Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:31])[C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[O:29][CH3:30])[CH2:16][CH2:15]1)[C:9](=[O:32])[CH2:8][CH2:7]2)([O-])=O>[C].[Pd].C(O)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH:14]1[CH2:15][CH2:16][N:17]([C:20](=[O:31])[C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[O:29][CH3:30])[CH2:18][CH2:19]1)[C:9](=[O:32])[CH2:8][CH2:7]2
Reactant: COc1ccc(C(=O)N2CCC(N3C(=O)CCc4cc([N+](=O)[O-])ccc43)CC2)c(OC)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(C(=O)N2CCC(N3C(=O)CCc4cc(N)ccc43)CC2)c(OC)c1
Reaction time: 1 h
Yield: 51 %

Procedure:
A mixture of 10% palladium-carbon (0.4 g) and acetic acid (50 ml) is added to 6-nitro-1-[1-(2,4-dimethoxybenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (4.0 g) and the mixture is subjected to catalytic reduction at 70° C. for 1 hour. The catalyst is filtered off and the filtrate is concentrated. The resulting residue is basified with 10% aqueous sodium hydroxide solution and extracted with dichloromethane. The solvent is concentrated and the resulting residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=20:1) to give 6-amino-1-[1-(2,4-dimethoxybenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (1.9 g).
Reaction SMILES: [F:1][C@:2]12[CH:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@H:14]([CH3:30])[C@:15]3([O:25][C:26](=[O:29])[CH2:27][CH3:28])[C:16](=[O:19])[CH2:17][SH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:32])[CH:4]=[CH:5][C:6](=[O:31])[CH:7]=1.[CH:33]([NH:35][C@H:36]([C:41](O)=[O:42])[CH2:37][CH2:38][S:39][CH3:40])=[O:34]>>[F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@H:14]([CH3:30])[C@:15]3([O:25][C:26](=[O:29])[CH2:27][CH3:28])[C:16](=[O:19])[CH2:17][S:18][C:41](=[O:42])[CH:36]([NH:35][CH:33]=[O:34])[CH2:37][CH2:38][S:39][CH3:40])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:32])[CH:4]=[CH:5][C:6](=[O:31])[CH:7]=1
Reactant: CCC(=O)O[C@]1(C(=O)CS)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)C(O)C[C@@]21C
Reactant: CSCC[C@H](NC=O)C(=O)O
Product: CCC(=O)O[C@]1(C(=O)CSC(=O)C(CCSC)NC=O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Yield: 43.8 %

Procedure:
The title compound (0.47 gm) was prepared from 9-fluoro-11 hydroxy-16β-methyl-17-(1-oxopropyloxy)-pregna-1,4-diene-3,20-dione-21-thiol (0.80 gm) and N-formyl-L-methionine (0.99 gm) in the same manner as in Synthetic Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.[Br:22]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C=CC=CC=1>[Br:22][CH2:12][C:11]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]([C:13]([F:16])([F:15])[F:14])[O:8]2)=[CH:3][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(C)cc2OC1C(F)(F)F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)C1=Cc2cc(Cl)c(CBr)cc2OC1C(F)(F)F
Temperature: 84 °C
Reaction time: 5 h
Yield: 78.1 %

Procedure:
To a mixture of the product of Example 157 Step 2 (4.0 g, 12.5 mmol), N-bromosuccinimide (2.3 g, 13.1 mmol), and 21 mL benzene, was added benzoyl peroxide (145 mg. 0.6 mmol). The reaction was heated to 84° C. After 5 h, the reaction was cooled to 25° C. and stored overnight. Solid was removed from the reaction by filtration, and washed with 4 mL benzene. To the filtrate, was added N-bromosuccinimide (1.0 g, 5.7 mmol) and benzoyl peroxide (145 mg, 0.6 mmol). The reaction was heated to 84° C. After 2.5 h, the reaction was cooled to 25° C. The solid was removed from the reaction by filtration and the filtrate was concentrated. The residue was purified by flash chromatography (toluene/EtOAc=9/1) to give 3.9 g a yellow solid of reasonably pure material, which was used without further purification.
Reaction SMILES: [C:1]([CH2:4][N:5]([CH2:19][C:20]([OH:22])=O)[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)([OH:3])=[O:2].C(=O)(O)[O-].[Na+].[C:28]([O:32][C:33]([NH:35][C@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C(OC(=O)C)(=O)C>[C:28]([O:32][C:33]([NH:35][C@H:36]1[CH2:40][CH2:39][N:38]([C:20](=[O:22])[CH2:19][N:5]([CH2:4][C:1]([OH:3])=[O:2])[C:6]2[CH:7]=[CH:8][C:9]([O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:10][CH:11]=2)[CH2:37]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=C(O)CN(CC(=O)O)c1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(CC(=O)O)c2ccc(Oc3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 44.9 %

Procedure:
A mixture of [carboxymethyl-(4-phenoxyphenyl)amino]acetic acid 19 (0.5 g, 1.66 mmol) in acetic anhydride (10 mL) was heated to reflux with stirring for 45 minutes. The reaction mixture was cooled to room temperature and poured into saturated aqueous sodium bicarbonate. Solid sodium bicarbonate was added and the mixture stirred until effervescence had ceased. The aqueous mixture was extracted with ethyl acetate (×2) and the organic fractions combined, washed with saturated aqueous sodium bicarbonate, brine, dried (Na2SO4) and evaporated to dryness. The residue was co-evaporated with toluene, dissolved in THF (10 mL) and added to (3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (0.39 g, 2.09 mmol). The reaction mixture was stirred for 3 days and then concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 10% hydrochloric acid (×2), brine, dried (Na2SO4) and evaporated to dryness. The crude product was crystallized from ethyl acetate to give the title compound as a cream powder (0.35 g, 45%). 1HNMR (300 MHz) (CDCl3) δ 1.45 (6H, s), 1.55 (3H, s), 1.8-2.4 (2H, m), 3.4-3.9 (5H, m), 4.05-4.75 (4H, m), 6.48 (2H, m), 6.90-7.07 (5H, m) and 7.18 (2H, t).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([N:13]2[CH2:16][CH:15]([OH:17])[CH2:14]2)=[O:12])[CH2:6][CH2:5]1)[CH3:3].F[C:19]1[CH:20]=[CH:21][C:22]([C:25]([OH:28])([CH3:27])[CH3:26])=[N:23][CH:24]=1>>[CH3:3][CH:2]([N:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([N:13]2[CH2:16][CH:15]([O:17][C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:28])([CH3:27])[CH3:26])=[N:23][CH:24]=3)[CH2:14]2)=[O:12])[CH2:6][CH2:5]1)[CH3:1]
Reactant: CC(C)(O)c1ccc(F)cn1
Reactant: CC(C)N1CCCN(C(=O)N2CC(O)C2)CC1
Product: CC(C)N1CCCN(C(=O)N2CC(Oc3ccc(C(C)(C)O)nc3)C2)CC1

Procedure:
In a similar fashion (Route 20, GP I), 1-{[4-(1-methylethyl)-1,4-diazepan-1-yl]carbonyl}azetidin-3-ol (100 mg, 0.41 mmol) and 2-(5-fluoropyridin-2-yl)propan-2-ol (90 mg, 0.41 mmol) were used to give the title compound. Crude material (50 mg) after workup gave the title compound as colourless oil (17.7 mg) after purification by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:20]3[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1ccc(-n2cc(C#Cc3ccnc(Cl)c3)nc2C)cc1

Procedure:
The title compound, MS: m/e=308.8 (M+H+), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 4-methyl-benzene boronic acid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].[N:9]12CCN(CC1)C[CH2:10]2>>[C:10]([C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3])#[N:9]
Reactant: C1CN2CCN1CC2
Reactant: CC(C)COC(=O)Cl
Product: CC(C)COC(=O)C#N
Yield: 53746 %

Procedure:
Isobutyl chloroformate (68.3 g; 0.5 mol), trimethylsilyl nitrile (49.5 g; 0.5 mol) and 1,4-diazabicyclo[2.2.2]octane (0.10 g; 0.9 mmol) was reacted to produce 61.5 g of isobutyl cyanoformate as a clear, colorless liquid (bp 52°-53° C./20 mmHg) Yield: 97% (theoretical); 98% purity 1H-NMR: δ4.1,d(2H), J=7 Hz; δ2.1, m(1H), δ1.00,d(6 H), J=7 Hz; IR 2250 cm-1 (CN), 1750 cm-1 (CO).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[N:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)[C:12]([C:13]#[N:14])=[C:8]2[NH:7][CH2:6][CH2:5]1.CS(C)=[O:30].[OH-].[Na+].OO>CCO>[CH3:1][NH:2][CH2:3][CH:4]1[N:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)[C:12]([C:13]([NH2:14])=[O:30])=[C:8]2[NH:7][CH2:6][CH2:5]1
Reactant: CNCC1CCNc2c(C#N)c(-c3ccc(Oc4ccccc4)cc3)nn21
Reactant: CS(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNCC1CCNc2c(C(N)=O)c(-c3ccc(Oc4ccccc4)cc3)nn21
Temperature: 60 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a solution of 7-((methylamino)methyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrimidine-3-carbonitrile (20 mg, 0.0557 mmol) in 2 mL of EtOH was added 1 mL of DMSO, 0.5 mL of NaOH (5N) and 0.5 mL of H2O2 (30% solution). The reaction mixture was stirred at 60° C. for 1 hr. Then the mixture was concentrated to remove EtOH. The residue was partitioned between water (20 mL) and EA (20 mL). The EA layer was concentrated to give the product as a white solid (10 mg, yield: 48%). 1H NMR (400 MHz, DMSO-d6) δ 7.51 (d, J=8 Hz, 2H), 7.47-7.40 (m, 2H), 7.19 (t, J=7.6 Hz, 1H), 7.11-7.04 (m, 4H), 6.61 (s, 1H), 4.26-4.16 (m, 1H), 3.34-3.27 (m, 2H), 2.97-2.95 (m, 1H), 2.83-2.77 (m, 1H), 2.33 (s, 3H), 2.08-2.02 (m, 2H). MS (ESI) m/e [M+1]+378.0.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[O:11])[C@@H:6]([CH3:25])[CH2:5]1)([CH3:3])[CH3:2].[ClH:26]>CO>[ClH:26].[ClH:26].[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([CH:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[O:11])[C@@H:6]([CH3:25])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)[C@@H](C)C1
Agent: Cl
Solvent: CO
Product: CC(C)N1CCN(C(=O)C2CCNCC2)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-1-Isopropyl4-[1-(tert-butoxycarbonyl)-piperidine4-carbonyl]-3-methylpiperazine (D22)(0.11 g) was dissolved in methanol (10 ml) and treated with HCl (4N HCl in diethyl ether; 10 ml). After being stirred at rt overnight the reaction mixture was evaporated to a minimum, co-evaporated from methanol, and then dried at 50° C. to give the title compound (D23) as a pale brown solid (0.10 g)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][N:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[CH:22]=1.[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([Cl:52])[C:38]=1[OH:53]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[N:20][N:21]([CH:23]4[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[CH2:27][CH2:28]4)[CH:22]=2)=[CH:3][C:2]([C:41]2[CH:42]=[C:37]([Cl:36])[C:38]([OH:53])=[C:39]([Cl:52])[CH:40]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)CC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)CC1
Yield: 57.8 %

Procedure:
Following general procedure D, tert-butyl 4-(4-((6-bromo-3-(cyclopropanecarbonyl)quinolin-4-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (54 mg, 0.10 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.15 mmol) to afford the desired product (36 mg, 58%) as a yellow-brown solid. ESI MS m/z 622 [C32H33Cl2N5O4+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([C:18](=[O:27])[CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)([CH3:17])[CH2:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:28][C:29]([Si](C)(C)C)([F:31])[F:30].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:28][C:29]([F:31])([F:30])[C:18]([C:13]1([CH3:17])[CH:14]=[CH:15][C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[CH:10][C:11]=2[CH2:12]1)([OH:27])[CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC1(C(=O)CCc2ccccc2)C=Cc2c(cnn2-c2ccc(F)cc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C(O)(CCc2ccccc2)C(F)(F)F)C=Cc2c(cnn2-c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
To a THF (1 mL) solution of Example 202 (7 mg, 0.019 mmol) and trifluoromethyl trimethylsilane (28 μL, 6.6 eq) at 0° C. was added a 1 M THF solution of tetrabutylammonium fluoride (128 μL, 6.7 eq). The mixture was slowly warmed to room temperature overnight. HPLC showed only about 10% conversion. Additional trifluoromethyl trimethylsilane (374 μL) was added and the reaction was completed in 1 h. The mixture was concentrated and purified by reverse-phase HPLC (80 to 100% solvent B gradient) to give the title compound (2.4 mg, 29%) as a 1:1 mixture of two isomers. MS found: (M+H)+=431.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5](=[O:8])[NH:6][CH:7]=1.[CH2:10](I)[CH3:11]>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5](=[O:8])[N:6]([CH2:10][CH3:11])[CH:7]=1
Reactant: Cc1cc(Br)c[nH]c1=O
Reactant: CCI
Product: CCn1cc(Br)cc(C)c1=O

Procedure:
5-Bromo-1-ethyl-3-methylpyridin-2(1H)-one was prepared by alkylation of 5-bromo-3-methylpyridin-2(1H)-one with ethyl iodide following a procedure analogous to that described in Example 59 Step 1.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>CCO.[Pd]>[NH:1]1[C:6]2[C:5](=[CH:10][CH:9]=[CH:8][N:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1cnc2ccncc2c1
Agent: [Pd]
Solvent: CCO
Product: c1cnc2c(c1)CCCN2
Reaction time: 24 h

Procedure:
To a solution of 0.8315 g (6.39 mmol) 1,6-naphthyridine in 25 mL EtOH was added 0.0875 g Pd (10% on C). The reaction mixture was stirred under H2 at atmospheric pressure. After 24 h, an additional 0.0431 g Pd (10% on C) was added. After a total of 46 h under H2 at atmospheric pressure, the reaction mixture was diluted with 50 mL EtOH and filtered over celite. The celite was washed with 300 mL EtOH, and the filtrate concentrated in vacuo. Purification by flash chromatography (50×105 mm silica gel, linear gradient 5-10% (10% NH4H:MeOH):CH2Cl2) yielded 32. 1H NMR (CDCl3, 400 MHz) δ 7.969 (d, 2H, J=4.94 Hz, ArH); 6.279 (d, 1H, J=5.57 Hz, ArH); 3.361-3.326 (m, 2H, CH2); 2.703 (t, 2H, J=6.27 Hz, CH2); 1.962-1.903 (m, 2H, CH2); MS (Electrospray): m/z 134.9 (M+H).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:9][CH:10]=1>CO>[CH3:1][O:2][C:5]1[N:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:9][CH:10]=1
Reactant: C[O-]
Reactant: Clc1ccc(-c2ccncc2)nn1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2ccncc2)nn1

Procedure:
63 ml of a 32% sodium methoxide solution in methanol are added to a solution of 57 g 3-chloro-6-pyridin-4-yl-pyridazine in methanol and the reaction mixture stirred under reflux for 1.5 h. The solvens is removed under reduced pressure, the residue suspended in 0.7 L water and the pH adjusted to 7. Extraction with dichloromethane yielded 57 g 3-methoxy-6-pyridin-4-yl-pyridazine, which is used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](OCC)=[O:10])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccc(CC=O)cc1
Yield: 1058.3 %

Procedure:
To a solution of ethyl 4-methylphenylacetate (0.89 g, 5.0 mmol) in dry methylene chloride (5 ml) cooled to −78° C. under nitrogen was added drop-wise 1.1 M di-isobutyl-aluminum hydride in toluene (4.5 ml, 5 mmol), keeping the internal temperature below −68° C. When the addition was complete, the reaction was quenched by drop-wise addition of methanol (5 ml), saturated potassium sodium tartrate solution (5 ml), and water (5 ml). The mixture was filtered through filter aid, the pad was washed with ethyl acetate (40 ml), and the filtrate layers were separated. The aqueous layer was extracted with ethyl acetate (40 ml). The combined ethyl acetate layers were washed with water (20 ml), and brine (20 ml), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure to give 7.1 g of 4-methylphenylacetaldehyde as a volatile liquid: 1H NMR (CDCl3) 9.73 (1H, t, J 2.5 Hz), 7.17 (2H, m), 7.12 (2H, m), 3.64 (2H, d, J 2.5 Hz), 2.35 (3H, s). To a stirred mixture of benzyl (trans-3-{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl)carbamate (524 mg, 1.5 mmol), triethylsilane (0.36 ml, 260 mg, 2.25 mmol), and bismuth tribromide (45 mg, 0.10 mmol), in anhydrous acetonitrile (7.5 ml), was added the freshly prepared 4-methylphenylacetaldehyde (460 mg, approx. 2.2 mmol) slowly, keeping the temperature at or below 25° C. After stirring for 4 h, the reaction was quenched with half-saturated sodium bicarbonate (30 ml) and ethyl acetate (25 ml). The mixture was filtered through filter aid, the pad was washed with ethyl acetate (3×8 ml), and the filtrate layers were separated. The organic layer was washed with one-fifth saturated brine (8 ml) and water (8 ml), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure to give a heterogeneous oil (1.19 g). The oil was chromatographed on silica gel, eluting with ethyl acetate:hexane (5:95 increasing to 25:75) to give a white solid. The solid was triturated with ethyl acetate:hexane (20:80), filtered off and dried to give benzyl {trans-3-[2-(4-methylphenyl)ethoxy]cyclopentyl}carbamate (291 mg, 55%) as a white solid. A second crop was obtained from the mother liquor (34 mg, 6%).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.[NH2:71][CH2:72][CH2:73][C:74]#[N:75]>CN(C=O)C>[C:72]([CH2:73][CH2:74][NH:75][C:30](=[O:32])[C:29]1[CH:33]=[CH:34][C:35]([CH3:36])=[C:27]([C:10]2[C:11]3[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]4[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=4[F:26])[C:12]=3[N:13]=[C:8]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:37][CH3:38])[N:9]=2)[CH:28]=1)#[N:71]
Reactant: N#CCCN
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NCCC#N)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.9 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and 3-aminopropanenitrile hydrochloride (9.3 mg, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (6 mg, 21%). LC-MS m/z 560 (M+H)+.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([N:9]1[CH2:14][CH2:13][C:12]3([C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][N:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:15]3)[CH2:11][CH2:10]1)[CH2:2]2.[C:31](Cl)(=[O:38])[O:32][C@@H:33]1[CH2:37][CH2:36][O:35][CH2:34]1.C(N(CC)CC)C.Cl>CCOCC>[O:35]1[CH2:36][CH2:37][C@@H:33]([O:32][C:31]([N:8]2[CH:1]3[CH2:7][CH2:6][CH:5]2[CH2:4][CH:3]([N:9]2[CH2:10][CH2:11][C:12]4([C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH2:17][N:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:15]4)[CH2:13][CH2:14]2)[CH2:2]3)=[O:38])[CH2:34]1
Reactant: O=C(Cl)O[C@@H]1CCOC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C2(CCN(C3CC4CCC(C3)N4)CC2)C1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C2(CCN(C3CC4CCC(C3)N4C(=O)O[C@@H]3CCOC3)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 1′-(8-azabicyclo[3.2.1]octan-3-yl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate 4c (205 mg, 0.5 mmol) was suspended in Et2O (10 mL) and treated with the (R)-tetrahydrofuran-3-yl carbonochloridate (150 mg, 1 mmol) and triethylamine (0.21 mL, 1.5 mmol, 3 eq). The reaction was stirred at room temperature for 30 min and was then treated with 1N aq. HCl. The phases were separated, the aqueous phase was brought to a basic pH by adding solid KOH, and the resulting suspension was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated to provide crude tert-butyl 1′-(8-(((R)-tetrahydrofuran-3-yloxy)carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate 4d as a colorless, viscous oil (230 mg, 88% yield). LC/MS m/z [M+H]+ 526.2, retention time 2.54 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min.
Reaction SMILES: C([Al](C[CH:11]([CH3:13])[CH3:12])CC(C)C)C(C)C.[C:14]1([CH3:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:20]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:13][CH2:11][CH3:12]
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Reactant: Cc1ccccc1
Product: C=CCCCCCCCC

Procedure:
An autoclave with an inner volume of 5 L was charged with 3 L of the decene oligomer produced in (a) in nitrogen gas stream, and here were added trisacetylacetonatocobalt (catalyst weight: 3.0 g) dissolved in toluene and triisobutylaluminum (30 mmol) diluted with toluene. After the reaction system was purged with hydrogen twice, it was heated and kept at 80° C. under a hydrogen pressure of 0.9 MPa. Hydrogenation immediately proceeded exothermically. When four hours passed after the reaction started, the temperature was lowered to terminate the reaction. The pressure was released, the reaction mixture was taken out of the autoclave, and the fraction of boiling at 240 to 270° C. under 530 Pa (desired compound) was isolated by simple distillation.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([NH:5][C@@H:6]1[CH2:9][NH:8][C@H:7]1[CH3:10])=[O:4].C(N(CC)CC)C.[C:20]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])[C:32]=1[OH:33])[C:27](Cl)=[O:28])([CH3:23])([CH3:22])[CH3:21]>ClCCl>[C:34]([C:31]1[CH:30]=[C:26]([CH:25]=[C:24]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:32]=1[OH:33])[C:27]([N:8]1[CH2:9][C@@H:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:11])[F:12])[C@@H:7]1[CH3:10])=[O:28])([CH3:37])([CH3:36])[CH3:35]
Reactant: C[C@@H]1NC[C@H]1NC(=O)C(F)(F)F
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1[C@H](NC(=O)C(F)(F)F)CN1C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.7 %

Procedure:
(2S,3R)-2,2,2-trifluoro-N-(2-methyl-azetidin-3-yl)-acetamide (1,04 g, 4,74 mmoles) hydrochloride was dissolved in dichloromethane (30 ml) and triethylamine (2,7 ml) was added, the mixture stirred for 10 minutes at room temperature, cooled to 0° C. and a solution of 3,5-di-tert-butyl-4-hydroxy-benzoyl chloride (1,16 g, 4,3 mmoles) in dichloromethane (20 ml) was added. The reaction mixture was stirred at room temperature overnight, then poured on ice, the phases were separated, the aqeous phase extracted with dichloromethane and the combined organic phases were dried over magnesium sulfate, filtered and evaporated to dryness to give 1,42 g (80% of theoretical yield) of N-[1-(3,5-di-tert-butyl-4-hydroxy-benzoyl)-(2S,3R)-2-methyl-azetidin-3-yl]-2,2,2-trifluoro-acetamide.