Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:21](I)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[F:23][C:24]1[CH:25]=[N:26][NH:27][C:28]=1[Sn](CCCC)(CCCC)CCCC>CS(C)=O.CCOC(C)=O.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>[Cl:1][C:2]1[C:21]([C:28]2[NH:27][N:26]=[CH:25][C:24]=2[F:23])=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1[nH]ncc1F
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2[nH]ncc2F)c1
Temperature: 100 °C

Procedure:
Pd(Ph3P)4 (17.33 mg, 0.015 mmol) was added to solution of 6-chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 4.2, 133 mg, 0.3 mmol) and 4-fluoro-5-(tributylstannyl)-1H-pyrazole (101 mg, 0.270 mmol) in DMSO (1 mL) in a vial under an argon atmosphere. The vial was sealed and the RM mixture was heated at 100° C. for 18 h. After cooling to RT, the RM was dissolved in EtOAc, washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, n-heptane/EtOAc from 10% to 50% EtOAc) to afford the title compound as an off-white powder. HPLC (Condition 4) tR=5.5 min, UPLC-MS (Condition 3) tR=1.05 min, m/z=399.2 [M−H]−.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:33])/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=3)=[CH:4][C:3]=2[O:2]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl.CO>CN(C=O)C>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:33])/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:5][CH2:10][N:11]([CH3:23])[CH3:12])[CH:27]=3)=[CH:4][C:3]=2[O:2]1
Reactant: O=C(/C=C/c1cccc(O)c1)N1CCc2c([nH]c3ccccc23)C1c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCOc1cccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)c1
Yield: 41.3 %

Procedure:
To a solution of Example 58 (0.25 g, 0.57 mmol) in 50 mL of DMF was added K2CO3 (0.24 g, 3 equiv.) and an excess of dimethylaminodiethyl chloride (about 15 equiv.). The resulting mixture was heated at 60° C. for four hours until disappearance of the Jstarting material (tlc monitoring, DCM:MeOH (90:10). A new compound was formed (Rf=0.20). After evaporation of DMF, the residue was taken up in 150 mL of DCM, washed with 2×50 mL of water, dried over Na2SO4 and recrystallized from EtOH:H2O to give the title compound (0.06 g, 22%) as yellow crystals.
Reaction SMILES: [N:1]1([CH:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]2)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:22]1([S:32](Cl)(=[O:34])=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>ClCCl>[C:22]1([S:32]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]2[CH:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH3:8])(=[O:34])=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: CC(C1CCCCN1)N1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C1CCCCN1S(=O)(=O)c1cccc2ccccc12)N1CCCCC1
Reaction time: 24 h
Yield: 58.2 %

Procedure:
To a stirred solution of 2-[1-(piperidinyl)ethyl]piperidine (196 mg, 1 mmol) and triethylamine (0.14 ml, 1 mmol) in dichloromethane (10 ml) cooled by an ice bath, was added dropwise a solution of 1 -naphthalene sulfonyl chloride (226 mg, 1 mmol) in dichloromethane. Stirring continued, allowing the solution to reach room temperature for 24 hours. The solution was washed thoroughly (10% NaOH), and brine, dried (Na2SO4) and concentrated in vacuo to afford a pale yellow oil (225 mg, 58%) M+=387.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:21]=[C:20](Cl)[N:19]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[CH:17]=2)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>[Pd].CCN(CC)CC>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:21]=[CH:20][N:19]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[CH:17]=2)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(N2CCC(CNC(=O)OC(C)(C)C)CC2)nc(Cl)n1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(N2CCC(CNC(=O)OC(C)(C)C)CC2)ncn1
Reaction time: 6 h

Procedure:
A 50 mL round-bottomed flask was charged with methyl 6-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)-2-chloropyrimidine-4-carboxylate and MeOH (4 mL) and Et3N (0.4 mL). 10% Pd/C (104 mg, 0.25 equiv.) was added under argon. The reaction mixture was stirred for 6 h under 1 atm H2. The catalyst was filtered and the solvent was evaporated to give the crude desired product (150 mg, 110% crude yield) which was used directly in the next step. LC-MS m/z 351 (M+1).
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[CH2:14][N:13]([C:15]([O:17]C(C)(C)C)=O)[C@H:12]([C:22]([OH:24])=O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=C=O.[CH2:33]([N:35]1[C:47]2[CH:46]=[CH:45][C:44]([NH2:48])=[CH:43][C:42]=2[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH3:34]>>[CH2:1]([O:8][N:9]=[C:10]1[CH2:14][N:13]([C:15]([NH:25][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:17])[C@H:12]([C:22]([NH:48][C:44]2[CH:45]=[CH:46][C:47]3[N:35]([CH2:33][CH3:34])[C:36]4[C:41]([C:42]=3[CH:43]=2)=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:24])[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccccc2)C[C@H]1C(=O)O
Reactant: CCCCCN=C=O
Product: CCCCCNC(=O)N1CC(=NOCc2ccccc2)C[C@H]1C(=O)Nc1ccc2c(c1)c1ccccc1n2CC

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, 1-isocyanatopentane, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 63% purity by LC/MS. MS(ESI+): m/z=540.4.
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[F:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1.[C@H:23]1([NH:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([NH2:43])[CH:39]=3)[N:34]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1>>[F:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:1]([NH:43][C:38]2[CH:39]=[C:40]3[C:35](=[CH:36][CH:37]=2)[N:34]=[C:33]([NH:32][C@H:23]2[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24]2)[CH:42]=[CH:41]3)=[O:12])[CH2:18][CH2:17]1
Reactant: NC1CCN(CCF)CC1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)NC1CCN(CCF)CC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 1-(2-fluoro-ethyl)-piperidin-4-ylamine and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=448.8 (M+H+).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)[CH3:16])=[C:11]([CH2:31][CH2:32][CH3:33])[N:10]3[N:34]=[CH:35][N:36]=[C:9]23)[CH2:4][CH2:3]1.[N+](=[CH:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N-].O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+]>[C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:20]1[CH:21]=[CH:22][C:17]([CH:15]([C:12]2[C:13](=[O:14])[N:8]([C@H:5]3[CH2:6][CH2:7][C@H:2]([O:1][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:3][CH2:4]3)[C:9]3[N:10]([N:34]=[CH:35][N:36]=3)[C:11]=2[CH2:31][CH2:32][CH3:33])[CH3:16])=[CH:18][CH:19]=1)#[N:30]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCCc1c(C(C)c2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Agent: [Rh+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1c(C(C)c2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ncnn12
Reaction time: 0.5 h

Procedure:
To a mixture of 4′-{1-[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]ethyl}biphenyl-2-carbonitrile (1.24 g), rhodium(I) acetate (0.34 g) and toluene (20 mL) was added dropwise a solution of ethyl diazoacetate (1.38 g) in toluene (10 mL) at 70° C., and the mixture was stirred at the same temperature for 30 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless oil (0.70 g, 48%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:19][CH:20]([CH3:22])[CH3:21])=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]([CH:12]([F:14])[F:13])=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[Cl:23][C:24]1[S:25][C:26]([C:33](Cl)=[O:34])=[C:27]([C:29]([F:32])([F:31])[F:30])[N:28]=1>>[Cl:23][C:24]1[S:25][C:26]([C:33]([NH:1][C:2]2[C:3]([CH2:19][CH:20]([CH3:22])[CH3:21])=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]([CH:12]([F:14])[F:13])=[N:6][C:7]=2[C:8]([F:10])([F:11])[F:9])=[O:34])=[C:27]([C:29]([F:30])([F:31])[F:32])[N:28]=1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(N)c1CC(C)C
Reactant: O=C(Cl)c1sc(Cl)nc1C(F)(F)F
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(NC(=O)c2sc(Cl)nc2C(F)(F)F)c1CC(C)C

Procedure:
Methyl 5-amino-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (example A1 of U.S. Pat. No. 5,114,465) was reacted with 2-chloro-4-(trifluoromethyl)-5-thiazolecarbonyl chloride according to the procedure in example 1 of U.S. Pat. No. 5,114,465 afforded the product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:17]=[C:16](F)[CH:15]=[CH:14][C:11]=1[CH:12]=[O:13].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[CH2:25]([O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:16]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[C:10]([Cl:9])[CH:17]=2)=[CH:4][CH:3]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Sc2ccc(OCc3ccccc3)cc2)cc1Cl
Temperature: 50 °C
Reaction time: 2 h

Procedure:
p-hydroxythiophenol (2.12 g) was dissolved in N,N-dimethylformamide (40 mL). To this solution, 2-chloro-4-fluorobenzaldehyde (2.66 g) and potassium carbonate (4.64 g) were added and the mixture was stirred for 2 hours at 50° C. Subsequently, benzyl bromide (4.00 mL) was added and the mixture was stirred for 1.5 hours at 50° C. and then for 2.5 hours at 70° C. The reaction mixture was extracted with ethyl acetate and the extract was washed sequentially with water and a saturated aqueous solution of sodium chloride. The organic phase was then dried over anhydrous sodium sulfate. Following addition of water, the solvent was removed by distillation and the residue was purified on a silica gel column chromatography (hexane:ethyl acetate=10:1). This gave the desired product as a colorless solid (5.70 g).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[C:4]([CH2:16][CH3:17])[CH:3]=1.C([Li])CCC.[CH:23](=[O:26])[CH2:24][CH3:25].[Cl-].[NH4+]>C1COCC1>[Si:7]([O:6][C:5]1[CH:14]=[CH:15][C:2]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:3][C:4]=1[CH2:16][CH3:17])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CCC=O
Reactant: CCc1cc(Br)ccc1O[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1cc(C(O)CC)ccc1O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
11.9 g (38 mmol) of (4-bromo-2-ethylphenoxy)-tert-butyldimethylsilane are placed in 200 ml of THF in a round-bottomed flask and under a stream of nitrogen. The reaction medium is cooled to −78° C. and 16.6 ml (41 mmol) of n-butyllithium (2.5 M/THF) are added dropwise. 30 minutes later, 3.2 ml (45 mmol) of propionaldehyde are added dropwise. The medium is stirred for 3 hours at −78° C. It is then poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and then evaporated. 11.1 g (100%) of the expected product are obtained in the form of a colorless oil.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:21]=[C:22]1[C:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH2:25][CH2:24][N:23]1[CH2:40][C:41](O)=[O:42].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[OH:8][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:9]1[CH2:14][CH2:13][N:12]([C:41](=[O:42])[CH2:40][N:23]2[CH2:24][CH2:25][CH2:26][C:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]2=[O:21])[CH2:11][CH2:10]1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(C(O)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of diphenyl(piperidin-4-yl)methanol (0.13 g, 0.5 mmol) in dichloromethane (10 mL) under nitrogen was added 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.16 g, 0.50 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.19 g, 1.00 mmol) and N,N-dimethylpyridin-4-amine (6 mg, 0.05 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:3) gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.42-7.48 (m, 4H), 7.16-7.35 (m, 16H), 4.63-4.71 (m, 1H), 4.20 (d, J=1.5 Hz, 2H), 3.77-3.84 (m, 1H), 3.42-3.54 (m, 2H), 2.97-3.06 (m, 1H), 2.57-2.68 (m, 4H), 1.74-1.87 (m, 2H), 1.46-1.64 (m, 3H), 1.29-1.42 (m, 2H); MS (ESI+) m/z 559 (M+H)+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[CH3:35][NH:36][CH2:37][CH2:38][OH:39]>>[OH:39][CH2:38][CH2:37][N:36]([CH3:35])[C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:29]1[CH:28]=[CH:27][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:31][CH:30]=1)=[O:7])=[O:18]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: CNCCO
Product: CON=C1C[C@@H](C(=O)N(C)CCO)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and 2-(methylamino)ethanol, the title compound was obtained in 78% purity by HPLC. MS(ESI+): m/z=410.
Reaction SMILES: [OH:1]O.[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][C:10]#[N:11])[CH:4]=1.O>C(O)(=O)C>[CH:7]1[CH:8]=[N+:3]([O-:1])[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=1
Reactant: N#CCc1cccnc1
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: N#CCc1ccc[n+]([O-])c1
Temperature: 95 °C
Reaction time: 72 h

Procedure:
30% Hydrogen peroxide (12 mL) was added to a solution of 3-pyridylacetonitrile (7.50 g, 63.5 mmol) in acetic acid (40 mL) and the mixture heated at 95° C. for 20 hours. The reaction mixture was then cooled and stirred at room temperature for 72 hours. Water (35 mL) was then added and the solution concentrated under reduced pressure. Water (2×100 mL) was added to the residue and solution concentrated under reduced pressure. Residual water was removed azeotropically using toluene (2×100 mL) to yield the title compound (I115) (8.3 g, 97%) as a pale yellow solid which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.O=[CH:26][CH2:27][CH2:28][NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[CH2:32]([O:31][C:30]([NH:29][CH2:28][CH2:27][CH2:26][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:15][CH2:16]1)=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccccc2N)CC1
Reactant: O=CCCNC(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccccc2NCCCNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
The compound prepared in Example 302 (0.455 g) was suspended in 1,2-dichloroethane (10 mL). Benzyl 3-oxopropylcarbamate (0.425 g) and beaded molecular sieves were added and the reaction mixture stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.870 g) was added and the reaction mixture stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine. The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 20-30% ethyl acetate/hexane) to furnish the title compound (0.629 g) with the following physical properties.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[N:17]=[C:16]3[N:18]([CH3:21])[CH:19]=[CH:20][C:15]3=[CH:14][CH:13]=2)[CH:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>CN1CCCC1=O>[C:32]([O:31][C:30](=[O:36])[NH:29][C@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@H:23]1[NH:22][C:2]1[N:7]=[N:6][C:5]([C:8](=[O:9])[NH2:10])=[C:4]([NH:11][C:12]2[N:17]=[C:16]3[N:18]([CH3:21])[CH:19]=[CH:20][C:15]3=[CH:14][CH:13]=2)[CH:3]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: Cn1ccc2ccc(Nc3cc(Cl)nnc3C(N)=O)nc21
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: CN1CCCC1=O
Product: Cn1ccc2ccc(Nc3cc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nnc3C(N)=O)nc21
Temperature: 150 °C
Reaction time: 16 h
Yield: 18 %

Procedure:
6-Chloro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-6-ylamino)-pyridazine-3-carboxylic acid amide (42 mg, 0.139 mmol), and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (89 mg, 0.416 mmol) were dissolved in N-methylpyrrolidinone (1.4 mL) and heated at 150° C. for 36 h. Additional tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (35 mg, 0.16 mmol) was added and the heating continued for 16 h more. The reaction mixture was cooled and concentrated in vacuo, then diluted with water, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by chromatography (silica, 0 to 5% methanol in dichloromethane) gave {(1S,2R)-2-[6-carbamoyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-6-ylamino)-pyridazin-3-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (12 mg, 18%) as a light brown amorphous residue. LCMS (EI/CI) m/z: 481 [M+H].
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.[OH:25][CH:26]1[CH2:29][NH:28][CH2:27]1.CCN(C(C)C)C(C)C.CO>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([N:28]5[CH2:29][CH:26]([OH:25])[CH2:27]5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Reactant: OC1CNC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CC(O)C3)cc1OCC2
Yield: 14 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and 3-hydroxyazetidine hydrochloride with added DIPEA (2.2 eq.), were reacted and the crude product subjected to flash chromatography (SiO2, gradient 0 to 8% methanol in DCM) then recrystallisation from IMS to give 370 as pale green crystals (16 mg, 14%). LCMS: RT=2.26 min, [M+H]+ 368. 1H NMR 400 MHz (DMSO-d6) δ: 9.09 (1H, s), 7.90 (1H, d, J=0.63 Hz), 7.84 (1H, s), 5.95-5.94 (1H, m), 5.91 (1H, s), 5.70 (1H, d, J=6.40 Hz), 4.59 (1H, s), 4.55-4.47 (4H, m), 4.18 (2H, t, J=7.66 Hz), 3.70 (2H, dd, J=8.85, 4.66 Hz), 1.48 (6H, d, J=6.60 Hz)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)NC=C4)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH2:37][C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:33][CH2:32]1.C([O-])([O-])=[O:54].[Na+].[Na+]>CC#N.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>[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([C:2]3[CH:3]=[C:4]4[C:10]([C:11]5[CH:12]=[CH:13][C:17]([OH:54])=[CH:18][CH:19]=5)=[CH:9][NH:8][C:5]4=[N:6][CH:7]=3)=[CH:42][CH:43]=2)[CH2:33][CH2:32]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(Br)cnc32)cc1
Reactant: O=C([O-])[O-]
Reactant: CN1CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CC#N
Product: CN1CCN(Cc2ccc(-c3cnc4[nH]cc(-c5ccc(O)cc5)c4c3)cc2)CC1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-3-(1H-indol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (0.220 g, 0.5 mmol) in CH3CN (2.5 mL) in a Personal Chemistry microwave reaction vial was added 1-Methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperazine (0.20 g, 0.65 mmol), bis(triphenylphosphine)-palladium(II) dichloride (0.003 g, 0.005 mmol), and 1 M Na2CO3 (1 mL). The resulting mixture was de-gassed with Ar for 10 min, after which it was heated at 150° C. for 30 min in a Personal Chemistry Optimizer. The organic layer was separated, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (3 mL) and acetone (2 mL), and 2 M NaOH (1.5 mL) was added. The resulting mixture was stirred at 65° C. for 30 min, after which it was partitioned between EtOAc and 1 M NaOH. The organic layer was separated, dried over MgSO4, filtered, and stripped to give a residue purified via preparatory HPLC to give the title compound as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 11.78 (s, 1H), 11.03 (s, 1H), 8.51 (d, J=2.1 Hz, 1H), 8.36 (d, J=1.8 Hz, 1H), 7.86 (s, 1H), 7.72 (d, J=2.4 Hz, 1H), 7.45 (s, 2H), 7.32 (m, 1H), 6.92 (s, 2H), 6.45 (m, 1H), 3.85 (s, 6H), 3.70 (s, 3H); HPLC retention time: 2.04 minutes; MS ESI (m/z): 399 (M+1)+, calc. 398.51.