Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16](O)=[O:17])=[CH:13][CH:14]=3)[CH:9]([CH2:19][CH2:20][C:21](=[O:34])[N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH2:32][CH2:31][CH2:30][C:29]4=[O:33])[CH2:24][CH2:23]3)[C:8]=2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:41][N:42]([CH3:47])[S:43]([NH2:46])(=[O:45])=[O:44].Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.CC(N(C)C)=O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([NH:46][S:43]([N:42]([CH3:47])[CH3:41])(=[O:45])=[O:44])=[O:17])=[CH:13][CH:14]=3)[CH:9]([CH2:19][CH2:20][C:21](=[O:34])[N:22]3[CH2:23][CH2:24][CH:25]([N:28]4[CH2:32][CH2:31][CH2:30][C:29]4=[O:33])[CH2:26][CH2:27]3)[C:8]=2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)S(N)(=O)=O
Reactant: O=C(O)c1ccc2c(c1)C(CCC(=O)N1CCC(N3CCCC3=O)CC1)C(c1ccccc1)=C2C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CN(C)S(=O)(=O)NC(=O)c1ccc2c(c1)C(CCC(=O)N1CCC(N3CCCC3=O)CC1)C(c1ccccc1)=C2C1CCCCC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-cyclohexyl-3-(3-oxo-3-(4-(2-oxopyrrolidin-1-yl)piperidin-1-yl)propyl)-2-phenyl-3H-indene-5-carboxylic acid, (46 mg, 0.083 mmol), N,N-dimethylsulfamide (51 mg, 0.42 mmol) and DMAP (51 mg, 0.42 mmol) in dimethylacetamide (1 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (64 mg, 0.33 mmol). The reaction solution was stirred in a sealed tube under nitrogen at 50° C. overnight and purified by reverse phase prep-HPLC to yield 1-cyclohexyl-N-[(dimethylamino)sulfonyl]3-(3-oxo-3-(4-(2-oxopyrrolidin-1-yl)piperidin-1-yl)propyl)-2-phenyl-3H-indene-5-carboxamide as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 8.91 (br s, 1H), 8.09 (s, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.57-7.41 (m, 5H), 6.86 (s, 1H), 5.10 (br s, 1H), 4.41 (br s, 1H), 4.05-3.50 (m, 7H), 3.07 (s, 6H), 2.81 (m, 1H), 2.44 (m, 2H), 2.05-1.38 (m, 16H). LCMS: m/e 658 (M+H)+, ret time 2.43 min, column 3, 2 minute gradient. The next set of experimental procedures constitute a the start of a new section which stand alone:
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7]([OH:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[I:11]N1C(=O)CCC1=O>CN(C=O)C.O.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[I:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:1]([CH3:10])[C:2]=1[C:7]([OH:9])=[O:8]
Reactant: Cc1ccccc1C(=O)O
Reactant: O=C1CCC(=O)N1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(I)c1C(=O)O
Temperature: 100 °C
Reaction time: 17 h
Yield: 92 %

Procedure:
To a solution of o-toluic acid (2.00 g, 14.7 mmol) in dry DMF (60 mL) under an atmosphere of nitrogen was added N-iodosuccinimide (3.64 g, 16.2 mmol) followed by Pd(OAc)2 (0.330 g, 1.47 mmol). The resulting reaction mixture was heated to 100° C. and stirred for 17 hours. Upon cooling to room temperature the reaction was diluted with water (100 mL) and EtOAc (150 mL), the layers were separated and the aqueous layer was extracted with EtOAc (2×100 mL), the combined organics were washed with water (100 mL), brine (100 mL), water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (I57) (3.56 g, 92% yield) as a brown oily solid; 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=7.9 Hz, 1H), 7.21 (d, J=7.6 Hz, 1H), 7.02 (t, J=7.8 Hz, 1H), 2.44 (s, 3H). LCMS Method C: rt 5.36 min.
Reaction SMILES: C[O-].[Na+].[CH:4]1([SH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.Br.Br[CH2:13][CH2:14][NH2:15].[ClH:16]>O.CCOCC.CO>[ClH:16].[CH:4]1([S:10][CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: NCCBr
Reactant: SC1CCCCC1
Agent: Br
Agent: C[O-]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: NCCSC1CCCCC1
Reaction time: 0.5 h

Procedure:
To a solution containing 30 parts of sodium methoxide and 198 parts of methanol, maintained at 25° under a nitrogen atmosphere, is added rapidly 39 parts of cyclohexyl mercaptan. 51 Parts of 2-bromoethylamine hydrobromide then is added portion wise while maintaining the temperature at 25-30°, and the reaction mixture is stirred for 30 minutes. Then the mixture is refluxed for 3 hours, and the solid which forms is separated by filtration and washed with methanol. Residual solvent is removed under reduced pressure to yield a solid which is diluted with water and extracted with ether. The ethereal extracts are dried over a molecular sieve and filtered. The solvent is removed under reduced pressure to afford an oil which is dissolved in anhydrous ether. That solution is cooled in an ice bath while slowly adding isopropanolic hydrochloric acid. The precipitate which forms is recovered by filtration, washed with ether and air dried to afford pure 2-(cyclohexylthio)ethylamine hydrochloride, melting at about 210°-211°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C@@H:6]([NH:21][C:22]1[C:27]([Br:28])=[CH:26][N:25]=[C:24](Cl)[N:23]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:9][CH:8]=1)[CH3:2].[CH3:31][NH:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>CC(O)C>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][C@@H:6]([NH:21][C:22]1[C:27]([Br:28])=[CH:26][N:25]=[C:24]([N:32]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH3:31])[N:23]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H](Nc1nc(Cl)ncc1Br)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Reactant: CNC1CCCCC1
Solvent: CC(C)O
Product: CCOC(=O)C[C@@H](Nc1nc(N(C)C2CCCCC2)ncc1Br)c1ccc(O[Si](C)(C)C(C)(C)C)cc1

Procedure:
A solution of (R)-3-(5-bromo-2-chloropyrimidin-4-ylamino)-3-(4-(tert-butyldimethylsiloxy)phenyl)propanoic acid ethyl ester (1.0 eq) and N-methylcyclohexylamine (10.0 eq) in iPrOH in a sealed tube was stirred at 130° C. for 5 h, and then the iPrOH was evaporated. The residue was partitioned between water and EtOAc, and then the EtOAc extracts were treated with MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel using 9:1 hexanes/EtOAc to give (R)-3-(5-bromo-2-(N-cyclohexyl-N-methylamino)pyrimidin-4-ylamino)-3-(4-(tert-butyldimethylsiloxy)phenyl)propanoic acid ethyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.Cl.[NH2:17][NH:18][C:19]([NH2:21])=[O:20].C([O-])(=O)C.[Na+]>C(O)C.O.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[N:17][NH:18][C:19]([NH2:21])=[O:20])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1
Reactant: NNC(N)=O
Reactant: O=Cc1ccc(Oc2ccncc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: NC(=O)NN=Cc1ccc(Oc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
To a solution of 4-(4-pyridinoxy)benzaldehyde (570 mg, 2.86 mmol) in ethanol (10 mL) was added a solution of semicarbazide hydrochloride (350 mg, 3.03 mmol) and sodium acetate (235 mg, 2.86 mmol) in water (5 mL). The mixture was stirred at room temperature for 30 min., diluted with ethyl acetate (75 mL), washed with 2N NaOH, water and brine, dried over Na2SO4, concentrated in vacuo to yield the title compound as a white solid (720 mg, 2.77 mmol, 97%), mp: 212-213° C. 1H NMR (DMSO-d6): δ 10.29 (s, 1H), 8.49 (d, J=4.9, 2H), 7.87 (s, 1H), 7.84 (d, J=8.5, 2H), 7.19 (d, J=8.5, 2H), 6.96 (d, J=4.9, 2H), 6.53 (s, 2H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[C:10]([Cl:12])[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:8]([OH:17])[C:7]=2[N+:18]([O-])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd]>[N:1]1([C:6]2[CH:11]=[C:10]([Cl:12])[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:8]([OH:17])[C:7]=2[NH2:18])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1c(Cl)cc(N2CCCC2)c([N+](=O)[O-])c1O
Reactant: [H][H]
Agent: [Pd]
Product: Nc1c(N2CCCC2)cc(Cl)c(S(N)(=O)=O)c1O
Yield: 98.5 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, (N-pyrrolidinyl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (0.73 g, 2.4 mmol) was reduced with hydrogen and 10% Pd/C (0.73 g) to form the desired product (0.69 g, crude). MS m/z (M+H) 276.9, 278.89, 279.88.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].Cl[C:13]1[C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1>O.[OH-].[Na+]>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:13]1[C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: Cc1[nH]cnc1CSCCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1[nH]cnc1CSCCNc1ncccc1C(=O)O

Procedure:
An intimate mixture of powdered 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.71 g; 0.010 moles) and 2-chloropyridine-3-carboxylic acid (1.73 g; 0.011 moles) was heated to 150° for 6 hours. The resulting cooled glass was dissolved in a little water and neutralised by slow addition of 2N sodium hydroxide solution. At pH6, solid precipitated out of solution. This was filtered off, and recrystallised from water to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethyl]amino pyridine 3-carboxylic cid as small, colourless crystals (1.04 g) which sublimed at 98°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].[CH3:24][S:25]([N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:37][CH2:36][CH:35]2[C:38]([O-])=[O:39])[CH2:30][CH2:29]1)(=[O:27])=[O:26].[Li+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:38]([CH:35]2[CH2:36][CH2:37][N:34]2[CH:31]2[CH2:32][CH2:33][N:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:29][CH2:30]2)=[O:39])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: CS(=O)(=O)N1CCC(N2CCC2C(=O)[O-])CC1
Agent: [Li+]
Product: CS(=O)(=O)N1CCC(N2CCC2C(=O)N2C[C@H](S(=O)(=O)c3ccccc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)CC1

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H and lithium 1-(1-(methylsulfonyl)piperidin-4-yl)azetidine-2-carboxylate 20L carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(1-(methylsulfonyl)piperidin-4-yl)azetidine-2-carbonyl)pyrrolidine-2-carboxamide 1:1 epimers as a light brown solid (quant.). MS ISP (m/e): 598.1 (100) [(M+H)]]+.
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=1.CO.C[O-].[Na+].[CH:19]1[C:28]2[C:23](=[CH:24][C:25]([CH:29]=[O:30])=[CH:26][CH:27]=2)[CH:22]=[CH:21][N:20]=1>O>[O:30]1[C:29]([C:25]2[CH:24]=[C:23]3[C:28](=[CH:27][CH:26]=2)[CH:19]=[N:20][CH:21]=[CH:22]3)=[CH:12][N:11]=[CH:10]1
Reactant: O=Cc1ccc2cnccc2c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: c1cc2cc(-c3cnco3)ccc2cn1
Temperature: 0 °C
Yield: 84.9 %

Procedure:
To a 150 mL round-bottomed flask was added p-toluenesulfonylmethyl isocyanide (3.50 g, 18.0 mmol) and MeOH, followed by sodium methoxide (11.0 mL, 50.9 mmol) and a MeOH solution of isoquinoline-6-carbaldehyde (2.35 g, 15.0 mmol). The solution was stirred at reflux for about 1 hour and followed by LCMS. Water was added (50 mL) and the MeOH was removed in vacuo. The suspension was cooled to 0° C., and the resulting precipitate was filtered and dried in a vacuum oven overnight to give 6-(oxazol-5-yl)isoquinoline (2.50 g, 85% yield) as a tan powder. LCMS (API-ES) m/z (%): (100%, M++H).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([N:13]1[CH2:30][CH2:29][C:16]2([C:21]3=[CH:22][CH:23]=[CH:24][N:20]3[C:19]3[CH:25]=[CH:26][CH:27]=[CH:28][C:18]=3[O:17]2)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN([CH:34]=[O:35])C>>[CH2:6]([N:13]1[CH2:30][CH2:29][C:16]2([O:17][C:18]3[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=3[N:20]3[C:24]([CH:34]=[O:35])=[CH:23][CH:22]=[C:21]23)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: c1ccc(CN2CCC3(CC2)Oc2ccccc2-n2cccc23)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc2n1-c1ccccc1OC21CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
N,N-Dimethylformamide (723 μL, 9.40 mmol), under nitrogen, was cooled to 0° C. and POCl3 (876 μL, 9.40 mmol) was added dropwise. The reaction was stirred for 20 min at 0° C. and a white solid formed. A solution of 1-benzylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (2.07 g, 6.27 mmol) in dry DMF (15.5 mL) was added dropwise and the cooling bath was removed. The reaction mixture was stirred for 2 h at 50° C., then cooled down to room temperature and poured onto ice. Sodium hydroxide (1M) was added until the pH reached 10, then the solution was acidified to pH 6 with 3 M HCl. The mixture was then extracted with EtOAc. The organics were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel: 10-70% EtOAc in hexanes) to give 1′-benzylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde (1.94 g, 86%). ESI-MS m/z calc. 358.4. found 359.3 (M+1)+; Retention time: 1.16 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 9.66 (s, 1H), 8.17-8.07 (m, 1H), 7.38-7.30 (m, 4H), 7.29-7.24 (m, 1H), 7.20-7.13 (m, 2H), 7.09 (m, 2H), 6.20 (d, J=4.1 Hz, 1H), 3.59 (s, 2H), 2.76 (m, 2H), 2.58-2.45 (m, 2H), 2.10-1.96 (m, 4H).
Reaction SMILES: [CH2:1]([C:4]#[N:5])[CH:2]=[CH2:3].[C:6]1([SiH:12]([Cl:14])[Cl:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[Pt].[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[C:4]([CH2:1][CH2:2][CH2:3][Si:12]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([Cl:14])[Cl:13])#[N:5]
Reactant: Cl[SiH](Cl)c1ccccc1
Reactant: C=CCC#N
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [Pt]
Agent: [H+]
Product: N#CCCC[Si](Cl)(Cl)c1ccccc1
Temperature: 120 °C

Procedure:
(γ-Cyanopropyl) phenyldichlorosilane was prepared by adding 67.1 grams (1.0 moles) of allylcyanide slowly to 177.1 grams (1.0 moles) of phenyldichlorosilane containing 10-4 moles of platinum as chloroplatinic acid at a temperature of 130° - 135° C. in a three-necked flask. After completion of the addition, the reaction mixture was heated at 120° C. for 16 hours. The pure (γ-cyanopropyl) phenyldichlorosilane was isolated by fractional distillation (b.p. 132° C./0.7 mm).
Reaction SMILES: [NH2:1][CH:2]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)[C:3]([N:5]([CH2:16][CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][N:13]=[CH:12]2)=[O:4].[CH2:36]([NH:43][C:44](=[O:54])[NH:45][C@H:46]([CH2:51][CH:52]=[CH2:53])[CH2:47][C:48](O)=[O:49])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[C:32]([O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH:2]([NH:1][C:48](=[O:49])[CH2:47][CH:46]([NH:45][C:44]([NH:43][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:54])[CH2:51][CH:52]=[CH2:53])[C:3](=[O:4])[N:5]([CH2:16][CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][N:13]=[CH:12]3)=[CH:26][CH:27]=1)([CH3:33])([CH3:35])[CH3:34]
Reactant: CCOC(CN(Cc1cccc2cn[nH]c12)C(=O)C(N)Cc1ccc(OC(C)(C)C)cc1)OCC
Reactant: C=CC[C@H](CC(=O)O)NC(=O)NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC(CC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc2cn[nH]c12)CC(OCC)OCC)NC(=O)NCc1ccccc1
Reaction time: 0.67 h

Procedure:
To a solution of 2-Amino-3-(4-tert-butoxy-phenyl)-N-(2,2-diethoxy-ethyl)-N-(1H-indazol-7-ylmethyl)-propionamide in CH2Cl2 (50 mL) was added a solution of (3R)-3-(3-Benzyl-ureido)-hex-5-enoic acid (1.6 g, 6.1 mmol), EDCI (1.17 g, 1.2 eq), HOBt (0.93 g, 1.2 eq), DIEA (2.13 mL, 12.2 mmol) in CH2Cl2 (100 mL) stirred for 40 min. The reaction mixture was stirred at room temperature for 14 h, and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The crude compound was used next step without further purification. MS ESI 727 (M+H), 749 (M+Na)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[C:10]1(C(O)=O)[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[CH2:12][CH2:11]1.CCN(CC)CC>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:10]1[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[CH2:12][CH2:11]1)[C:8]#[N:9]
Reactant: N#Cc1ccc(C2(C(=O)O)CCc3cncn32)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: N#Cc1ccc(C2CCc3cncn32)c(Cl)c1

Procedure:
The 5-(2-chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid (0.02 g, 70 mol) is dissolved in DMSO (2 mL) and Et3N (0.2 mL) and heated at 100° C. for 2 h. The solution is evaporated to dryness and residue purified via reverse phase HPLC (5-100% MeCN/water w/0.1% TFA) to give 3-chloro-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile as a white solid. MS (ESI) m/z 244.2, 246.2 (M+H); 1H NMR (400 MHz, CDCl3) (TFA salt) δ ppm 2.60-2.73 (m, 1H), 3.08-3.20 (m, 2H), 3.22-3.36 (m, 1H), 6.04 (dd, J=7.6, 5.8 Hz, 1H), 6.91 (d, J=8.1 Hz, 1H), 7.24 (s, 1H), 7.61 (d, J=8.1 Hz, H), 7.81 (d, J=1.5 Hz, 1H), 8.53 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:29]2[CH2:30][CH2:31][N:26]([C:21]3[N:20]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:27][CH2:28]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Product: COc1nc2ccc(C)cc2nc1NC(=O)N1CCN(c2ncccn2)CC1
Yield: 93 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(2-pyrimidyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 93%). 1H NMR (300 MHz, CDCl3): δ 2.47 (s, 4H), 3.71 (s, 3H), 3.91-3.99 (m, 4H), 4.13 (s, 3H), 6.53 (s, 1H), 7.01-7.13 (m, 1H), 7.27-7.30 (m, 1H), 7.52-7.61 (m, 2H), 8.33 (d, J=4.8 Hz, 2H).
Reaction SMILES: C(OC([NH:8][C:9]1([CH3:22])[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[N:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[NH2:8][C:9]1([CH3:22])[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[N:16]=2)[CH2:11][CH2:10]1
Reactant: CC1(NC(=O)OC(C)(C)C)CCN(c2ccnc(Cl)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC1(N)CCN(c2ccnc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The procedure described in Example 2 is followed up to the end of step (c). A solution of 6.81 g (0.021 mol) of 4-t-butoxycarbonylamino-1-(2-chloropyrimidin-4-yl)-4-methylpiperidine (step c) in 80 ml of anhydrous methylene chloride is cooled under a nitrogen atmosphere and 16.4 ml of anisole and 83 ml of trifluoroacetic acid are added slowly. The mixture is stirred for 1 hour at room temperature and 80 ml of a 30% solution of NaOH are added slowly. The reaction medium is extracted with methylene chloride and dried over Na2SO4 and the solvent and the anisole are evaporated off under reduced pressure to give 4-amino-1-(2- chloropyrimidin-4-yl)-4-methylpiperidine as the base, which is treated with maleic acid in an ethanol/ethyl ether mixture. The maleate obtained in this way is isolated by filtration (yield 65%, m.p. 125°-126° C.).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[CH3:40][C:41]1[CH:42]=[C:43]([CH:59]=[CH:60][CH:61]=1)[CH2:44][N:45]1[CH:49]=[C:48](B2OC(C)(C)C(C)(C)O2)[CH:47]=[N:46]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:40][C:41]1[CH:42]=[C:43]([CH:59]=[CH:60][CH:61]=1)[CH2:44][N:45]1[CH:49]=[C:48]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[CH:47]=[N:46]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Reactant: Cc1cccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 93.9 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (intermediate 41) (200 mg, 0.303 mmol) was coupled with 1-(3-methylbenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 64D) (136 mg, 0.455 mmol) using sodium carbonate (81 mg, 0.759 mmol) and Pd(PPh3)2Cl2 (11 mg, 0.015 mmol) in toluene/ethanol/water (10/2/1 ml) to afford 200 mg (93.8% yield) of titled compound after purification by column (Silica gel 6/120) using 50% EtOAc/hexane as eluent. MS: m/z=703.2 (M+1).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:28]=3[N:29]=2)=[CH:21][CH:20]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[S:26][C:27]4[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:28]=4[N:29]=3)=[CH:23][CH:24]=2)=[O:11])=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc(OCCF)cc1
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(OCCF)cc4)cc3)sc2c1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
A mixture of 4-(2-fluoroethoxy)benzoic acid (0.20 g, 1.11 mmol) and thionyl chloride (0.53 g, 4.44 mmol) in chloroform (5 ml) was heated under reflux for 5 h. The reaction mixture was cooled to room temperature and the excess reagent and solvent was removed under reduced pressure to give the crude acid chloride. The amide was prepared as described in the Amide Coupling section using the crude acid chloride, and 2-(4-aminophenyl)-6-methoxybenzothiazole (0.28 g, 1.11 mmol) in dry pyridine (10 ml) to give the title compound (0.34 g, 72%) as a pale yellow solid after work-up.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[CH:3]=1.[I:23]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[C:3]=1[I:23]
Reactant: Nc1cc(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Nc1c(I)c(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
To a stirred solution of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole (0.182 g) in acetonitrile (3 ml) at room temperature was added N-iodosuccinimide (0.113 g). After 20 minutes the mixture was evaporated to dryness and the residue taken up in dichloromethane (20 ml). After washing with water (20 ml, ×2), brine (20 ml) and drying (MgSO4) the solution was evaporated. The residue was triturated with hexane and the supernatant evaporated to give the title compound as an off-white solid, m.p. 126° C.