Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[N:10][C:11]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:26]=2)[C:22]([NH:24][NH2:25])=[O:23])=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:36](=O)[C:37]([O:39][CH3:40])=[O:38].C(=O)([O-])[O-].[K+].[K+].S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.N1C=CC=CC=1>C(Cl)Cl.O>[C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[N:10][C:11]([C:17]2[CH:26]=[C:21]([C:22]4[O:23][C:36]([C:37]([O:39][CH3:40])=[O:38])=[N:25][N:24]=4)[CH:20]=[N:19][CH:18]=2)=[N:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NNC(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Reactant: COC(=O)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1nnc(-c2cncc(-c3nc(NCc4ccccn4)c4c(-c5ccccc5)cccc4n3)c2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.4 %

Procedure:
To a solution of 5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)nicotinohydrazide (from Example 185, 0.30 g, 0.66 mmol) in DCM at 0° C. was added methyl 2-chloro-2-oxoacetate (0.062 mL, 0.66 mmol) and potassium carbonate (0.273 g, 1.90 mmol). Upon completion of addition, the mixture was stirred at RT for 16 h. After this time, water was added and the mixture was extracted into DCM, dried and concentrated. The resulting residue was dissolved in DCM. Triflic anhydride (0.187 mL, 1.1 mmol) and pyridine (0.149 mL, 1.8 mmol) were added and the resulting mixture was stirred at RT for 16 h. At the conclusion of this period, the reaction mixture was quenched with water and extracted with DCM (100 mL). The DCM layer was washed with water and brine. Chromatographic purification provided methyl 5-(5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)pyridin-3-yl)-1,3,4-oxadiazole-2-carboxylate (270 mg, 78% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.81 (s, 1H), 9.17 (s, 1H), 9.09 (s, 1H), 8.24 (d, J=4.4 Hz, 1H), 7.94 (d, J=7.2 Hz, 1H), 7.86 (t, J=7.6 Hz, 1H), 7.75-7.72 (t, J=7.6 Hz, 3H), 7.59-7.51 (m, 5H), 7.34 (d, J=7.2 Hz, 2H), 7.24 (t, J=6.4 Hz, 1H), 6.98 (t, J=3.2 Hz, 1H), 4.77 (d, J=4.0 Hz, 2H). LCMS Method Q: retention time 1.39 min; [M+1]=514.5; HPLC Method B: purity 98.1%, retention time=8.74 min.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][NH2:20].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH2:28])[CH:22]=1>>[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:28][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([NH:20][CH2:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)[CH:11]=[CH:10]3)[CH:22]=1
Reactant: NCc1cccnc1
Reactant: NCc1ccccn1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Product: c1ccc(CNc2ccc3cc(NCc4cccnc4)ccc3n2)nc1

Procedure:
The title compound, MS: m/e=342.1 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-picolylamine and 3-picolylamine.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=O.[CH3:11][Li].O>CCOCC>[CH3:10][C:2]([CH3:1])([CH2:6][CH2:7][CH2:8][CH3:9])[C:3](=[O:5])[CH3:11]
Reactant: [Li]C
Reactant: CCCCC(C)(C)C(=O)O
Solvent: O
Solvent: CCOCC
Product: CCCCC(C)(C)C(C)=O

Procedure:
A solution of 14.4 g (100 mmol) of 2,2-dimethylhexanoic acid (XXIX) in 100 ml of dry ether was stirred a 0° C. under argon as 130 ml (237 mol) of a solution of methyllithium (1.82 M) in ether was added dropwise. The resultant mixture was stirred with ice-bath cooling for 1 hour and then without cooling overnight. It was then poured into a vigorously stirred 500 ml portion of water in a large beaker. The phases were separated and the aqueous phase was back-extracted twice with ether. The combined extract was dried (MgSO4) and evaporated in vacuo. The residue was distilled at 20 mm to yield 12.7 g of XXX as a colorless oil, bp 125°-130°; Rf (CHCl3) 0.54; nmr 0.9 (3, broad t, J=6.0 Hz), 1.12 (6, s), 1.0-1.8 (6, m) and 2.14 (3, s); ir (film) 8.85, 7.45, 6.80, 5.85, 3.50, 3.41 and 3.38μ.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([S:14](Cl)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][C:27]([O:30][C:31]([NH:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)=[O:32])([CH3:29])[CH3:28]>C1COCC1>[C:27]([O:30][C:31](=[O:32])[NH:33][CH:34]1[CH2:39][CH2:38][N:37]([S:14]([C:13]2[C:7]3[O:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:9][C:8]=3[CH:10]=[CH:11][C:12]=2[Cl:18])(=[O:16])=[O:15])[CH2:36][CH2:35]1)([CH3:29])([CH3:26])[CH3:28]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2c(Cl)ccc3nc(C(C)(C)C)oc23)CC1
Yield: 54 %

Procedure:
Following the general procedure for the synthesis of sulfonylamides outlined in example 51, 2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl chloride (5.05 g, 16.4 mmol), triethylamine (4.57 mL, 32.8 mmol), and 4-N-Boc-aminopiperidine (3.288 g, 16.4 mmol) were reacted in THF (125 mL) to afford the title compound (4.18 g, 54%). 1H NMR (DMSO-d6) • 7.98 (d, 1H, J=8.48 Hz), 7.63 (d, 1H, J=8.47 Hz), 3.73 (d, 2H), 3.35 (bs, 2H), 2.92 (m, 2H), 1.75 (d, 2H), 1.35 (s, 10H).
Reaction SMILES: [OH-].[Na+].[C:3]([OH:7])(=[S:6])[CH2:4][CH3:5].[C:8]([NH:11][C:12](=[O:15])[CH2:13]Cl)(=[O:10])[CH3:9]>O>[C:8]([NH:11][C:12](=[O:15])[CH2:13][S:6][C:3](=[O:7])[CH2:4][CH3:5])(=[O:10])[CH3:9]
Reactant: CCC(O)=S
Reactant: CC(=O)NC(=O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(=O)SCC(=O)NC(C)=O
Reaction time: 0.08 h

Procedure:
To a solution of 4.0 g. (0.1 mole) of sodium hydroxide in 50 ml. of water, cooled in ice and having nitrogen bubbled therethrough, was added 9.5 g. (0.1 mole) of thiopropionic acid. The reaction mixture was stirred for 5 minutes, after which there was added 13.7 g. of N-acetyl-chloroacetamide in 50 ml. of water. The reaction mixture was heated on a steam bath for 10 minutes, then cooled, filtered, and air dried. The product was washed with ether/hexane (3:1) three times with 150 ml. each washing, and then air dried. The product was recrystallized from water to yield 8.0 g. of white crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[CH3:11][C:12]([CH3:14])=[O:13].[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18].[NH4+].[Cl-]>C1COCC1.CCOCC>[CH2:24]([Sn:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:20][CH2:21][CH2:22][CH3:23])[C:5]1[S:1][C:2]([C:12]([OH:13])([CH3:14])[CH3:11])=[N:3][CH:4]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CC(C)=O
Reactant: c1cscn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(C(C)(C)O)s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of thiazole (1.0 eq) in THF (0.2M) at −78° C. was added nBuLi (1.6M, 1.1 eq). After 1 h at −78° C., acetone (1.0 eq) was added and the mixture stirred 30 min at −78° C., 5 min −50° C. then cooled back to −78° C. to add a second equivalent of nBuLi (1.6M, 1.1 eq). After 1.5 h at −78° C., tri-n-butyltin chloride (1.2 eq) was added and the mixture stirred 12 h at −78° C. The reaction mixture was diluted with Et2O and a solution of NH4Cl. The organic extracts were washed with water, brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hexane:EtOAc, 90:10) afforded the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:35]=[CH:34][C:22]([CH2:23][O:24][C:25]2[C:30]([CH2:31][C:32]#N)=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:21][CH:20]=1.[OH-:36].[Na+].C(O)C.Cl.[OH2:42]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][O:24][C:25]2[C:30]([CH2:31][C:32]([OH:42])=[O:36])=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:34][CH:35]=1
Reactant: [OH-]
Reactant: O
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(COc2ncccc2CC#N)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(COc2ncccc2CC(=O)O)cc1
Yield: 58 %

Procedure:
A mixture of 2-[2-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]benzyloxy]-3-pyridyl]acetonitrile (700 mg), a 2N aqueous sodium hydroxide solution (20 mL) and ethanol (40 mL) was heated under reflux for 18 hours. Water was added to the reaction mixture, and the mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give crystals (420 mg, 58%) of 2-[2-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]benzyloxy]-3-pyridyl]acetic acid from a fraction eluted with acetone-hexane (2:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 155-156° C.
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH2:13][CH3:14])[CH3:12])[C:6]=1[N:15]=[C:16]=[S:17])([CH2:3][CH3:4])[CH3:2].[CH:18]([NH2:21])([CH3:20])[CH3:19].Cl>>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[C:6]=1[NH:15][C:16]([NH:21][CH:18]([CH3:20])[CH3:19])=[S:17])([CH2:13][CH3:14])[CH3:12]
Reactant: CCC(C)c1cccc(C(C)CC)c1N=C=S
Reactant: CC(C)N
Agent: Cl
Product: CCC(C)c1cccc(C(C)CC)c1NC(=S)NC(C)C
Reaction time: 3 h

Procedure:
15.0 g of 2,6-di-sec.-butyl-phenyl isothiocyanate are introduced, whilst cooling, into 20 g of a 65% strength aqueous solution of isopropylamine. After stirring for 3 hours at 20°, the batch is stirred into dilute hydrochloric acid, the reaction product which has precipitated in a crystalline form is filtered off and washed until neutral, and the paste is triturated with 50% strength methanol, again filtered off and dried.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:7][O:6][C:5]2([CH2:12][C:11]([CH3:14])([CH3:13])[N:10]([O:15][CH:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C(=O)C)=[CH:20][CH:19]=3)[CH3:17])[C:9]([CH3:29])([CH3:28])[CH2:8]2)[O:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl>CO.O>[CH3:30][C:2]1([CH3:1])[CH2:7][O:6][C:5]2([CH2:8][C:9]([CH3:28])([CH3:29])[N:10]([O:15][CH:16]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)[CH3:17])[C:11]([CH3:14])([CH3:13])[CH2:12]2)[O:4][CH2:3]1
Reactant: CC(=O)Oc1ccc(C(C)ON2C(C)(C)CC3(CC2(C)C)OCC(C)(C)CO3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(ON1C(C)(C)CC2(CC1(C)C)OCC(C)(C)CO2)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 8 g acetic acid 4-[1-(3,3,8,8,10,10-hexamethyl-1,5-dioxa-9-aza-spiro[5.5]undec-9-yloxy)-ethyl]-phenyl ester and 3.9 g potassium carbonate in 60 ml methanol is stirred for one hour at room temperature. The mixture is cooled to 0° C. and neutralized by adding 60 ml of 0.5 M hydrochloric acid. The white suspension is diluted with water (60 ml) and filtered through a buchner funnel. The residue is washed with water and dried in a vacuum oven at 50° C. A white solid having a melting point of 133–134° C. is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:12]([CH:15]=2)[C:13]#[N:14])[CH:5]=[CH:4][N:3]=1.O1CCOCC1.[CH3:29][O:30][CH2:31][CH2:32][CH2:33][N:34]1[CH:38]=[C:37]([NH2:39])[CH:36]=[N:35]1.C(N(CC)CC)C>C(O)C>[CH3:29][O:30][CH2:31][CH2:32][CH2:33][N:34]1[CH:38]=[C:37]([NH:39][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[CH:10][C:11]([O:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[C:12]([CH:15]=3)[C:13]#[N:14])[CH:5]=[CH:4][N:3]=2)[CH:36]=[N:35]1
Reactant: COCCCn1cc(N)cn1
Reactant: N#Cc1cc(-c2ccnc(Cl)n2)ccc1OC1CCOCC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CCO
Product: COCCCn1cc(Nc2nccc(-c3ccc(OC4CCOCC4)c(C#N)c3)n2)cn1
Temperature: 100 °C
Reaction time: 48 h
Yield: 25.8 %

Procedure:
5-(2-Chloropyrimidin-4-yl)-2-(tetrahydropyran-4-yloxy)benzonitrile (200 mg) are dissolved in ethanol and dioxane in a 100 ml three-necked flask, and the 1-(3-methoxypropyl)-1H-pyrazol-4-ylamine (129 mg) prepared above and 0.8 ml of triethylamine are added. The yellow solution is stirred at 100° C. for two days. For work-up, the mixture is evaporated in a rotary evaporator and purified by chromatography, giving 71 mg of the desired product; HPLC-MS Rt. [min] 2.041; HPLC-MS [M+H] 435;
Reaction SMILES: [CH2:1]([SnH:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C([N-]C(C)C)(C)C.[Li+].[CH2:22]=[O:23].[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29]Cl>C1CCCCC1.O1CCCC1>[CH2:10]([Sn:5]([CH2:22][O:23][CH2:29][O:28][CH2:27][CH2:26][O:25][CH3:24])([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:11][CH2:12][CH3:13]
Reactant: C=O
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: COCCOCCl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCCC[Sn](CCCC)(CCCC)COCOCCOC
Reaction time: 0.25 h

Procedure:
Tributyltin hydride (2.69 ml, 0.01 mol) was added dropwise to a solution of lithium diisopropylamide (a 1.5M solution in cyclohexane; 6.7 ml, 0.01 mol) in tetrahydrofuran (20 ml) at 0° under argon. After 15 minutes, paraformaldehyde (300 mg, 0.01 mol) was added, followed by 2-methoxyethoxymethyl chloride (1.15 ml, 0.01 mol) after 3 hours. Stirring was continued at room temperature for 12 hours and the mixture was quenched with water. Extraction (ethyl ether) and evaporation of the dried (magnesium sulphate) extracts gave an oil, which was flash chromatographed on silica using 5% ethyl ether/petroleum ether. Fractions with Rf of about 0.24 on evaporation afforded the desired ether as a colorless oil (1.11 g, 27%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH2:18][CH2:19]Cl)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CC#N.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH2:18][CH2:19][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CCCCl)CC1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CCCN2CCOCC2)CC1
Reaction time: 16 h

Procedure:
Amine preparation: A mixture of 1-BOC-piperazine (3.26 g), 3-chloropropanesulfonyl chloride (2.63 g) and triethylamine (2.68 mL) was stirred at room temperature in DCM (25 mL). After 2 h the reaction mixture was diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 4-(3-chloro-propane-1-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (4.65 g). A mixture of 4-(3-chloro-propane-1-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (4.65 g), potassium iodide (1.1 g), potassium carbonate and morpholine (1.6 mL) was heated to reflux in MeCN (100 ml). After 16 h, the reaction mixture was cooled, diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 4-(3-morpholin-4-yl-propane-1-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (4.8 g). Treatment of this compound with HCl in DCM/MeOH yielded the desired compound, which was isolated as the hydrochloride salt.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.[CH2:14]=O.[BH4-].[Na+].O>CO>[CH3:14][N:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
In a dried reaction flask, (S)-tert-butyl pyrrolidin-3-ylcarbamate (5.774 g, 31.0 mmol) and formaldehyde solution (6.82 mL, 37%) were dissolved in methanol (124 mL) under a nitrogen atmosphere. The solution was stirred at room temperature for 1 hr. Sodium borohydride (3.518 g, 93.1 mmol) was added in portion under an ice bath. The solution was stirred at room temperature for 3 hr. Water was added to the reaction solution. After rotary-evaporation, ethyl acetate and saturated aqueous sodium bicarbonate solution were added. The reaction solution was extracted with ethyl acetate. The combined organic phase was washed with salt water, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:1) to produce a pale yellow solid (4.037 g) in 65% yield.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[Br:34][C:35]1[S:36][C:37]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[C:38]([C:40]([OH:42])=O)[N:39]=1.[NH2:51][C:52]1[CH:53]=[N:54][N:55]([CH3:74])[C:56]=1[N:57]1[CH2:63][C:62]([F:65])([F:64])[CH2:61][CH:60]([NH:66][C:67](=[O:73])[O:68][C:69]([CH3:72])([CH3:71])[CH3:70])[CH2:59][CH2:58]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:47]([O:46][C:44]([NH:43][C:37]1[S:36][C:35]([Br:34])=[N:39][C:38]=1[C:40]([NH:51][C:52]1[CH:53]=[N:54][N:55]([CH3:74])[C:56]=1[N:57]1[CH2:63][C:62]([F:65])([F:64])[CH2:61][CH:60]([NH:66][C:67](=[O:73])[O:68][C:69]([CH3:70])([CH3:71])[CH3:72])[CH2:59][CH2:58]1)=[O:42])=[O:45])([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)O
Reactant: Cn1ncc(N)c1N1CCC(NC(=O)OC(C)(C)C)CC(F)(F)C1
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(Br)sc2NC(=O)OC(C)(C)C)c1N1CCC(NC(=O)OC(C)(C)C)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 6,6-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate (2.5 g, 6.67 mmol) in ethanol (100 mL) and water (10 mL) was added ammonium chloride (3.5 g, 65.0 mmol) and iron powder (3.0 g, 53.7 mmol). The reaction mixture was heated at 100° C. for 2.5 hr, before being cooled down at room temperature, filtered through Celite®, washed with MeOH and the filtrate concentrated under reduced pressure. The residue was dissolved in DCM (200 mL), quenched with a saturated solution of sodium hydrogencarbonate (300 mL) and a 10% solution of sodium sulfite (100 mL) and the mixture stirred for 30 min. The layers were separated and the aqueous layer extracted with DCM (100 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-30% EtOAc/isohexane) gave tert-butyl 1-(4-amino-1-methyl-1H-pyrazol-5-yl)-6,6-difluoroazepan-4-ylcarbamate as an orange foam (2.12 g). A solution of PyBOP (1.92 g, 3.70 mmol) and 2-bromo-5-(tert-butoxycarbonyl-amino)thiazole-4-carboxylic acid (795 mg, 2.46 mmol) in DCM (50 mL) was stirred at room temperature for 15 min. tert-Butyl 1-(4-amino-1-methyl-1H-pyrazol-5-yl)-6,6-difluoroazepan-4-ylcarbamate (850 mg, 2.46 mmol) and DIPEA (2.0 mL, 11.4 mmol) were added and the mixture stirred at room temperature for 18 hr. The reaction mixture was diluted with DCM (50 mL) and washed with a saturated solution of sodium hydrogencarbonate (100 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification of the residue via silica gel column chromatography (0-100% EtOAc/isohexane) gave tert-butyl 1-(4-(5-(tert-butoxycabonyl-amino)-2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-6,6-difluoroazepan-4-ylcarbamate as a pale yellow foam (1.35 g, 77% over two steps). 1H NMR (400 MHz, CDCl3) δ 10.24 (s, 1H), 8.37 (s, 1H), 7.65 (s, 1H), 4.88 (s, 1H), 4.04 (s, 1H), 3.77 (s, 3H), 3.63-3.43 (m, 2H), 3.38-3.24 (m, 2H), 2.52-2.40 (m, 2H), 2.13-2.05 (m, 1H), 1.99 (s, 1H), 1.53 (s, 9H), 1.43 (s, 9H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:17]=[CH:16][C:15]([CH2:18]O)=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=1.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:53]>C(Cl)Cl.CCOC(C)=O>[Br:53][CH2:18][C:15]1[C:14]([C:20]([F:23])([F:22])[F:21])=[CH:13][C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[N:17][CH:16]=1
Reactant: COCCCc1ccccc1-c1cc(C(F)(F)F)c(CO)cn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCCCc1ccccc1-c1cc(C(F)(F)F)c(CBr)cn1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of [6-[2-(3-methoxypropyl)phenyl]-4-(trifluoromethyl)pyridin-3-yl]methanol (1 eq.) from step 2, in CH2Cl2 (0.1M) at 0° C. was added 1-2 bis(diphenylphosphine)ethane (1 eq.) the CBr4 (1 eq.). The mixture was stirred at 0° C. for 45 min, diluted with Hex/EtOAc 10%, filtered in celite and concentrated afforded the desired compound as an oil.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15](=[O:18])[CH:14]2[CH3:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:20].[Na+:21]>O>[OH2:8].[NH2:16][C:17]1[C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=[CH:12][C:13]=1[CH:14]([CH3:19])[C:15]([O-:20])=[O:18].[Na+:21]
Reactant: CC1C(=O)Nc2c(C(=O)c3ccccc3)cccc21
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CC(C(=O)[O-])c1cccc(C(=O)c2ccccc2)c1N

Procedure:
A suspension of 9 g. (0.036 mole) of 7-benzoyl-3-methylindolin-2-one in 100 ml. of 3N sodium hydroxide was refluxed for 18 hrs. under nitrogen. The mixture was filtered and stripped under water pump vacuum to yield a gummy mixture of sodium hydroxide, water, and product. The mixture was triturated with boiling isopropanol and filtered. The isopropanol solution was cooled and filtered to separate the bright yellow product. The product weighed 4.0 g. and melted at 218° C. (dec.)
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]2[N:15]=[CH:16][N:17]=[C:4]2[N:3]=1.C(O)(=O)C.CO>C1COCC1>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]2[N:15]=[CH:16][N:17]=[C:4]2[N:3]=1
Reactant: Clc1nc2ncnn2c(Cl)c1-c1ccccc1
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Clc1nc2ncnn2cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.5 g 5,7-dichloro-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidine, 0.22 mL glacial acetic acid, 0.5 mL methanol, 3 mL THF and 366 mg of Zn/Cu pair were stirred for 3 h at ambient temperature. The mixture was filtered through celite, evaporated to dryness and the residue was purified on silica gel (dichloromethane/ethyl acetate) to yield the desired product.