Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[C:9]([OH:17])[C:6]=1[CH:7]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:18][NH2:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(O)(=O)C>[C:1]([C:5]1[C:6]([CH2:7][NH:19][CH3:18])=[C:9]([OH:17])[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)(C)c1cc(O)c(C=O)c(C(C)(C)C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CNCc1c(O)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 0.234 g (1.00 mmol) of the product of Step A, 3 mL of 2 N methylamine in TMF, and 0.5 mL acetic acid dissolved in 4.0 mL 1,2-dichloroethane was stirred at room temperature for 5 h. Sodium triacetoxyborohydride (0.422 g; 2.0 mmol) and 10 mL of 1,2-dichloroethane was then added and the resulting mixture was stirred overnight at room temperature. The reaction mixture was then treated with excess saturated aqueous NaHCO3. The aqueous layer was separated and extracted with CH2Cl2, the organic layers were combined, dried (Na2SO4), filtered, and evaporated. The residue was purified on a silica gel flash chromatography column eluted with CH2Cl2-MeOH—NH4OH (95:5:0.5). Evaporation of the purified fractions and drying in vacuo afforded the title compound. HPLC/MS: 250.2 (M+1); Rt=2.5 min.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2(O)[C:14]3[C:15]([CH3:37])=[C:16]([N:21]4[CH2:26][CH2:25][CH:24]([C:27]5[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=5)[CH2:23][CH2:22]4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:39])[CH3:38])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>CCCCCC.CO>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:37])=[C:16]([N:21]4[CH2:22][CH2:23][CH:24]([C:27]5[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=5)[CH2:25][CH2:26]4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:39])[CH3:38])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc(C(C)C)cc3)C(C)(C)O4)CC2)cc1OC
Solvent: CCCCCC
Solvent: CO
Product: COc1ccc(C2CCN(c3c(C)c(C)c4c(c3C)C(c3ccc(C(C)C)cc3)C(C)(C)O4)CC2)cc1OC
Yield: 90 %

Procedure:
Using 3-(4-isopropylphenyl)-5-(4-(3,4-dimethoxyphenyl)piperidino)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Example 83, the title compound was synthesized in the same manner as in Example 46. Yield 90%. mp. 129–132° C. (hexane-methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][CH:10]=[C:9]([OH:21])[C:8]=2[C:7]1=[O:22].[CH3:27][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][CH:10]=[C:9]([O:21][CH3:27])[C:8]=2[C:7]1=[O:22]
Reactant: CCOC(=O)c1ncc(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1ncc(OC)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 10 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (208 g, 0.55 mol) in a mixture of dichloromethane (830 mL) and methanol (410 mL) at 10° C., a solution of (trimethyl-silyl)diazomethane (600 mL, 1.2 mol; 2M) in hexanes was added over a period of 1 hour with the reaction temperature maintained below 15° C. The reaction mixture (unstirred) was allowed to stand at 10° C. overnight, and then at 20° C. for additional 4 hours. The reaction mixture was cooled back to 10° C. and quenched with acetic acid (˜75 mL). The product mixture was concentrated under vacuum and the residue recrystallized from boiling methyl tert-butyl ether and heptane. The solid recrystallized was collected by filtration, washed with a mixture of methyl tert-butyl ether and heptane (1:1, v/v), and air dried to afford the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([Sn](CCCC)(CCCC)CCCC)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[CH2:41]([N:43]1[C:51](I)=[C:50]2[C:45]([CH:46]=[CH:47][CH:48]=[CH:49]2)=[N:44]1)[CH3:42]>>[CH2:41]([N:43]1[C:51]([C:5]2[N:4]=[C:3]3[C:8]([N:9]=[C:10]([CH2:11][N:12]4[CH2:13][CH2:14][CH:15]([C:18]([OH:21])([CH3:19])[CH3:20])[CH2:16][CH2:17]4)[N:2]3[CH3:1])=[C:7]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:6]=2)=[C:50]2[C:45]([CH:46]=[CH:47][CH:48]=[CH:49]2)=[N:44]1)[CH3:42]
Reactant: CCn1nc2ccccc2c1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Product: CCn1nc2ccccc2c1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1

Procedure:
Following the procedures for 165, 2-[1-(9-methyl-6-morpholin-4-yl-2-(tributylstannanyl)-9H-purin-8-ylmethyl)piperidin-4-yl]propan-2-ol and 2-ethyl-3-iodo-2H-indazole were reacted to give 189. LCMS m/z: 519.3 (MH+)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10]C)=O)=[CH:3][CH:2]=1>C(N)CC>[CH2:2]([NH:1][C:8](=[O:10])[CH2:7][CH:4]1[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]1)[CH2:3][CH3:4]
Reactant: COC(=O)Cc1ccncc1
Solvent: CCCN
Product: CCCNC(=O)CC1CCNCC1

Procedure:
Methyl 2-(pyrid-4-yl)acetate (10 g.), n-propylamine (30 ml.) and 3 A molecular sieves (10 g.) were heated together at 100° for 148 hours in a stainless steel bomb. Excess amine and molecular sieves were removed and the crude product in glacial acetic acid (100 ml.) was hydrogenated over platinum oxide catalyst at 30°/50 p.s.i. until uptake of hydrogen ceased. The catalyst was removed by filtration, the excess acetic acid distilled off in vacuo, and the residue basified with aqueous sodium bicarbonate and extracted with ethyl acetate (100 ml.). The organic layer was dried (MgSO4) and evaporated in vacuo to give crude N-n-propyl-2-(piperid-4-yl) acetamide as an oil. This was utilized without further purification.
Reaction SMILES: CSC[C@@H](C(O)=O)NC(=O)C.C(N)C.[CH2:15]([S:17][CH2:18][C@@H:19]([C:24]([OH:26])=O)[NH:20][C:21](=[O:23])[CH3:22])[CH3:16].[CH2:27]([NH2:31])[CH2:28][CH2:29][CH3:30]>>[CH2:27]([NH:31][C:24](=[O:26])[C@H:19]([CH2:18][S:17][CH2:15][CH3:16])[NH:20][C:21](=[O:23])[CH3:22])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCN
Reactant: CCSC[C@H](NC(C)=O)C(=O)O
Agent: CCN
Agent: CSC[C@H](NC(C)=O)C(=O)O
Product: CCCCNC(=O)[C@H](CSCC)NC(C)=O

Procedure:
S-Ethyl-N-acetyl-L-cysteine butylamide was synthesized in exactly the same manner as described in Example 14 except that the S-methyl-N-acetyl-L-cysteine and aqueous 70% ethylamine solution used in that example was replaced by S-ethyl-N-acetyl-L-cysteine and n-butylamine, respectively.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][C@@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:13][CH2:12][C@H:11]([CH3:14])[CH2:10][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: C[C@@H](CCl)CBr
Reactant: Oc1ccc(Br)cc1
Product: C[C@@H](CCl)COc1ccc(Br)cc1

Procedure:
Prepared by Procedure U and Scheme AK using 4-bromophenol and (2S)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH3:5].C([Li])CCC.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]([C:1]#[C:2][CH2:3][CH2:4][CH3:5])([OH:24])[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: C#CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC#CC1(O)CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 17 h
Yield: 77.6 %

Procedure:
To a solution of 5.47 g (80.3 mmol) of 1-pentyne in 65 mL THF at −78° C. was added 32.1 ml n-butyl lithium (80.3 mmol; 2.5M in hexanes). After the addition was complete the reaction mixture was warmed to 0° C. and a solution of 8.44 g (44.6 mmol) of 1-benzyl-4-piperidone and 40 mL of THF was added dropwise. The cooling bath was removed and the reaction mixture was stirred at ambient temperature. After 17 h, the reaction was quenched by addition of saturated ammonium chloride and diluted with EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated to afford a reddish-gold oil. The crude product was purified by flash chromatography on silica gel (EtOAc/hexane 1:1→65:35). The light gold oil was dried over sodium sulfate to afford 8.91 g (78%) of 1-benzyl-4-pentynyl-4-piperidinol: ms (EST) [M+H]+=258.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][O:7][CH3:8])[C:3]([OH:5])=[O:4].C(OC(=O)C(C)(C)CO)C.C(Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][C:2]([CH3:9])([CH2:6][O:7][CH2:8][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]([OH:5])=[O:4]
Reactant: ClCc1ccccc1
Reactant: COCC(C)(C)C(=O)O
Agent: CCOC(=O)C(C)(C)CO
Product: CC(C)(COCc1ccccc1)C(=O)O

Procedure:
The title compound was prepared following the procedure described in Intermediate 68 using 2,2-dimethyl-3-hydroxypropionic acid ethyl ester and benzyl chloride.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(N(CC)CC)C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:10]([C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1)#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: C#CCCCCCCCCCCCCCC
Reactant: O=Cc1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCC#Cc1cccc(C=O)n1
Temperature: 25 °C
Yield: 53.1 %

Procedure:
A solution of 6-bromo-2-pyridinecarboxaldehyde (12.3 g), 1-hexadecyne (16.1 g), triethylamine (20.0 g), bis(triphenylphosphine)palladium(II)chloride (0.92 g), and copper(I)iodide (0.13 g) in dry tetrahydrofuran (55 ml) was heated at 50° C. for 29 hrs, under nitrogen. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate. The filtrate was evaporated and the residue was taken up in ethyl acetate (100 ml). The mixture was washed with 1:1-water:saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was flash chromatographed on silica gel, eluting with 1% ethyl acetate:hexanes. The appropriate fractions were collected and evaporated. The residue was dissolved in ethyl acetate and the solution was washed with half-saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to give 11.5 g (53.5%) of product, mp 38.5°-40° C.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([C:32]([F:43])([F:42])[F:31])[CH:38]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:28])[CH3:29])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(C(F)(F)F)c2)CC1
Yield: 48 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 140, intermediate a)), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown foam (48%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:5]=[CH:6][CH:7]=O.[C:13]([CH2:15][C:16]([NH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:17])#[N:14]>>[CH2:22]([O:21][C:19](=[O:20])[NH:18][C:16](=[O:17])/[C:15](/[C:13]#[N:14])=[CH:7]/[CH:6]=[CH:5]/[C:4]1[CH:9]=[CH:10][C:11]([OH:12])=[C:2]([OH:1])[CH:3]=1)[CH3:23]
Reactant: O=CC=Cc1ccc(O)c(O)c1
Reactant: CCOC(=O)NC(=O)CC#N
Product: CCOC(=O)NC(=O)/C(C#N)=C/C=C/c1ccc(O)c(O)c1

Procedure:
The compound was prepared as described in Example 3 by adding 3,4-dihydroxycinnamaldehyde (32 mg, 0.2 mmol) to N-cyanoacetylurethane (32 mg, 0.2 mmol). After refluxing for 1 h and recrystallization from ethanol-water an orange solid was obtained (54 mg, 90%). The product gave the following analytical data:
Reaction SMILES: II.Br[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:10]1[C:17]([Cl:18])=[N:16][C:14](Cl)=[N:13][C:11]=1[Cl:12].Cl>C1COCC1.C1(C)C=CC=CC=1>[Cl:12][C:11]1[N:10]=[C:17]([Cl:18])[N:16]=[C:14]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:13]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Brc1ccccc1
Agent: Cl
Agent: II
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Clc1nc(Cl)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
7.80 g (0.32 mol) of iodine-activated magnesium turnings in 20 ml of anhydrous THF are heated briefly to 60° C. Then 47.1 g (0.30 mol) of bromobenzene and 80 ml of THF are added dropwise over 30 min and the mixture is heated for 1.5 hours to 65° C. After cooling, the Grignard solution is added over 1 hour to a mixture of 51.6 g (0.28 mol) of cyanuric chloride and 140 ml of THF, while keeping the temperature of the mixture in the range from 10° to 20° C. When the addition is complete, the mixture is stirred at for 3 hours at 25° C. The mixture is then diluted with 280 ml of toluene, the resultant suspension is poured into 300 g of 12% aqueous HCl, the organic phase is separated, washed with a total amount of 400 g of water and concentrated. The resultant material (melting point 117°-120° C.) is recrystallised from hexane, giving the title compound in a yield of 61%.
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[CH2:15][CH2:14][CH2:13][C@@:12]2([CH3:16])[C@H:8]1[CH2:9][CH2:10][C@@H:11]2[C@H:17]([CH3:20])[C:18]#[CH:19])(C)(C)C.F>C1COCC1.[Cl-].[Na+].O>[CH3:16][C@@:12]12[C@@H:11]([C@H:17]([CH3:20])[C:18]#[CH:19])[CH2:10][CH2:9][C@H:8]1[C@@H:7]([OH:6])[CH2:15][CH2:14][CH2:13]2
Reactant: C#C[C@@H](C)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Agent: F
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#C[C@@H](C)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
Typically, the compound of formula IX, (1R,3aR,4S,7aR)-4-(tert-Butyl-dimethyl-silanyloxy)-7a-methyl-1-[(S)-1-methyl-propynyl]-octahydro-indene (900 mg; 2.81 mmol) was dissolved in THF (35 ml). Hydrofluoric acid (40% aqueous solution; 18 ml) was added and the reaction mixture was stirred at room temperature for three hours. The reaction mixture was then poured on chilled brine, extracted twice with ethyl acetate, washed twice with brine, dried over anhydrous sodium sulfate and the solvent was removed. After flash-chromatography (eluent: hexanes/ethyl-acetate 82/18) the compound [1R,3aR,4S,7aR]-7a-Methyl-1-[(S)-1-methyl-prop-2-ynyl]-octahydro-inden-4-ol (497 mg; yield: 86%) was obtained as a yellow oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:29])[CH2:25][CH:26]1[CH2:28][CH2:27]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:37])C=CC=CC=1.C(O)(=O)C>O1CCCC1>[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:29])[C@H:25]([CH:26]1[CH2:27][CH2:28]1)[OH:37])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(CC1CC1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](O)C1CC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 81.3 %

Procedure:
A cooled (−78° C.) solution of sodium bis(trimethylsilyl)amide (0.6 M in toluene, 65 mL, 38.918 mmol) was diluted with anhydrous tetrahydrofuran (100 mL) and treated with a solution of (S)-4-benzyl-3-(2-cyclopropyl-acetyl)-oxazolidin-2-one (9.174 g, 35.380 mmol) in anhydrous tetrahydrofuran (50 mL). After stirring at −78° C. for 45 min, the mixture was treated with a solution of 2-benzenesulfonyl-3-phenyl-oxaziridine (11.064 g, 42.456 mmol) in anhydrous tetrahydrofuran (50 mL). After stirring at −78° C. for 55 min, the reaction was quenched with acetic acid (10.1 mL, 176.9 mmol) and allowed to warm to room temperature. The mixture was quenched with sodium bicarbonate solution (300 mL) and poured over dichloromethane/iso-hexanes (3:1, 400 mL). The aqueous layer was extracted with dichloromethane and the organics were combined, washed with saturated sodium thiosulfate, hydrochloric acid (1 M, 300 mL), water and filtered through a phase separator. The volatiles were removed in vacuo and the residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 7:3 followed by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 4:1 to afford the title compound (7.922 g, 81%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.42-0.65 (m, 4H), 1.25-1.38 (m, 1H), 2.88 (dd, J=13.4, 9.6 Hz, 1H), 3.35 (dd, J=13.4, 3.4 Hz, 1H), 3.44 (d, J=8.2 Hz, 1H), 4.25-4.37 (m, 2H), 4.67-4.72 (m, 1H), 4.80 (dd, J=8.0, 6.0 Hz, 1H), 7.21-7.41 (m, 5H). LCMS (m/z) 298.1 [M+Na], Tr=2.27 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][NH:7][CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:2].C(=O)(O)[O-].[Na+].C(Cl)Cl.[N:19]#[C:20]Cl>O>[CH2:1]([O:3][C:4]([NH:6][N:7]([CH:8]([CH3:10])[CH3:9])[C:20]#[N:19])=[O:5])[CH3:2]
Reactant: N#CCl
Reactant: CCOC(=O)NNC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)NN(C#N)C(C)C
Yield: 87.7 %

Procedure:
73.0 g of 2-isopropylhydrazinecarboxylic acid ethyl ester and 42.0 g of sodium bicarbonate are stirred into 200 ml of methylene chloride and 400 ml of water. There is then introduced at room temperature in the course of 20 minutes, with continuous stirring, 30.8 g of gaseous cyanogen chloride. After an hour's stirring, the methylene chloride base is separated, dried over sodium sulphate and the solvent is distilled off in vacuo. There is obtained as residue 75.0 g (87.5% of theory) of 2-isopropyl-2-cyanohydrazinecarboxylic acid ethyl ester as colourless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[C:5]([NH2:13])[CH:4]=[N:3]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:56]([O:60][C:61]([NH:63][C:64]1[S:68][C:67]([C:69]2[C:74]([F:75])=[CH:73][CH:72]=[CH:71][C:70]=2[F:76])=[N:66][C:65]=1[C:77](O)=[O:78])=[O:62])([CH3:59])([CH3:58])[CH3:57]>C(Cl)Cl>[F:76][C:70]1[CH:71]=[CH:72][CH:73]=[C:74]([F:75])[C:69]=1[C:67]1[S:68][C:64]([NH:63][C:61](=[O:62])[O:60][C:56]([CH3:58])([CH3:57])[CH3:59])=[C:65]([C:77](=[O:78])[NH:13][C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[N:66]=1
Reactant: Cn1ncc(N)c1C1CCOCC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1C1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.5 %

Procedure:
A solution of 5-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-4-nitro-1H-pyrazole (80 mg, 0.38 mmol) in MeOH (20 mL) was passed through the H-Cube® (30 bar, 25° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to afford crude 1-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine as a light yellow oil (64 mg, 0.35 mmol). To a solution of this amine (60 mg, 0.33 mmol) in DCM (20 mL) was added DIPEA (0.5 mL, 2.87 mmol), PyBOP (0.34 g, 0.66 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (124 mg, 0.35 mmol) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM and washed with water. The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-80% EtOAc/isohexane) gave tert-butyl 2-(2,6-difluorophenyl)-4-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as an off-white solid (102 mg, 59%). This solid (100 mg, 0.19 mmol) was stirred in HCl in 1,4-dioxane (4.0 M, 1.9 mL) at room temperature for 18 hr. The solvents were removed under reduced pressure and the crude residue was re-dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and 7 N ammonia in MeOH to yield 301 as a peach solid (59 mg, 73%). 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.69 (s, 1H), 7.34-7.29 (m, 1H), 7.02 (t, J=8.7 Hz, 2H), 6.11 (s, 2H), 4.09 (dd, J=11.6, 4.2 Hz, 2H), 3.88 (s, 3H), 3.50 (t, J=11.6 Hz, 2H), 3.02-2.95 (m, 1H), 2.17-2.08 (m, 2H), 1.78 (d, J=13.4 Hz, 2H). LCMS (ES+) m/z 420 (M+1)
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([CH3:20])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:24][C:25](=[O:42])[CH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=1)[CH3:23]>>[CH2:22]([O:24][C:25](=[O:42])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:16]2[CH:17]=[CH:18][C:13]([C:12]3[O:11][N:10]=[C:9]([CH3:20])[C:8]=3[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])=[CH:14][CH:15]=2)=[CH:29][CH:28]=1)[CH3:23]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)(C)C)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid tert-butyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [Cr](O)(O)(=O)=O.[F:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][C:10]([CH3:28])([CH3:27])[N:11]=[C:12]2[C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2.S([O-])([O-])=[O:30].[Na+].[Na+].C(=O)([O-])O.[Na+]>O.C(O)(=O)C>[F:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=[O:30])[C:10]([CH3:28])([CH3:27])[N:11]=[C:12]2[C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2
Reactant: O=S([O-])[O-]
Reactant: CC1(C)Cc2c(F)cccc2C(c2cnc3ccccc3c2)=N1
Agent: O=[Cr](=O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)N=C(c2cnc3ccccc3c2)c2cccc(F)c2C1=O
Reaction time: 0.5 h
Yield: 6 %

Procedure:
Chromic acid (4.9 g) was added to an acetic acid (50 mL) solution of 3-(5-fluoro-3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)quinoline (5.0 g, 16.4 mmol), followed by heating and refluxing for 14 hours, pouring water, aqueous sodium sulfite solution and aqueous sodium hydrogencarbonate solution. After stirring for 30 minutes, extracting with ethyl acetate, and applying the resulting residue to chromatography to obtain 0.3 g (yield 6%) of the target compound.