Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1O[C:4]([CH2:6][N:7]2[C:11](=[O:12])[C:10]3=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]3[C:8]2=[O:17])([CH3:5])[O:3]C1.[Br:19]Br>C(O)COCCO>[C:11]1(=[O:12])[N:7]([CH2:6][C:4](=[O:3])[CH2:5][Br:19])[C:8](=[O:17])[C:9]2=[CH:16][CH:15]=[CH:14][CH:13]=[C:10]12
Reactant: CC1(CN2C(=O)c3ccccc3C2=O)OCCO1
Reactant: BrBr
Solvent: OCCOCCO
Product: O=C(CBr)CN1C(=O)c2ccccc2C1=O
Yield: 70.9 %

Procedure:
A solution of phthalimidoacetone ethylene ketal (2.47 g, 10 mmole) in 10 mlof diethylene glycol is heated on a steambath. To this hot solution bromine(1.6 g, 10 mmole) is added dropwise under nitrogen. The reaction mixture iscooled to room temperature and is quenched in 20 ml hexane. To this mixtureis added solid sodium carbonate followed by chloroform and ice water. The organic layer is separated and the aqueous layer is extracted 3 times withchloroform. The chloroform extracts are washed with water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue is crystallized from ethyl acetate/hexane to afford 2 g (55%) of (3-phthalimidoacetonyl)bromide, ethylene ketal as white prisms of melting point 139°-141° C. An analytical sample has a melting point of 140°-141° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][C:8](O)=[O:9].B.N#N>C1COCC1>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][CH2:8][OH:9]
Reactant: O=C(O)CCC1CCCO1
Agent: B
Agent: N#N
Solvent: C1CCOC1
Product: OCCCC1CCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(tetrahydrofuran-2-yl)propanoic acid (11.5 g, 80.0 mmol) in anhydrous THF (200 mL) was added borane (160 mL, 160 mmol, 1 mol/L in THF) dropwise under N2 and the mixture was stirred at rt overnight. The reaction mixture was quenched with MeOH and concentrated in vacuo to give the title compound, which was used for next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10](I)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[C:14]([C:16]1([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([S:29][Si](C(C)C)(C(C)C)C(C)C)[CH:24]=2)[CH2:21][CH2:20][O:19][CH:18]([CH3:22])[CH2:17]1)#[N:15].CC(C)([O-])C.[K+]>C(O)C.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>[C:14]([C:16]1([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([S:29][C:10]3[CH:11]=[CH:12][C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[CH3:1])=[CH:8][CH:9]=3)[CH:24]=2)[CH2:21][CH2:20][O:19][CH:18]([CH3:22])[CH2:17]1)#[N:15]
Reactant: Cc1nccn1-c1ccc(I)cc1
Reactant: CC1CC(C#N)(c2cccc(S[Si](C(C)C)(C(C)C)C(C)C)c2)CCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1nccn1-c1ccc(Sc2cccc(C3(C#N)CCOC(C)C3)c2)cc1
Yield: 92.6 %

Procedure:
To a stirred solution of 4-(2-methylimidazol-1-yl)phenyl iodide (1.21 g, 3.1 mmol) and (2SR, 4RS)-4-cyano-2-methyl-4-(3-triisopropylsilylthiophenyl)-3,4,5,6-tetrahydro-2H-pyran (795 mg, 2.8 mmol) in ethanol (20 ml) was added tetrakis(triphenylphosphine)palladium(0) (215 mg, 0.2 mmol) and potassium tert-butoxide (383 mg, 3.4 mmol) under a nitrogen atmosphere. The resulting mixture was heated at reflux temperature for 15.5 h, then cooled and concentrated in vacuo. The residue was diluted in ethyl acetate (100 ml), and washed with water (2×100 ml), brine (100 ml) and dried (MgSO4) and concentrated. Purification by silica-gel column chromatography, eluting with dichloromethane-methanol (25:1), gave 1.01 g (93%) of the titled compound as a yellow gum.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[C:10]([C:12]34[CH2:19][CH2:18][C:15]([CH:16]=[CH:17]3)=[CH:14][CH2:13]4)[CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.[NH2:20][NH2:21].Cl>C(O)C>[NH:20]([C:2]1[N:3]=[C:4]2[C:9](=[C:10]([C:12]34[CH2:19][CH2:18][C:15]([CH:16]=[CH:17]3)=[CH:14][CH2:13]4)[CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2)[NH2:21]
Reactant: Clc1cc(C23C=CC(=CC2)CC3)c2c(n1)CCCN2
Reactant: NN
Agent: Cl
Solvent: CCO
Product: NNc1cc(C23C=CC(=CC2)CC3)c2c(n1)CCCN2
Temperature: 25 °C

Procedure:
6-Chloro-1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridine (1.03 g) was treated with anhydrous ethanol (10 mL), anhydrous hydrazine (Aldrich, 4.0 mL) and concentrated HCl (0.4 mL). The reaction mixture was then heated in a screw cap pressure tube at 150° C. until LCMS showed complete conversion to the hydrazine (approx. 96 h). The reaction mixture was cooled to ambient temperature, then concentrated under vacuum. The residue was partitioned between chloroform and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 6-hydrazino-1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridine as a pale yellow solid (0.68 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].C(=O)(O)[O-].[Na+].Br[CH2:18][C:19](Br)=[O:20]>C(Cl)(Cl)Cl>[O:20]=[C:19]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][C:10]=2[O:11][CH2:18]1
Reactant: Nc1cc(C(=O)O)ccc1O
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C1COc2ccc(C(=O)O)cc2N1
Temperature: 0 °C
Yield: 95 %

Procedure:
3-amino-4-hydroxybenzoic acid (4.0 g, 26.0 mmol) was dissolved in 168 mL of chloroform. 92 mL of saturated sodium bicarbonate solution was added and the new bi-phase mixture was stirred vigorously and cooled to 0° C. using an ice bath. Bromoacetylbromide (3.42 mL, 39 mmol) was added drop-wise. Fifteen minutes later the solution was removed from the ice bath and maintained at room temperature for 48 hours. HPLC (Eclipse XDB-C18, 4.6×250 mm, 5 micron, 1-99% CH3CN/H2O with 0.1% trifluoroacetic acid) chromatogram indicated that all of the starting material was gone and a new peak (Rt=3.7 min) had formed. The reaction mixture was quenched using concentrated hydrochloric acid until the solution reached a pH of 2. The organic layer was separated and the aqueous phase was extracted with 100 mL of chloroform. The combined organic layers were treated with 75 mL of 10% hydrochloric acid solution and separated once again. The organic phase was dried over Na2SO4, filtered and concentrated to give 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (4.8 g, 24.7 mmol, 95%) as an off-white amorphous solid. MS (ES) m/e 194 [M+H]+.
Reaction SMILES: [H][H].[C:3](#[N:6])[CH:4]=[CH2:5].[OH2:7]>>[C:3](#[N:6])[CH:4]=[CH2:5].[C:3]([NH2:6])(=[O:7])[CH:4]=[CH2:5]
Reactant: [H][H]
Reactant: O
Solvent: C=CC#N
Product: C=CC(N)=O

Procedure:
Sample 1: A reaction tube made of SUS-27 stainless steel measuring 30 mm in inside diameter and 300 mm in length is filled with 390g (bulk volume: 220 ml) of cupric oxide tablets (manufactured by Nikki Kagaku KK). Then, reduction is carried out at 200° - 270°C by flowing hydrogen gas and nitrogen gas at the rates 200 and 400 ml/min respectively. By this, a reduced copper catalyst of percent reduction of 98%, as determined from the degree of decrease in quantity, is prepared. After this, acrylonitrile and water are continuously supplied to the reaction tube at the rates of 140 and 690 g/hr. respectively to carry out reaction at 120°C. At the same time, the reacting solution is circulated at a rate of 40 liters/hr. An acrylamide aqueous solution is obtained through this reaction, wherein the rate of conversion from acrylonitrile to acrylamide is 70%.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][OH:8])[CH2:2][CH2:3][CH3:4].[CH:9](O)=[O:10].O.CI>C(O)(=O)C.C(Cl)(Cl)Cl>[CH:9]([O:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:10]
Reactant: CCCCOCCO
Reactant: O=CO
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCCCOCCOC=O

Procedure:
2-n-Butoxyethanol formate was prepared in 96% purity by reaction of 2-n-butoxyethanol with excess formic acid and azeotropic removal of H2O in the presence of chloroform. To 480 g there was added 100 g of a solution consisting of 300 ml CH3I, 20 ml acetic acid, and 0.05 g of Co2 (CO)8. The resultant solution was pumped at 0.17 ml/min to a 25 cc reactor containing 25 cc of Sorbonorit B-3 (same system as Example 6) while CO was simultaneously fed to the reactor at 5 or 7.5 liters/hr. The reactor was operated at elevated temperature and pressure. GLC analyses of liquid effluent collected under various conditions were as follows:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](/[C:9](=[N:11]/[C:12]2[C:17]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH:21]([CH3:23])[CH3:22])/[CH3:10])[C:3]=1[OH:24].[Li]CCCC.Br[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH3:38].O>C1COCC1.[Cl-].[Cl-].[Zn+2].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:21]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([CH:18]([CH3:20])[CH3:19])[C:12]=1/[N:11]=[C:9](/[C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH3:38])[C:3]=1[OH:24])\[CH3:10])([CH3:23])[CH3:22]
Reactant: COc1ccccc1Br
Reactant: C/C(=N\c1c(C(C)C)cccc1C(C)C)c1cc(C)cc(Br)c1O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1-c1cc(C)cc(/C(C)=N/c2c(C(C)C)cccc2C(C)C)c1O
Temperature: -100 °C
Reaction time: 1 h
Yield: 29.8 %

Procedure:
To a solution of 1.94 g (5.0 mmol) of 30 in 20 mL of THF, 4.0 mL (10.0 mmol) of 2.5 M nBuLi in hexanes was added at −80° C. This mixture was stirred at this temperature for 1 hr, then cooled to −100° C., and 10.8 mL (10.8 mmol) of 1.0 M ZnCl2 in THF was added. The resulting mixture was slowly warmed to ambient temperature, stirred for 30 min, and then 2.82 g (15.0 mmol) of 2-bromoanisole and 0.14 g (0.25 mmol) of Pd(PtBu3)2 was added. This mixture was refluxed for 8 hr, then 5 mL of water was added. The resulting mixture was passed through short layer of silica gel 60. The silica gel layer was additionally washed with 30 mL of dichloromethane. The combined organic elute was evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um, eluent: from hexanes to hexanes-ether, 20:1, vol.) to give 0.62 g (30%) of yellowish solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[N:3]1.O1CCCC1.S(Cl)(Cl)=O.[NH2:19][C:20]1[CH:21]=[C:22]([CH:39]=[CH:40][C:41]=1[CH3:42])[O:23][C:24]1[CH:25]=[CH:26][C:27]2[N:28]([N:30]=[C:31]([NH:33][C:34]([CH:36]3[CH2:38][CH2:37]3)=[O:35])[N:32]=2)[CH:29]=1>CN(C)C=O.CN(C)C(=O)C>[CH:36]1([C:34]([NH:33][C:31]2[N:32]=[C:27]3[CH:26]=[CH:25][C:24]([O:23][C:22]4[CH:39]=[CH:40][C:41]([CH3:42])=[C:20]([NH:19][C:7]([C:4]5[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=5)=[O:9])[CH:21]=4)=[CH:29][N:28]3[N:30]=2)=[O:35])[CH2:37][CH2:38]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1N
Reactant: Cn1ccc(C(=O)O)n1
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1NC(=O)c1ccn(C)n1
Yield: 58.1 %

Procedure:
In the same manner as in Example 55 and using 1-methyl-1H-pyrazole-3-carboxylic acid (55.5 mg, 0.440 mmol), tetrahydrofuran (5 mL), thionyl chloride (77.0 μL, 0.888 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (129 mg, 0.399 mmol) and N,N-dimethylacetamide (6 mL) as starting materials, the title compound (100 mg, 58%) was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]([NH2:18])=O)[O:13][N:12]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[Br:1][C:2]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[N:15]=[C:14]([C:16]#[N:18])[O:13][N:12]=2)[CH2:9][CH2:10]1
Reactant: NC(=O)c1nc(N2CCC(Oc3cc(F)ccc3Br)CC2)no1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: N#Cc1nc(N2CCC(Oc3cc(F)ccc3Br)CC2)no1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazole-5-carboxamide (11 g, 28.6 mmol) and triethylamine (12.74 ml, 91 mmol) in THF (95 ml) was added trifluoroacetic anhydride (6.05 mL, 42.8 mmol) dropwise at 0° C. The mixture was warmed to RT and stirred for a further 30 min. The solvent was evaporated and the residue was diluted with Et2O (50 mL) then with dilute NaHCO3 solution (100 mL). The aqueous layer was extracted with Et2O (3×100 mL). The combined organic fractions were dried over Na2SO4 and the solvent was evaporated under reduced pressure. Purification by Combiflash chromatography (SiO2-120 g, gradient elution of 10-30% EtOAc/hexanes over 25 min) afforded the title compound.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Na].[Cl-].[CH3:12][O:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:34]([N:39]1[CH2:44][CH2:43][C:42](=O)[CH2:41][CH2:40]1)([O:36][CH2:37][CH3:38])=[O:35].O>C1COCC1.CCOCC>[CH3:12][O:13][CH:14]=[C:42]1[CH2:43][CH2:44][N:39]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:40][CH2:41]1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)N1CCC(=COC)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 89.4 %

Procedure:
A 1M solution of sodium hexamethyldisilazane (NaHMDS, 350 mL, 0.35 mol) in THF was added slowly to a suspension of (methoxymethyl)triphenyl phosphonium chloride (120 g, 0.35 mol,) in THF (100 mL) at −78° C. under N2. The resulting brown solution was stirred at −78° C. for 20 minutes and then 1-carbethoxy-4-piperidone (50 g, 0.292 mol) in THF (50 mL) was added dropwise. The mixture was stirred at −78° C. for 5 minutes and then for 2 hours at room temperature. Water (200 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic extracts were dried over Na2SO4. The solvent was evaporated to give an orange solid which was suspended in Et2O (200 mL). The solid was removed by filtration and the filtrate was concentrated to give a yellow oil which was triturated with hexane (200 mL). The white solid which precipitated was removed by filtration. The filtrate was concentrated in vacuo and this was procedure repeated twice more to give the title compound (52 g, 89%) as a pale yellow oil. TLC Rf=0.72 (EtOAc:hexane, 1:2); 1H NMR (CDCl3) δ 5.84 (s, 1H), 4.11 (q, J=7 Hz, 2H), 3.54 (s, 3H), 3.37-3.42 (mult, 4H), 2.24 (t, J=5.6 Hz, 2H), 1.99 (t, J=5.6 Hz, 2H), 1.24 (t, J=7 Hz, 3H); 13C NMR (CDCl3) δ 1.55, 140.8, 113.4, 61.3, 59.5, 45.8, 44.6, 29.6, 25.2, 14.8; mass spectrum (API-TIS) m/z 200 (M+H). Anal Calcd for C10H17N1O3: C, 60.28; H, 8.60; 7.03. Found: C, 60.29; H, 8.63; N, 6.81.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCCCC>C1COCC1>[C:1]1(/[CH:7]=[CH:8]\[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(#Cc1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C(=C\c1ccccc1)\c1ccccc1

Procedure:
In the foregoing epititanations of diphenylacetylene conducted in THF or hexane, parallel epititanations were conducted in the same manner but the hydrolytic workup in each case was performed with 3N DCl in D2O. In these experiments the cis-stilbene isolated was >98% dideuteriated at the vinylic carbon atoms (12).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10]C)=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1.Cl>CN(C)C=O>[N:18]1([C:2]2[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=2)[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: c1nc[nH]n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cnc(-n2cncn2)cn1
Temperature: 100 °C

Procedure:
A mixture of methyl 5-chloropyrazine-2-carboxylate (0.75 g), K2CO3 (1.8 g) and 1H-1,2,4-triazole (1.2 g) in N,N-dimethylformamide (6 mL) is heated to 100° C. overnight. Analysis of the crude mixture by LCMS shows saponified product. The product is acidified with 1N HCl and the precipitate is filtered and washed with water and diethyl ether to afford the title compound. LC (method 20): tR=1.06 min; Mass spectrum (APCI): m/z=192 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Rh]>[C:1]([CH:5]1[CH2:10][CH:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:8][CH2:7][C:6]1=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: [Rh]
Solvent: CCO
Product: CC(C)(C)C1CCC(=O)C(C(C)(C)C)C1
Reaction time: 17 h
Yield: 91 %

Procedure:
410.0 g of 2,4-di-tert-butylphenol are hydrogenated in 820 ml of ethanol under 40 bar at 60° C. using 20 g of rhodium on carbon (5%) for 21 hours. To complete the reaction, the pressure is raised to 120 bar, a further 10 g of rhodium on carbon (5%) are added, and the hydrogenation is continued at 100° C. for 17 hours. The catalyst is filtered off, the solvent is distilled off under reduced pressure, and the residue is distilled off under high vacuum to leave 380.43 g (91% of theory) of 2,4-di-tert-butylcyclohexanone (mixed isomers) as a colourless liquid. Boiling point: 79-86° C./0.22 mbar.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:7][CH:8]=1)#[N:2].C[Al]([NH2:19])Cl>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])=[N:7][CH:8]=1)(=[NH:19])[NH2:2]
Reactant: CC(C)(C)C(=O)Nc1ccc(C#N)cn1
Reactant: C[Al](N)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)Nc1ccc(C(=N)N)cn1
Temperature: 80 °C

Procedure:
A mixture of N-(5-cyanopyridin-2-yl)pivalamide (1.22 g, 6.00 mmol) and MeAl(Cl)NH2 (18 mL, 0.67M solution in toluene, 12.00 mmol) in 25 mL toluene is heated at 80° C. for 15 hours. The resulting N-(5-carbamimidoylpyridin-2-yl)pivalamide is used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@@H:13]([C:24]([O:26]C)=[O:25])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:11].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@@H:13]([C:24]([OH:26])=[O:25])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:11]
Reactant: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(C=Cc1ccccc1F)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Yield: 93.9 %

Procedure:
The same procedures as in Example 64 were carried out from the compound obtained in Example 31 (3.1 g), 1 mol/L of an aqueous sodium hydroxide solution (13 mL), and methanol (130 mL), to give the captioned compound (2.8 g, 95%) as crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[CH:20]1([NH:23][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([B:11]3[O:12][C:13]([CH3:18])([CH3:19])[C:14]([CH3:16])([CH3:17])[O:15]3)[CH:4]=2)[CH2:22][CH2:21]1
Reactant: NC1CC1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (WO200700565, 5.47 g, 20.87 mmol) in N,N′-dimethylformamide (55 mL) were added cyclopropylamine (1.76 mL, 25.08 mmol), diisopropylethylamine (8.00 mL, 45.93 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (7.62 g, 20.04 mmol). The clear solution was stirred at room temperature overnight. The mixture was then concentrated in vacuo and the residue was taken up with ethyl acetate and the organic phase was washed with 4% aqueous sodium bicarbonate solution, water, brine, dried (MgSO4) and concentrated to afford an oily residue. The oil was triturated with a mixture of hexanes and diethyl ether to give the title compound (5.78 g, 96%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:12](=[O:13])[CH2:11][O:10][C:9]3[N:14]=[C:15]([C:24]4[CH:29]=[CH:28][C:27]([C:30]5([NH:34]C(=O)OC(C)(C)C)[CH2:33][CH2:32][CH2:31]5)=[CH:26][CH:25]=4)[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:17][C:8]2=3)[CH:4]=[N:3]1>C(O)(C(F)(F)F)=O>[NH2:34][C:30]1([C:27]2[CH:28]=[CH:29][C:24]([C:15]3[C:16]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:17][C:8]4[N:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)[C:12](=[O:13])[CH2:11][O:10][C:9]=4[N:14]=3)=[CH:25][CH:26]=2)[CH2:31][CH2:32][CH2:33]1
Reactant: Cn1cc(N2C(=O)COc3nc(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)cc32)cn1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(N2C(=O)COc3nc(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)cc32)cn1
Reaction time: 0.01 h
Yield: 118.9 %

Procedure:
tert-Butyl 1-(4-(1-(1-methyl-1H-pyrazol-4-yl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (30 mg, 0.054 mmol) was dissolved in TFA (2 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (2 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed by freeze drying overnight to give the desired compound as an off-white solid (29 mg, 94% yield). 1H-NMR (500 MHz, MeOD) δ 7.89 (1H, s), 7.62 (1H, s), 7.42-7.51 (4H, m), 7.40 (2H, d), 7.37 (2H, d), 7.18-7.27 (3H, m), 7.03-7.12 (3H, m), 5.06 (2H, s), 3.96 (3H, s), 2.66-2.78 (2H, m), 2.48-2.58 (2H, m), 2.13-2.26 (1H, m), 1.85-1.98 (1H, m). LCMS (Method D) RT=0.86 min, M+H+=452.20.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([NH:22]C(=O)OC(C)(C)C)[C:20]([CH2:30][O:31][CH2:32][CH3:33])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([NH2:22])[C:20]([CH2:30][O:31][CH2:32][CH3:33])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1N
Temperature: 100 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
A suspension of tert-butyl (7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)carbamate (14.4 g, 32.1 mmol) in 100 mL of ethanol was treated with HCl in ethanol (38 mL, 160 mmol, 4.3 M). The mixture was heated to 100° C. under an atmosphere of nitrogen. After 2 h, the reaction mixture was cooled to ambient temperature at which point a solid precipitated from solution. The mixture was diluted with 100 mL of diethyl ether and the solid was triturated for 15 min. The solid was collected by vacuum filtration and washed with several portions of diethyl ether. The solid was dried under vacuum for 2 h. The dry solid was suspended in 150 mL of water and treated with 50% NaOH solution until the pH of the liquid was 12. A brown solid precipitated. The mixture was diluted with 200 mL of CH2Cl2 and stirred until the solid dissolved. The layers were then separated. The aqueous portion was extracted with CH2Cl2 (2×100 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 6.91 g of 7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-amine as a dark tan solid.