CCN(CC)CC>[Cl:26][C:27]1[CH:44]=[CH:43][C:42]([C@H:45]2[C@H:50]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C@@H:49]([O:59][CH2:60][C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)[C@H:48]([O:67][CH2:68][C:69]3[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=3)[C@@H:47]([CH2:75][O:76][CH2:77][C:78]3[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=3)[O:46]2)=[CH:41][C:28]=1[CH2:29][C:30]1[CH:40]=[CH:39][C:33]([CH2:34][N:35]([CH:36]2[CH2:37][CH2:38]2)[C:1](=[O:3])[CH3:2])=[CH:32][CH:31]=1
Reactant: CC(=O)O
Reactant: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(CNC2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(Cc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of acetic acid (0.11 g) and Et3N (0.14 mL) in CH2Cl2 (1 mL) at room temperature, EDCI (96 mg) and HOBt (68 mg) was added. The mixture was stirred for 30 min at room temperature. A solution of N-(4-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)benzyl)cyclopropanamine (Intermediate AQ) (40 mg) in CH2Cl2 (0.2 mL) was added dropwise. The reaction was monitored by LC-MS. After the starting material was consumed, CH2Cl2 was added to dilute the solution. The resulting mixture was then washed with H2O, 1N HCl, aqueous NaHCO3 and brine. CH2Cl2 was removed under reduced pressure, and the crude product was purified by preparative TLC to give intermediate AR (20 mg). MS ESI (m/z): 836 (M+H)+, 853 (M+NH4)+.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9](OCC)=[O:10])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[CH2:9][OH:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cccc(OC(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)Oc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 3-tert-butyloxybenzoate (16.7 g, 80 mmol) in tetrahydrofuran (100 ml) was added lithium aluminum hydride (4.55 g, 120 mmol) by small portions under ice-cooling. The mixture was stirred at room temperature for 1 hr. and water (10 ml) was added under ice-cooling to allow decomposition. Insoluble material was filtered off and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1-2:1) to give the objective substance (12.8 g, 88%) as an oil.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:13]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[CH:12][NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1>CN(C=O)C>[C:3]1([C:9]2[C:13]([N:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]3)=[CH:12][N:11]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[N:10]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c[nH]nc2-c2ccccc2)CC1
Reactant: ClCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cn(Cc3ccccn3)nc2-c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To sodium hydride (0.1 g) taken in a dry 100 ml 3-necked round bottom flask cooled to 0° C. dry DMF (2 ml) was added under nitrogen. To the above mixture compound tert-butyl 4-(3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate (0.5 g) in DMF (2 ml) was slowly added and allowed to stir at 0° C. for 30 minutes. 2-Chloromethyl pyridine (300 mg) in DMF (1 ml) was slowly added to the above mixture at 0° C. The reaction mixture was allowed to stir at room temperature for overnight and quenched with ice. The product was extracted with ethyl acetate (3×10 ml). The combined organic layer was washed with water, brine, dried over sodiumsulphate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography using 6% ethyl acetate in hexane, to afford tert-butyl 4-(3-phenyl-1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)piperazine-1-carboxylate as half white solid.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:7]([O:11][CH3:12])(=[O:10])[CH:8]=[O:9]>>[OH:9][CH:8]([CH2:1][CH:2]=[CH:3][CH2:4][CH2:5][CH3:6])[C:7]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C=O
Reactant: C=CCCCC
Product: CCCC=CCC(O)C(=O)OC

Procedure:
The synthesis of this acid is in accordance with the following scheme, in which 1-hexene (22) is the alkene starting material which is reacted with methyl glyoxalate to form methyl 2-hydroxy-4-octenoate (23) and then hydrolysed to form the free acid (21): ##STR13##
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.C(Cl)(Cl)Cl.[Br:18]N1C(=O)CCC1=O>O>[Br:18][C:8]1[C:3]([NH:2][CH3:1])=[N:4][CH:5]=[C:6]([S:9][C:10]([F:11])([F:13])[F:12])[CH:7]=1
Reactant: CNc1ccc(SC(F)(F)F)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: CNc1ncc(SC(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a mixture of methyl-(5-trifluoromethylsulfanylpyridine-2-yl)-amine (1.52 g) and chloroform (24 mL), N-bromosuccinimide (1.43 g) was added, and stirred at room temperature for 1 hour. Into the reaction mixture, water was poured, and extracted with chloroform. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 1.96 g of (3-bromo-5-trifluoromethylsulfanylpyridine-2-yl)-methylamine.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.Cl.[C:24]([C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][NH:29][CH2:30]2)#[N:25]>>[C:24]([C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][N:29]([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]1)[CH2:30]2)#[N:25]
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Reactant: N#Cc1cccc2c1CNC2
Agent: Cl
Product: N#Cc1cccc2c1CN(CCn1cnc(-c3cc(C(=O)O)ccn3)c1)C2
Yield: 11 %

Procedure:
The title compound was prepared in 11% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 4-cyanoisoindoline hydrogen chloride according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 3.13 (2H, t, J=6.0 Hz), 4.03 (2H, s), 4.13 (2H, s), 4.23 (2H, t, J=4.5 Hz), 7.41 (1H, d, J=7.6 Hz), 7.55 (2H, m), 7.66 (1H, d, J=5.7 Hz), 7.80 (1H, s), 7.87 (1H, s), 8.26 (1H, s), 8.57 (1H, d, J=4.9 Hz). [M+H] Calc'd for C20H17N5O2, 360. Found, 360.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[CH:18]=1)#[N:2].ClC1C=CC=C(C(OO)=[O:27])C=1.[OH-].[Ca+2].[OH-]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:9]=3[S:8](=[O:27])[C:7]=2[CH:18]=1)#[N:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#Cc1ccc2c(c1)Sc1ccc(F)cc1C=C2
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)S(=O)c1ccc(F)cc1C=C2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Dissolve 1.7 gm. of 3-cyano-8-fluorodibenzo[b,f]thiepine in 90 ml. of methylene chloride and add 1.36 gm. of 85% m-chloroperbenzoic acid. Stir the mixture at room temperature for 90 minutes. Add 4 gm. of calcium hydroxide over 15 minutes. Filter and strip the filtrate to dryness. Triturate the residue in 30 ml. of ether for 2 hours. Separate the solids by filtration to obtain the title product. (mp. 240°-243° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.[CH2:26]([O:28][C:29](=[O:40])[CH:30]([CH2:36][CH2:37][CH2:38]Cl)[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:27].C(N(CC)CC)C>CN1C(=O)CCC1>[CH2:26]([O:28][C:29](=[O:40])[CH:30]([CH2:36][CH2:37][CH2:38][N:22]1[CH2:21][CH2:20][N:19]([C:16]2[S:17][CH:18]=[C:14]([C:6]3[CH:5]=[CH:4][C:3]4[C:2]([CH3:25])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=4[CH:7]=3)[N:15]=2)[CH2:24][CH2:23]1)[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:27]
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCNCC4)n3)ccc21
Reactant: CCOC(=O)C(CCCCl)C(=O)OCC
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CCCN1CCN(c2nc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cs2)CC1)C(=O)OCC
Temperature: 100 °C
Reaction time: 8 h

Procedure:
200 mg (0.53 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperazine were dissolved in 5 ml of NMP, 235 μl (1.06 mmol) of 2-(3-chloropropyl)malonic acid diethyl ester and 220 μl (1.59 mmol) of triethylamine were added, and the mixture was stirred at 100° C. overnight. The reaction mixture was evaporated to dryness and purified by means of preparative HPLC. The product is in the form of the TFA salt.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=3)[C:10]([C:18]([OH:21])([CH3:20])[CH3:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([OH:32])([C:30]#[CH:31])[CH3:29]>N1CCCCC1.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.[Cu]I>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:31]#[C:30][C:28]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)([OH:32])[CH3:29])[CH:15]=3)[C:10]([C:18]([OH:21])([CH3:20])[CH3:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: C#CC(C)(O)c1ccccn1
Reactant: CC(C)(O)c1nn(-c2ccnc(N)n2)c2cc(I)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CC(C)(O)c1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3ccccn3)ccc12
Temperature: 35 °C

Procedure:
To a solution of 2-[1-(2-aminopyrimidin-4-yl)-6-iodo-1H-indazol-3-yl]propan-2-ol (150 mg, 0.36 mmol) in piperidine (2 mL) was introduced tetrakis(triphenylphosphine)palladium (0) (16.8 mg, 0.02 mmol), copper(I) iodide (2.8 mg, 0.02 mmol) and 2-(pyridin-2-yl)but-3-yn-2-ol (112 mg, 0.73 mmol). The reaction was warmed to 35° C. for 1 hr. After cooling to RT, the reaction mixture was concentrated in vacuo and the residue purified by flash chromatography (Biotage, DCM containing a 1-10% MeOH gradient) to furnish the title compound as a brown oil: 1H NMR (500 MHz, CDCl3) delta 1.78 (6H, s), 1.94 (3H, s), 2.84 (1H, br. s.), 5.18 (2H, br. s.), 5.80 (1H, br. s.), 7.19-7.39 (1H, m), 7.74 (1H, d, J=7.88 Hz), 7.82 (1H, td, J=7.72, 1.58 Hz), 7.90 (1H, d, J=8.35 Hz), 8.29 (1H, d, J=5.36 Hz), 8.58 (1H, d, J=4.73 Hz), 8.89 (1 H, s); LCMS: m/z=+415.05 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1([CH2:16][O:17]S(C)(=O)=O)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[H-].[Na+].O>O1CCCC1>[CH2:2]1[C:3]2([CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:7][CH2:8]2)[CH2:16][O:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(COS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)COC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 71 %

Procedure:
A solution of 1,1-dimethylethyl 4-hydroxymethyl-4-methanesulfonyloxymethyl-1-piperidinecarboxylate (Description 68, 3 g, 9.3 mmol) in tetrahydrofuran (200 mL) was added dropwise to a stirred suspension of sodium hydride (60% dispersion in mineral oil, 2.2 g, 55.8 mmol) in tetrahydrofuran (50 mL) and the mixture was stirred at room temperature for 72 hours. Water (5 mL) was added and the mixture was extracted with ethyl acetate (3×400 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (80:20 increasing to 50:50), to give the title compound (1.5 g, 71%). m/z (ES+) 228 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH2:26]([O:28][C:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[F:37])=[O:30])[CH3:27]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH2:26]([O:28][C:29](=[O:30])[C:31]1[CH:32]=[C:33]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:25])[C:10]([C:16]3[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=3)([OH:15])[C:11]([F:13])([F:14])[F:12])=[C:2]([Cl:1])[CH:7]=2)[CH:34]=[CH:35][C:36]=1[F:37])[CH3:27]
Reactant: CCOC(=O)c1cc(B(O)O)ccc1F
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn(C)c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(Oc2ccc(C(C)C(O)(c3cc(C)c(=O)n(C)c3)C(F)(F)F)c(Cl)c2)ccc1F

Procedure:
In analogy to Example 151, step 8, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1H-pyridin-2-one (Example 203, step 5) was reacted with 3-ethoxycarbonyl-4-fluorophenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless solid. MS (m/e)=542.2 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[NH:16][C:17](=O)[CH:18]([CH3:35])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])=[CH:22][CH:21]=1>C(O)C.[OH-].[K+].O>[CH2:12]([N:5]1[C:4](=[O:15])[C:3]2[N:16]=[C:17]([CH:18]([CH3:35])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][CH:21]=3)[NH:1][C:2]=2[N:7]([CH2:8][CH2:9][CH3:10])[C:6]1=[O:11])[CH2:13][CH3:14]
Reactant: CCCn1c(N)c(NC(=O)C(C)Cc2ccc(OCC(=O)OC(C)(C)C)cc2)c(=O)n(CCC)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCn1c(=O)c2nc(C(C)Cc3ccc(OCC(=O)O)cc3)[nH]c2n(CCC)c1=O
Temperature: 55 °C
Reaction time: 5 h
Yield: 40.1 %

Procedure:
Dissolve 2-[[4-[3-[(6-amino-1-propyl-1,2,3,4-tetrahydro-3-propyl-2,4-dioxo-5-pyrimidinyl)amino]-2-methyl-3-oxopropyl]phenyl]oxy]-acetic acid, 1,1-dimethylethyl ester (1.6 g, 3.18 mmol) in a mixture of ethanol (30 mL) and 15% potassium hydroxide (30 mL). Heat at 55° C. and stir for 5 hours. Cool, acidify and dilute with water (200 mL). Filter to give 0.69 g crude product. Recrystallize (5% isopropanol/hexane) to give the title compound (0.546 g); mp 168-70° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:25][OH:26]>CO.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[N:25][OH:26])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(C=O)cc2)CC1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(C=NO)cc2)CC1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
A mixture of 4-(N-t-butyloxycarbonylpiperidin-4-ylmethoxy)benzaldehyde (3.16 g, 9.89 mmol) and hydroxylamine hydrochloride (1.27 g, 18.3 mmol) in 9:1 MeOH/pyridine (30 mL) was heated at reflux for 18 hours. The mixture was cooled to room temperature and concentrated to dryness. The residue was dissolved in EtOAc and washed with 0.1M HCl (3×), water, sat. CuSO4 (2×), water, sat. NaCl, dried (MgSO4) and concentrated, giving 3.19 g (96%) of the oxime; mp: 140.1°-141.8° C.; 1H NMR (300 MHz, CDCl3) δ 8.07 (s, 1H), 7.48 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 4.14 (bs, 2H), 3.80 (d, J=6.2 Hz, 2H), 2.71 (bt, J=12.4 Hz, 2H), 1.95 (m, 1H), 1.80 (bd, J=12.4 Hz, 2H), 1.45 (s, 9H), 1.26 (m, 2H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:9]1[C:13]2=[C:14]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:15]=[C:16]([C:18]#[N:19])[CH:17]=[C:12]2[CH:11]=[C:10]1[CH3:30])[CH:7]=[CH2:8].CN(C)[CH:33]=[O:34]>ClCCl>[CH2:6]([N:9]1[C:13]2=[C:14]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:15]=[C:16]([C:18]#[N:19])[CH:17]=[C:12]2[C:11]([CH:33]=[O:34])=[C:10]1[CH3:30])[CH:7]=[CH2:8]
Reactant: CN(C)C=O
Reactant: C=CCn1c(C)cc2cc(C#N)nc(N3CCc4ccccc4C3)c21
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: C=CCn1c(C)c(C=O)c2cc(C#N)nc(N3CCc4ccccc4C3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.3 %

Procedure:
Phosphorus oxychloride (425 μl, 4.56 mmol) was added at room temperature to a solution of 1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile (1 g, 3.04 mmol) prepared in Step 3 in a mixture of anhydrous dichloromethane (20 ml) and N,N-dimethylformamide (353 μl, 4.56 mmol). The reaction mixture was refluxed for 3 hours, cooled to room temperature, and then filtered. The resulting solid washed with water and 1M sodium acetate (30 ml) was added thereto. The reaction mixture was stirred for 1 hour at room temperature and then filtered. The resulting solid washed with water and then dried to give 350 mg of the titled compound as a white solid.