Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:4]([NH:6][C@H:7]([C:17]([NH:19][C@H:20]([C:29]([NH:31][C@H:32]([C:42]([NH:44][C@H:45]([C:48]([NH:50][C@H:51]([C:53]([NH:55][C@H:56]([C:66]([NH:68][C@H:69]([C:71]([NH:73][C@H:74]([C:82]([N:84]1[CH2:127][CH2:126][CH2:125][C@H:85]1[C:86]([NH:88][C@H:89]([C:94]([NH:96][C@H:97]([C:107]([NH:109][C@H:110]([C:118]([O:120][C:121]([CH3:124])([CH3:123])[CH3:122])=[O:119])[CH2:111][C:112]1[CH:117]=[CH:116][CH:115]=[CH:114][CH:113]=1)=[O:108])[CH2:98][CH2:99][C:100](=[O:106])[O:101][C:102]([CH3:105])([CH3:104])[CH3:103])=[O:95])[CH2:90][CH:91]([CH3:93])[CH3:92])=[O:87])=[O:83])[CH2:75][C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)=[O:72])[CH3:70])=[O:67])[CH2:57][CH2:58][C:59](=[O:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:54])[CH3:52])=[O:49])[CH2:46][OH:47])=[O:43])[CH2:33][CH2:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:30])[CH2:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:18])[CH2:8][CH2:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:5])[CH3:3]>[Pd].CN(C=O)C>[NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:17]([NH:19][C@H:20]([C:29]([NH:31][C@H:32]([C:42]([NH:44][C@H:45]([C:48]([NH:50][C@H:51]([C:53]([NH:55][C@H:56]([C:66]([NH:68][C@H:69]([C:71]([NH:73][C@H:74]([C:82]([N:84]1[CH2:127][CH2:126][CH2:125][C@H:85]1[C:86]([NH:88][C@H:89]([C:94]([NH:96][C@H:97]([C:107]([NH:109][C@H:110]([C:118]([O:120][C:121]([CH3:122])([CH3:123])[CH3:124])=[O:119])[CH2:111][C:112]1[CH:117]=[CH:116][CH:115]=[CH:114][CH:113]=1)=[O:108])[CH2:98][CH2:99][C:100](=[O:106])[O:101][C:102]([CH3:103])([CH3:104])[CH3:105])=[O:95])[CH2:90][CH:91]([CH3:93])[CH3:92])=[O:87])=[O:83])[CH2:75][C:76]1[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=1)=[O:72])[CH3:70])=[O:67])[CH2:57][CH2:58][C:59](=[O:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:54])[CH3:52])=[O:49])[CH2:46][OH:47])=[O:43])[CH2:33][CH2:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:30])[CH2:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:18])[CH2:8][CH2:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:5])[CH3:3]
Reactant: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](C)N)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Yield: 96.9 %

Procedure:
8.5 g. 4.41 mmoles) of Z-27-39-OtBu are dissolved in 850 ml. of dry DMF, and the mixture is hydrogenated in the presence of palladium-on-carbon. At the end of the reaction, the catalyst is removed by filtration; the filtate is evaporated to dryness, and the residue is triturated with ether. 7.65 g. (96.9 %) of H-27-39-OtBu are obtained. M.p.: 197°C (under decomposition), Rf12 = 0.3.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:20])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])=[CH:10][CH:9]=1)C.O.S([O-])(O)(=O)=O.[K+]>O1CCCC1.C(O)C>[O:19]=[C:15]1[CH2:16][CH2:17][CH2:18][N:14]1[C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:6]([OH:20])=[O:5])=[CH:9][CH:10]=1
Reactant: CCOC(=O)Cc1ccc(N2CCCC2=O)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1ccc(N2CCCC2=O)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
Aqueous 1 N sodium hydroxide solution (10 ml, 10 mmols) was added to a solution of ethyl[4-(2-oxopyrrolidin-1-yl)phenyl]acetate (0.97 g, 3.9 mmols) in tetrahydrofuran (20 ml) and ethanol (20 ml). The resulting mixture was stirred at 60° C. for 1 hour. Water was added to the reaction mixture, which was acidified with potassium hydrogensulfate added thereto, and then extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was crystallized from hexane/ethanol to give a solid of [4-(2-oxopyrrolidin-1-yl)phenyl]acetic acid (0.5 g, 57%).
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].[CH3:38][O:39][C:40]1([CH3:54])[C:44]2[CH:45]=[CH:46][C:47](Br)=[CH:48][C:43]=2[S:42](=[O:51])(=[O:50])[C:41]1([CH3:53])[CH3:52]>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:47]1[CH:46]=[CH:45][C:44]2[C:40]([O:39][CH3:38])([CH3:54])[C:41]([CH3:53])([CH3:52])[S:42](=[O:50])(=[O:51])[C:43]=2[CH:48]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: COC1(C)c2ccc(Br)cc2S(=O)(=O)C1(C)C
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: COC1(C)c2ccc(C#Cc3cc(Cl)ccc3OCC(=O)OC(C)(C)C)cc2S(=O)(=O)C1(C)C

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 6-bromo-2,2,3-trimethyl-1,1-dioxido-2,3-dihydro-1-benzothien-3-yl methyl ether (Intermediate 250), the title compound was obtained after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: ClC1C=CC=CC=1CC=O.[CH:11]([CH:14]([CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])[C:15]([O:17][CH2:18][CH3:19])=[O:16])([CH3:13])[CH3:12].[OH-].[K+].O.CO.C(C(C=CC1C=CC=CC=1Cl)C(O)=O)(C)C.[O:50]([C:57]1[CH:58]=C([CH:62]=[CH:63][CH:64]=1)CBr)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>>[CH:11]([CH:14]([CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])[C:15]([O:17][CH2:18][C:19]1[CH:62]=[CH:63][CH:64]=[C:57]([O:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:58]=1)=[O:16])([CH3:12])[CH3:13]
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)C(C=Cc1ccccc1Cl)C(C)C
Agent: CC(C)C(C=Cc1ccccc1Cl)C(=O)O
Agent: O=CCc1ccccc1Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)C(C=Cc1ccccc1Cl)C(=O)OCc1cccc(Oc2ccccc2)c1

Procedure:
The process of Example 3 is repeated using o-chlorophenylacetaldehyde to prepare ethyl 2-isopropyl-4-(o-chlorophenyl)-3-butenoate, which is hydrolyzed (potassium hydroxide-water/methanol) to the acid, 2-isopropyl-4-(o-chlorophenyl)-3-butenoic acid. The acid is reacted with m-phenoxybenzyl bromide as in Example 1 to yield m-phenoxybenzyl 2-isopropyl-4-(o-chlorophenyl)-3-butenoate. MS m/e 420 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15](=[O:16])[N:14]3[CH:17]=[CH:18][S:19][C:13]3=[N:12][C:11]=2[CH3:20])=[CH:6][CH:5]=1)[CH3:2].BrCC[CH2:24][C:25]#[N:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:20][C:11]1[N:12]=[C:13]2[S:19][CH:18]=[CH:17][N:14]2[C:15](=[O:16])[C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH2:2][CH2:24][C:25]#[N:26])=[CH:9][CH:8]=1
Reactant: CCOc1ccc(-c2c(C)nc3sccn3c2=O)cc1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc2sccn2c(=O)c1-c1ccc(OCCCC#N)cc1
Temperature: 80 °C
Yield: 56.7 %

Procedure:
To a solution of Step 1 intermediate, Intermediate 10 (350 mg, 1.355 mmol) in DMF (10 ml) was added 4-bromobutyronitrile (280 mg, 1.897 mmol) at room temperature followed by K2CO3 (560 mg, 4.065 mmol) and the reaction temperature was heated to 80° C. for 15.0 h overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine and purified by column chromatography to afford 250 mg the desired compound as a white solid; 1H NMR (300 MHz, CDCl3) δ 2.17 (s, 3H), 3.80-3.85 (m, 2H), 7.07-7.10 (m, 2H), 7.24-7.27 (m, 2H), 7.50 (d, J=4.8 Hz, 1H), 7.98 (d, J=4.5 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[CH2:23]([NH:30][C:14]1[N:15]=[CH:16][C:11]2[CH:10]=[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[C:20](=[O:21])[N:19]([CH3:22])[C:12]=2[N:13]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Reactant: NCc1ccccc1
Solvent: CN(C)C=O
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(NCc3ccccc3)nc21
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 47.6 %

Procedure:
A mixture of 0.165 g (0.47 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido-[2,3-d]pyrimidin-7-one of Example 37, 0.50 g (4.70 mmol) of benzylamine and 0.5 mL of dimethylformamide was heated with stirring in a 120° C. oil bath. After 5 minutes, solution was complete. After 5 hours, the excess amine and dimethylformamide were evaporated at reduced pressure, and the residue was triturated with a solution of 1 mL of acetone and 2 mL of petroleum ether. The tacky solid was filtered and recrystallized from ethyl acetate/petroleum ether to give 0.092 g of pure product; mp 217°-219° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[CH3:27][C:28]([O-])=O.[K+]>CC#N.O>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:28]4[CH:27]=[CH:18][N:17]=[CH:15][CH:13]=4)=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: CC(=O)[O-]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(C(=O)c1cc2c(s1)-c1ccc(-c3ccncc3)cc1OCC2)c1ccccc1Cl
Temperature: 140 °C

Procedure:
A suspension of 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 (50 mg, 0.11 mmol) in 1.0 mL MeCN and 1.0 mL 1M KOAc in water in a 10 mL microwave vial was degassed with bubbling nitrogen for approximately 10 min. 4-pyridineboronic acid (16 mg) was added followed by Pd(PPh3)4 (13 mg). The vessel was sealed and heated in a microwave at 140° C. for 30 min. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethylacetate. The combined organics were concentrated and the residue purified by reverse phase HPLC to give 134. 1H NMR (DMSO-d6) δ 8.77 (m, 2H), 8.05 (m, 2H), 7.70-7.53 (m, 7H), 6.65 (br s, 1H), 4.25 (m, 2H), 3.31 (s, 3H), 3.02 (m, 2H). MS: (ESI+) 447.1
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23]([CH:25]=[O:26])=[N:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[CH3:28][Mg]Cl>O1CCCC1>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23]([CH:25]([OH:26])[CH3:28])=[N:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc2nc(C=O)n3c2c1OC[C@@H]3c1ccccn1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc2nc(C(C)O)n3c2c1OC[C@@H]3c1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To the solution of (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine-2-carbaldehyde (8 mg, 0.02 mmol) in tetrahydrofuran (1 mL) at 0° C., 3.0 M methylmagnesium chloride in THF (0.01 mL, 0.04 mmol) [Aldrich, cat. #189901] was added dropwise. After continued stirring for 30 min at 0° C., the reaction was quenched by adding saturated aqueous ammonium chloride (0.5 mL) dropwise. The resulting mixture was diluted with ethyl acetate/brine (3:1), and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) afforded the desired product as a mixture of diastereomers (4 mg, 50%). LCMS for C21H21O3N4 (M+H)+: calculated m/z=377.2. found 377.1.
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][NH:4][CH:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]1.[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([S:29]([CH2:32][CH2:33][C:34](O)=[O:35])(=[O:31])=[O:30])[CH:23]=[CH:22]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(N(CC)CC)C>[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([S:29]([CH2:32][CH2:33][C:34]([N:4]1[CH2:5][CH2:6][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2][CH:3]1[C:7]([O:9][CH3:10])=[O:8])=[O:35])(=[O:30])=[O:31])[CH:23]=[CH:22]2
Reactant: O=C(O)CCS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)CCS(=O)(=O)c1ccc2cc(Cl)ccc2c1

Procedure:
1-tert-Butyl 3-methyl piperazine-1,3-dicarboxylate (JP-W No. 3-232864: 5.0 g) was dissolved in dichloromethane (20 mL), and triethylamine (3.8 mL) was added thereto. With ice cooling, 3-((6-chloro-2-naphthyl)sulfonyl)propionic acid (8.0 g), HOBt (4.5 g) and WSC (5.7 g) were added thereto, and the mixture was mixed at room temperature for 16 hours. The reaction solution was basified with an aqueous potassium carbonate solution, then extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off to give the title compound (8.7 g) as a pale brown oily matter.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[C:3]=1[SH:12].[CH3:13]O>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:13])=[O:7])=[C:4]([CH3:11])[C:3]=1[SH:12]
Reactant: CO
Reactant: Cc1c(C(=O)O)ccc(Cl)c1S
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(Cl)c(S)c1C

Procedure:
Under an atmosphere of nitrogen, 3.60 g (17.8 mmol) of 4-chloro-3-mercapto-2-methylbenzoic acid in 50 ml of absolute methanol and 1 ml of concentrated sulfuric acid were heated under reflux for 17 h. The mixture was freed from solvent, and the residue was taken up in water. After two extractions with ethyl acetate, the combined organic phases were dried, filtered under an atmosphere of nitrogen and freed from the solvent. What was isolated were 3.2 g of pure product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH:36]1([NH:39][C:40]([CH3:44])([CH3:43])[CH:41]=O)[CH2:38][CH2:37]1>N1CCCCC1.CC#N>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:41][C:40]([NH:39][CH:36]3[CH2:38][CH2:37]3)([CH3:44])[CH3:43])[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)(C=O)NC1CC1
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: CC#N
Solvent: C1CCNCC1
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC1CC1
Reaction time: 0.33 h
Yield: 27.6 %

Procedure:
A solution of 3-((S)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (118 mg, 0.25 mmol, 1.0 equiv), 2-(cyclopropylamino)-2-methylpropanal (0.16 g, 1.25 mmol, 5.0 equiv) and one drop of piperidine in MeCN (10 mL) was stirred overnight at 40° C. The solvent was removed and the residue was purified on Prep-HPLC. Conditions: (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (40% CH3CN up to 100% in 20 min); Detector, 254 mm. This resulted in 40 mg (27%) of the title compound as a white solid and bis TFA salt. LC-MS: m/z 581 (M+H+). H1-NMR (400 MHz, CDCl3+D2O, ppm): 8.33 (s, 1H), 7.54-7.43 (m, 3H), 7.33 (s, 1H), 7.28-7.25 (m, 1H), 7.07 (d, J=8.0 Hz, 2H), 6.94 (dd, J=8.4, 2.0 Hz, 1H), 6.85 (dd, J=11.6, 2.0 Hz, 1H), 4.89-4.64 (m, 3H), 3.65-3.52 (m, 2H), 2.78 (m, 1H), 2.14-1.79 (m, 4H), 1.57-1.55 (d, 6H), 1.20 (m, 2H), 0.98 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([C:13]([CH3:49])([CH3:48])[C:14]([N:16]([CH3:47])[C:17]2[C:18]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=3[CH3:46])=[CH:19][C:20]([C:23]#[C:24][CH2:25][C@@H:26]([NH:31]C(OC(C)(C)C)=O)[C:27]([O:29][CH3:30])=[O:28])=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:31][C@H:26]([CH2:25][C:24]#[C:23][C:20]1[CH:19]=[C:18]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=2[CH3:46])[C:17]([N:16]([C:14](=[O:15])[C:13]([C:5]2[CH:4]=[C:3]([C:2]([F:50])([F:51])[F:1])[CH:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:6]=2)([CH3:48])[CH3:49])[CH3:47])=[CH:22][N:21]=1)[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)[C@@H](CC#Cc1cc(-c2ccc(F)cc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](N)CC#Cc1cc(-c2ccc(F)cc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl (2R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-pentynoate (Intermediate 12, 1 g, 1.382 mmol) in Dichloromethane (15 ml), TFA (5 ml, 64.9 mmol) was added and the reaction mixture was stirred for 1 h at r.t. The solvent and the excess of TFA were evaporated and the residue purified by SPE-SCX cartridge to obtain Intermediate 13. This residue was dissolved in Acetonitrile (14 ml) and Silver trifluoromethanesulfonate (0.036 g, 0.138 mmol) was added; the reaction mixture was stirred for 6 hours at 60° C. The solvent was evaporated and the residue was dissolved in DCM (15 ml) and the metal catalyst was filtered off. The organic solution was evaporated affording the title compound (800 mg, 1.283 mmol, 93% yield) as an orange solid. UPLC: Rt 0.95 min, m/z 624 [M+H+].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].Cl.[C@H:14]12[CH2:20][C@H:17]([NH:18][CH2:19]1)[CH2:16][N:15]2[CH2:21][C@@H:22]([C:24]1[C:25]([CH3:34])=[C:26]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[O:28][CH2:27]2)[OH:23].CCN(C(C)C)C(C)C>CN(C=O)C.CS(C)=O>[OH:23][C@H:22]([C:24]1[C:25]([CH3:34])=[C:26]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[O:28][CH2:27]2)[CH2:21][N:15]1[CH2:16][C@@H:17]2[CH2:20][C@H:14]1[CH2:19][N:18]2[S:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: Cc1c([C@@H](O)CN2C[C@@H]3C[C@H]2CN3)ccc2c1COC2=O
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c([C@@H](O)CN2C[C@@H]3C[C@H]2CN3S(=O)(=O)c2ccc(C#N)cc2)ccc2c1COC2=O

Procedure:
A solution of 4-cyanobenzene-1-sulfonyl chloride (31 mg, 0.12 mmol) in 0.3 mL of DMF was added to a solution of 5-((R)-2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one hydrochloride (32 mg, 0.10 mmol) (INTERMEDIATE 14) in 0.2 mL of DMF and DIEA (87 uL, 0.50 mmol). The combined solution was shaken for sixteen hours and then diluted with 0.5 mL DMSO. The resulting solution was purified by HPLC to afford 4-((1S,4S)-5-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-2,5-diazabicyclo[2.2.1]heptan-2-ylsulfonyl)benzonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:30]1(B(O)O)[CH2:32][CH2:31]1.C1(C)C=CC=CC=1>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Cl-].[Cl-].[Pd+2].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH:30]3[CH2:32][CH2:31]3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Br)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 68.6 %

Procedure:
To a mixture of 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (3.6 g), bis(tricyclohexylphosphine)palladium(II)dichloride (396 mg), tripotassium phosphate (12 g) and cyclopropylboronic acid (2.1 g) were added toluene (30 mL) and water (1.5 mL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform) to give 4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (2.2 g). The obtained 4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (2.2 g) was dissolved in chloroform (5 mL), 4N hydrogen chloride/ethyl acetate (5 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added ethyl acetate (20 mL), and the precipitate was collected by filtration to give the title compound (1.3 g).
Reaction SMILES: [C:1]([C:3]1([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=2)[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)#[N:2].ClC(Cl)(Cl)[C:26]([N:28]=C=O)=[O:27].C(N(CC)CC)C.CO>C(Cl)Cl.O>[NH:2]=[C:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[N:16]([C:17]2[CH:18]=[CH:19][C:20]([I:23])=[CH:21][CH:22]=2)[C:26](=[O:27])[NH:28]1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(Nc2ccc(I)cc2)CC1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=N)NC(=O)N2c1ccc(I)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-cyano-4-[(4-iodophenyl)amino]piperidine-1-carboxylate (22 g, 51.5 mmol) in DCM (150 mL) was added trichloroacetylisocyanate (6.12 mL, 51.5 mmol) dropwise. After stirring at rt for 1 h30, triethylamine (7.18 mL, 51.5 mmol), water (4.64 mL, 257.5 mmol) and methanol (10.43 mL, 257.5 mmol), and the reaction mixture was stirred at 40° C. for 3 h, cooled to rt, diluted with water (200 mL), and a purple solid was filtered on paper, washed with water and a small amount of DCM, and air dried to afford the desired product as a white solid. LRMS (M+1)=471.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](=[S:28])[NH2:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:30][C:31](=O)[C:32]([CH3:35])([CH3:34])[CH3:33]>>[C:32]([C:31]1[N:27]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[S:28][CH:30]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: NC(=S)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: CC(C)(C)C(=O)CBr
Product: CC(C)(C)c1csc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
100 mg (about 0.182 mmol) of the compound from Example 115A and 49 mg (0.273 mmol) of 1-bromo-3,3-dimethylbutan-2-one were reacted according to the General Method 3. Yield: 56 mg (59% of theory).