Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=C.[CH:3]12[CH2:9][CH:6]([CH2:7][CH2:8]1)[CH:5]=[CH:4]2.[CH:10](O)([CH3:12])[CH3:11]>CC(C)=O>[CH2:3]=[CH2:4].[CH:3]12[CH2:9][CH:6]([CH2:7][CH2:8]1)[CH:5]=[CH:4]2.[CH2:11]=[CH:10][C:12]1[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=1
Reactant: CC(C)O
Agent: C1=CC2CCC1C2
Agent: C=C
Solvent: CC(C)=O
Product: C=Cc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a 15-liter autoclave vacuum dried and purged with nitrogen, 887 g of norbornene, 1,100 ml of styrene, 777 ml of cyclohexane and 3 ml of a cyclohexane solution of triisobutylaluminum (1 mmol/ml) were introduced at ambient temperature. The autoclave was pressurized up to 6 kg/cm2 -G with ethylene while stirring, and then the pressure was released. The operations of pressurizing and pressure release were repeated three times. Thereafter, the system was pressurized to 1.5 kg/cm2 -G with ethylene, and the temperature was raised to 70° C. The system was then pressurized with ethylene so that the internal pressure became 6 kg/cm2 -G. After stirring for 15 minutes, 13.7 ml of the catalyst solution previously prepared was added to the system to initiate copolymerization of ethylene and norbornene. With respect to the catalyst concentration at this time, the concentration of the isopropylidene-bis(indenyl)zirconium dichloride in the whole system was 0.0123 mmol/l, and the concentration of the methylaluminoxane in the whole system was 7.5 mmol/l. During the polymerization, ethylene was continuously fed to maintain the internal pressure at 6 kg/cm2 -G. After 60 minutes, isopropyl alcohol was added to terminate the polymerization reaction. After the pressure was released, the polymer solution was drawn out and washed with an aqueous solution of 5 ml of concentrated hydrochloric acid in 1 liter of water in a ratio between the polymer solution and the aqueous solution of 1:1, to transfer the catalyst residue into the aqueous phase. This contact mixed solution was allowed to stand, then the aqueous phase was removed by separation, and the remainder was further washed twice with distilled water to separate the polymerization liquid phase into an oil portion and an aqueous portion. The oil portion was brought into contact with acetone in an amount 3 times as much as the oil portion with vigorous stirring to precipitate a polymer and then sufficiently washed with acetone. The resulting solid portion (copolymer) was collected by filtration and dried at 130° C. and 350 mmHg for 12 hours in a stream of nitrogen. Thus, an ethylene/norbornene/styrene copolymer was obtained in a yield of 240 g, and the copolymer had an intrinsic viscosity [η], as measured in a decalin solvent at 135° C., of 0.8 dl/g, a glass transition temperature (Tg) of 142° C., a norbornene content of 41.1% by mol, a styrene content of 9.8% by mol and an activity of 6,500 g/mmol-Zr.
Reaction SMILES: [C:1](=[O:14])([O:3][CH2:4][C@H:5]([NH2:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:2].CS(O)(=O)=O.[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Na+].Cl>ClCCl.C(OCC)C.O>[NH:26]([C:27]([NH:2][C:1](=[O:14])[O:3][CH2:4][C@H:5]([NH2:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC(=O)OC[C@H](N)Cc1ccccc1
Reactant: O=C=Nc1ccccc1
Agent: CS(=O)(=O)O
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: N[C@@H](COC(=O)NC(=O)Nc1ccccc1)Cc1ccccc1
Reaction time: 24 h

Procedure:
(2R)-2-amino-3-phenylpropyl carbamate (2.397 mmol) was dissolved in dichloromethane and methansulfonic acid (0.47 ml, 3 eq) and phenyl isocyanate (1.56 ml, 6 eq) was added in an ice bath. The resulting reaction mixture was stirred for 1 day. Water was added to terminate the reaction and the reaction mixture was neutralized to pH 7-8 with 1N NaOH solution. The organic layer was extracted 3 times with dichloromethane, dried over magnesium sulfate and concentrated in vacuo, to give oil. This was dissolved in dichloromethane and the solution was treated with a solution of HCl in ethyl ether. The resulting precipitate was filtered to give (2R)-2-amino-3-phenylpropyl (anilinocarbonyl)carbamate; hydrochloride.
Reaction SMILES: [Br:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:11].[NH4+].[Cl-].[N-:14]=[N+:15]=[N-:16].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([C:6]2[NH:16][N:15]=[N:14][N:7]=2)=[CH:8][C:9]=1[CH3:10]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(C#N)cc(C)c1Br
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2nnn[nH]2)cc(C)c1Br
Temperature: 100 °C

Procedure:
To a solution of 4-bromo-3,5-dimethylbenzonitrile (1 g) in N,N-dimethylformamide (10 mL) is added NH4Cl (770 mg) and NaN3 (800 mg) and the mixture is heated to 100° C. for 12 hours. After cooling to room temperature the mixture is diluted with water. The formed precipitate is filtered off, washed with water and dried to give the title compound. Yield: 650 mg; Mass spectrum (ESI+): m/z=253 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH3:37][C:38]1[C:42]([C:43]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[O:44])=[C:41]([CH3:51])[O:40][N:39]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:48]3[CH2:49][CH2:50][N:45]([C:43]([C:42]4[C:38]([CH3:37])=[N:39][O:40][C:41]=4[CH3:51])=[O:44])[CH2:46][CH2:47]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:31])([CH3:30])[C:32]#[N:33])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1noc(C)c1C(=O)N1CCNCC1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)c2c(C)noc2C)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(3,5-dimethyl-isoxazole-4-carbonyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxy-phenyl)-2-methyl-propionitrile was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12j) and (3,5-dimethyl-isoxazol-4-yl)-piperazin-1-yl-methanone (example 13) in an analogous manner as described in example 25. LR-MS: 713.3 [(M+H)+]
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][CH2:16][NH2:17])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH3:21][N:22]=[C:23]=[O:24]>C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH2:18]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][CH2:16][NH:17][C:23]([NH:22][CH3:21])=[O:24])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:19][CH3:20]
Reactant: CCCN(CCC)C1CCc2cccc(CCN)c2C1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCN(CCC)C1CCc2cccc(CCNC(=O)NC)c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.3 g (4.7 mmol) of 2-dipropylamino-8-(2-aminoethyl)-1,2,3,4-tetrahydronaphthalene were initially introduced into 20 ml of toluene. The reaction was catalyzed using 3 drops of triethylamine, and 0.31 ml (5.17 mmol) of methyl isocyanate were then added dropwise. The mixture was stirred overnight at room temperature, and then evaporated. After subsequent chromatography over silica gel 60, 40-63 μm, using diisopropyl ether/ethanol/triethylamine, the product was stirred with petroleum ether and a little diisopropyl ether, and filtered off under suction.
Reaction SMILES: [ClH:1].[OH:2][C@@H:3]([CH2:20][CH3:21])[C@H:4]([NH:12]C(=O)OC(C)(C)C)[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1>O1CCOCC1>[ClH:1].[ClH:1].[NH2:12][C@@H:4]([C@@H:3]([OH:2])[CH2:20][CH3:21])[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1
Reactant: CC[C@H](O)[C@@H](Cc1ccncc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@H](O)[C@H](N)Cc1ccncc1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
a solution of 50 cm3 of 4N hydrochloric acid in dioxane is added, with stirring and at a temperature in the region of 20° C., to a solution of 4 g of tert-butyl N-[(1R,2S)-2-hydroxy-1-(4-pyridylmethyl)-butyl]carbamate in 50 cm3 of dioxane. The mixture is stirred at a temperature in the region of 20° C. for 18 hours and is then concentrated under reduced pressure (1 kPa) at a temperature in the region of 60° C. 3.6 g of (2R,3S)-2-amino-1-(4-pyridyl)-3-pentanol dihydrochloride are obtained in the form of a white solid [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 0.92 (t, J=7.5 Hz: 3H); from 1.30 to 1.65 (mt: 2H); 3.13 (dd, J=14 and 9 Hz: 1H); 3.28 (dd, J=14 and 5 Hz: 1H); 3.52 (mt: 1H); 3.68 (mt: 1H); 8.11 (broad d, J=6.5 Hz: 2H); 8.25 (unresolved complex: 3H); 8.90 (broad d, J=6.5 Hz: 2H)].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:29]1[CH:30]=[C:31]([C:35]2([OH:45])[CH2:39][CH2:38][CH:37]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:36]2)[CH:32]=[N:33][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.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(Cl)Cl>[OH:45][C:35]1([C:31]2[CH:32]=[N:33][CH:34]=[C:29]([C:6]3[CH:5]=[C:4]([NH:17][C:18]4[N:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][N:19]=4)[CH:3]=[C:2]([CH3:1])[CH:7]=3)[CH:30]=2)[CH2:39][CH2:38][CH:37]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:36]1
Reactant: CCOC(=O)C1CCC(O)(c2cncc(Br)c2)C1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1CCC(O)(c2cncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)c2)C1
Temperature: 85 °C

Procedure:
A mixture of N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (211 mg, 0.557 mmol), ethyl 3-(5-bromopyridin-3-yl)-3-hydroxycyclopentanecarboxylate (175 mg, 0.557 mmol), and sodium carbonate (2 M, 557 μl, 1.11 mmol) in 2-methyl THF (2785 μl) was purged with argon for 10 minutes. PdCl2(dppf)-CH2Cl2 adduct (22.7 mg, 0.028 mmol) was added to the reaction mixture and heated to 85° C. overnight. Upon cooling, the reaction was diluted with water and extracted with DCM (3×). The combined organic layers were dried under reduced pressure and purified by silica gel chromatography (ethyl acetate/hexanes) to afford ethyl 3-hydroxy-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-3-yl]cyclopentanecarboxylate. MS ESI calc'd for C25H26F3N4O3 [M+H]+ 487. found 487.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:19]=[CH:18][N:17]([Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH:16]=2)[CH:12]=[CH:11][C:10]=1[N:30]1[S:34](=[O:36])(=[O:35])[NH:33][C:32](=[O:37])[CH2:31]1)C1C=CC=CC=1>CCO.CCOC(C)=O.CCO.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:19]=[CH:18][N:17]([Si:20]([CH:21]([CH3:22])[CH3:23])([CH:24]([CH3:25])[CH3:26])[CH:27]([CH3:29])[CH3:28])[CH:16]=2)[CH:12]=[CH:11][C:10]=1[N:30]1[S:34](=[O:36])(=[O:35])[NH:33][C:32](=[O:37])[CH2:31]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2ccc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)c2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2ccc(N3CC(=O)NS3(=O)=O)c(O)c2)c1
Reaction time: 18 h

Procedure:
To a slurry of Pd/C (10 mg) in 10 mL of EtOH/EtOAc (1:1) is added a solution of 5-[2-benzyloxy-4-(1-triisopropylsilanyl-1H-pyrrol-3-yl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one in EtOH. The mixture is stirred under an atmosphere of H2 for 18 h then the catalyst is removed by filtration through a pad of Celite. The filtrate is concentrated under reduced pressure to afford the title compound which is used directly in the next step: (M−1)−=448.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH:9][C:10](=[O:12])[CH3:11])=O.P(Cl)(Cl)(Cl)=O>>[CH3:11][C:10]1[O:12][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:8][N:9]=1
Reactant: CC(=O)NNC(=O)c1cccs1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nnc(-c2cccs2)o1
Temperature: 90 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
A mixture of N-(2-thienylcarbonylamino)ethanamide (5.37 g) and phosphorus oxychloride (15 ml) was stirred for 8 hours at 90° C. After cooling to ambient temperature, the mixture was concentrated. The residue was partitioned between AcOEt and saturated aqueous NaHCO3 solution. The organic layer was separated and washed with saturated aqueous NaHCO3 solution and brine. The resulting solution was dried over sodium sulfate and concentrated to give 3.65 g of 2methyl-5-(2-thienyl)-1,3,4-oxadiazole as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[C:10]([C:13]1[O:14][C:15](=O)[C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:20][C:19]([Br:29])=[CH:18][CH:17]=2)(=[O:12])[CH3:11]>>[C:10]([C:13]1[N:6]([CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=2)[C:15](=[O:14])[C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:20][C:19]([Br:29])=[CH:18][CH:17]=2)(=[O:12])[CH3:11]
Reactant: NCc1cccc(F)c1
Reactant: CC(=O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Product: CC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1cccc(F)c1

Procedure:
In the same manner as in Example 411, the title compound was synthesized from 3-fluorobenzylamine and 3-acetyl-6-bromo-4-phenylisochromen-1-one.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH2:17])=[C:11]([Cl:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH:17][S:21]([CH3:20])(=[O:23])=[O:22])=[C:11]([Cl:18])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=Cc1cc(CNC(=O)OC(C)(C)C)cc(Cl)c1N
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1cc(CNC(=O)OC(C)(C)C)cc(Cl)c1NS(C)(=O)=O
Reaction time: 5 h
Yield: 60.8 %

Procedure:
(4-Amino-3-chloro-5-vinylbenzyl)carbamic acid tert-butyl ester (40.2 mg, 0.14 mmol), methanesulfonyl chloride (5 eq, 0.71 mmol, 55.15 μl), and triethylamine (3 eq, 0.42 mmol, 58.34 μl) were added in methylene chloride. The reaction mixture was stirred for 5 hr. The reaction mixture was purified with similar procedure to step 5 of Example 8 to obtain a title compound (30.7 mg, 59.83%).
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([OH:16])=O)[N:10]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[N:9]=[CH:8]2.[NH2:27][C@H:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33].Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:27][C@H:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])=[O:16])[N:10]([CH2:17][C:18]([OH:21])([CH3:19])[CH3:20])[N:9]=[CH:8]2
Reactant: CC(C)(O)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)O)cc21
Reactant: N[C@H]1CCNC1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCNC3=O)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.8 %

Procedure:
5-(2,4-Difluorophenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-indazole-6-carboxylic acid (200 mg, 0.552 mmol) was dissolved in N,N-dimethylformamide (2 mL). To his was added (S)-3-aminopyrrolidin-2-one (4a) (111 mg, 1.10 mmol), 4-(dimethylamino)pyridine (6.7 mg, 0.055 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (116 mg, 0.607 mmol) successively, and the reaction mixture was allowed to stir at ambient temperature for 16 hours. The reaction mixture was partitioned between water and ethyl acetate, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography on a silica gel column, eluting with 100% acetone to yield pure (S)-5-(2,4-difluorophenoxy)-1-(2-hydroxy-2-methylpropyl)-N-(2-oxopyrrolidin-3-yl)-1H-indazole-6-carboxamide (Ij) (83 mg, 34%). Mass spec: 445 (M+1). 1H NMR (CDCl3) δ 8.39 (s, 1H), 8.26 (brd, 1H), 7.93 (s, 1H), 7.18 (m, 1H), 7.04 (s, 1H), 7.02 (m, 1H), 6.92 (m, 1H), 6.04 (br, 1H), 4.59 (ddd, 1H), 4.37 (s, 2H), 3.64 (brs, 1H), 3.45 (m, 2H), 2.87 (m, 1H), 2.09 (m, 1H), 1.21 (s, 3H), 1.12 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]([O:16][CH2:17][CH3:18])=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][C:12]([O:14][CH3:15])=[O:13].[C:20]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]([O:16][CH2:17][CH3:18])=[C:6]2[C:10]=1[N:9]([CH3:20])[CH:8]=[C:7]2[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: CCOc1c(F)cc(Cl)c2[nH]cc(CC(=O)OC)c12
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOc1c(F)cc(Cl)c2c1c(CC(=O)OC)cn2C
Temperature: 25 °C
Yield: 66.7 %

Procedure:
To a solution of 30-10 (2 g, 7 mmol) in acetone (40 mL) was added K2CO3 (3 g, 21 mmol) and MeI (1.2 g, 8.4 mmol). The reaction mixture was refluxed overnight before it was cooled to room temperature. The solid was filtered off and the filtrate was evaporated to give the crude product, which was purified on silica gel column chromatography eluting with hexane/ethyl acetate (1:5) to afford 30-11 (1.4 g, 67%) as a yellow solid. LRMS: calc 299.1 and found: 300.1 [M+1].
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48](O)=[O:49])[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)C(C)C)(C)C.[NH2:60][CH:61]([C:69]1[CH:74]=[CH:73][C:72]([Cl:75])=[CH:71][CH:70]=1)[CH2:62][CH2:63][NH:64][S:65]([CH3:68])(=[O:67])=[O:66]>CN1C(=O)CCC1>[Cl:75][C:72]1[CH:71]=[CH:70][C:69]([CH:61]([NH:60][C:48]([C:33]2([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:38][CH2:37][N:36]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH2:35][CH2:34]2)=[O:49])[CH2:62][CH2:63][NH:64][S:65]([CH3:68])(=[O:67])=[O:66])=[CH:74][CH:73]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: CS(=O)(=O)NCCC(N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CCNS(C)(=O)=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (245 mg, 0.65 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (155 mg, 0.43 mmol) and N,N-diisopropylethylamine (0.213 mL, 1.29 mmol) in NMP (2 mL) at 20° C. under nitrogen. The resulting solution was stirred at 20° C. for 5 minutes. N-(3-amino-3-(4-chlorophenyl)propyl)methanesulfonamide (Intermediate 116) (113 mg, 0.43 mmol) in NMP (2 mL) was then added to the reaction and stirred for 18 hours. The reaction mixture was concentrated and diluted with EtOAc (20 mL) and washed with water (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford tert-butyl 4-(1-(4-chlorophenyl)-3-(methylsulfonamido)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (261 mg, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17](O)([CH3:19])[CH3:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C[Si](C)(C)[O:23][CH:24]=[CH2:25]>ClCCl.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([CH3:19])([CH3:18])[CH2:23][CH:24]=[O:25])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: C=CO[Si](C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(C)(CC=O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2-(1-(4-fluorophenyl)-1H-indazol-5-yl)propan-2-ol (Example 113(d), 200 mg, 0.74 mmol) and trimethyl(vinyloxy)silane (0.5 mL) in anhydrous dichloromethane (1 mL) was added zinc chloride (1M solution in diethyl ether, 2.2 mL, 2.2 mmol) dropwise at 0° C. under argon. The reaction mixture was stirred at rt for 1.5 hr before being quenched by the addition of saturated aqueous ammonium chloride solution (2 mL). The aqueous layer was separated and extracted with ethyl acetate (2×2 mL). The combined organic layers were dried (Na2SO4), concentrated and purified by silica gel flash chromatography to give 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylbutanal as a liquid.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:10])[N:5]([CH2:7][CH2:8][NH2:9])[CH:6]=1.[F:11][C:12]1[CH:13]=[C:14]([CH2:20][CH2:21][CH:22]=O)[CH:15]=[C:16]([F:19])[C:17]=1[CH3:18]>>[F:11][C:12]1[CH:13]=[C:14]([CH2:20][CH2:21][CH:22]2[NH:9][CH2:8][CH2:7][N:5]3[C:4]([CH3:10])=[N:3][C:2]([I:1])=[C:6]23)[CH:15]=[C:16]([F:19])[C:17]=1[CH3:18]
Reactant: Cc1nc(I)cn1CCN
Reactant: Cc1c(F)cc(CCC=O)cc1F
Product: Cc1c(F)cc(CCC2NCCn3c(C)nc(I)c32)cc1F

Procedure:
According to the general procedure (GP10), the microwave-assisted Pictet-Spengler reaction (60 W; 110° C.; 5 bars; 10 min.) between 2-(4-iodo-2-methyl-imidazol-1-yl)-ethylamine (696 mg; 2.774 mmol) and 3-(3,5-difluoro-4-methyl-phenyl)-propionaldehyde (510 mg; 2.774 mmol) afforded 8-[2-(3,5-difluoro-4-methyl-phenyl)-ethyl]-1-iodo-3-methyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine which was Boc-protected and finally purified by FC (DCM/MeOH=25/1).
Reaction SMILES: C(OC([N:6]=[S:7]([CH2:35][CH3:36])([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([NH:27][C:28]4[S:29][CH:30]=[CH:31][N:32]=4)=[N:22][CH:23]=[N:24]3)=[CH:19][C:18]=2[O:33][CH3:34])[CH:10]=1)=[O:8])=O)C.ClCCl.CO>CO>[CH2:35]([S:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([NH:27][C:28]4[S:29][CH:30]=[CH:31][N:32]=4)=[N:22][CH:23]=[N:24]3)=[CH:19][C:18]=2[O:33][CH3:34])[CH:10]=1)(=[NH:6])=[O:8])[CH3:36]
Reactant: CCOC(=O)N=S(=O)(CC)c1cccc(COc2cc3ncnc(Nc4nccs4)c3cc2OC)c1
Solvent: ClCCl
Solvent: CO
Product: CCS(=N)(=O)c1cccc(COc2cc3ncnc(Nc4nccs4)c3cc2OC)c1
Yield: 66 %

Procedure:
According to GWP 6, the conversion of (RS)-N-(ethoxycarbonyl)-S-ethyl-S-[3-({[6-methoxy-4-(thiazol-2-ylamino)quinazolin-7-yl]oxy}methyl)phenyl]-sulphoximide (40 mg, 0.076 mmol) and chromatographic purification (silica gel, dichloromethane/methanol: 0→30% methanol) gives the desired product in 66% yield (23 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:70][O:71][CH2:72][CH2:73][NH2:74]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:25](=[O:26])[NH:74][CH2:73][CH2:72][O:71][CH3:70])([CH3:28])[CH3:27])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1
Reactant: COCCN
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)CO)C12C(=O)Nc1cc(Cl)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCNC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxy-1,1-dimethyl-ethoxy)-phenyl]-2′-[5-fluoro-2-methylphenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (35 mg, 0.06 mmol), EDCl (18 mg, 0.094 mmol), HOBt (14 mg, 0.094 mmol) and DIPEA (23 mg, 0.2 mmol) in THF (2 mL) was added 2-methoxy-ethylamine (14 mg, 0.18 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (10 mg).