Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:34])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][C:26]([O:30]C)=[CH:27][C:28]=5[CH3:29])[C:20]([CH3:32])=[C:19]([CH3:33])[CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[Si](I)(C)(C)C.CO>CC#N>[F:34][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][C:26]([OH:30])=[CH:27][C:28]=5[CH3:29])[C:20]([CH3:32])=[C:19]([CH3:33])[CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: COc1cc(C)c(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc(C)c2C)cn1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: CC#N
Product: Cc1cc(O)ncc1-c1nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)cc(C)c1C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
To a suspension of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3,4,4′-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (17 mg, 0.036 mmol) in CH3CN (0.7 mL) was added TMSI (10 uL, 0.072 mmol) dropwise at 20° C. The reaction was stirred at 50° C. for 30 min. Additional TMSI (10 uL, 0.072 mmol) was added and the reaction was heated at 50° C. for 2 h. Additional TMSI (10 uL, 0.072 mmol) was added and the reaction was heated at 70° C. for 2 h. MeOH (1.0 mL) was added and the solution was re-partitioned between EtOAc and H2O. The organic layer was washed with NaHSO3 (2×), brine, dried over MgSO4 and evaporated to dryness to yield a white solid that was further purified by preparative TLC (10% MeOH-EtOAc) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-hydroxy-3,4,4′-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (8 mg, 49%). 1H NMR (400 MHz, MeOD) 7.92 (s, 1H), 7.28 (d, J=1.6 Hz, 1H), 7.22 (dd, J=1.7, 8.3 Hz, 1H), 7.14-7.10 (m, 2H), 6.36 (s, 1H), 2.27 (s, 3H), 1.95 (s, 3H), 1.81 (d, J=0.6 Hz, 3H), 1.56 (dd, J=3.9, 7.0 Hz, 2H), 1.14 (dd, J=3.9, 7.0 Hz, 2H). Retention time: 1.49 min; ESI-MS m/z calc. 453.4. found 454.2 (M+H)+.
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:17][CH2:16][CH2:15][C:14]3[CH:18]=[CH:19][C:20]([C:22](=[O:31])[CH2:23][CH2:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:21][C:13]=3[CH2:12]2)=[CH:6][CH:5]=1.[Cl:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36]Br>>[ClH:32].[ClH:1].[Cl:32][C:33]1[CH:34]=[C:35]([CH2:36][N:28]2[CH2:27][CH2:26][CH:25]([CH2:24][CH2:23][C:22]([C:20]3[CH:19]=[CH:18][C:14]4[CH2:15][CH2:16][CH2:17][N:11]([CH2:10][C:7]5[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=5)[CH2:12][C:13]=4[CH:21]=3)=[O:31])[CH2:30][CH2:29]2)[CH:38]=[CH:39][CH:40]=1
Reactant: O=C(CCC1CCNCC1)c1ccc2c(c1)CN(Cc1ccc(F)cc1)CCC2
Reactant: Clc1cccc(CBr)c1
Agent: Cl
Product: O=C(CCC1CCN(Cc2cccc(Cl)c2)CC1)c1ccc2c(c1)CN(Cc1ccc(F)cc1)CCC2

Procedure:
Using 1-[2-[(4-fluorophenyl)methyl]-2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl]-3-(4-piperidinyl)-1-propanone(free base) obtained in Example 211, and 3-chlorobenzyl bromide, the procedure of Example 51-3 was otherewise repeated to provide the title compound as colorless amorphous powders.
Reaction SMILES: Cl.Cl.[I:3][C:4]1[CH:5]=[N:6][C:7]([C:10]2([NH:13][C:14]([C:16]3([NH2:19])[CH2:18][CH2:17]3)=[O:15])[CH2:12][CH2:11]2)=[N:8][CH:9]=1.C(N(CC)CC)C.[C:27]([C:29]1[CH:57]=[CH:56][C:32]([CH2:33][C@@:34]2([CH3:55])[N:38]3[C:39]([C:42](Cl)=[O:43])=[CH:40][N:41]=[C:37]3[N:36]([C:45]3[CH:50]=[C:49]([Cl:51])[C:48]([F:52])=[C:47]([Cl:53])[CH:46]=3)[C:35]2=[O:54])=[CH:31][CH:30]=1)#[N:28]>C1COCC1>[I:3][C:4]1[CH:9]=[N:8][C:7]([C:10]2([NH:13][C:14]([C:16]3([NH:19][C:42]([C:39]4[N:38]5[C@@:34]([CH2:33][C:32]6[CH:31]=[CH:30][C:29]([C:27]#[N:28])=[CH:57][CH:56]=6)([CH3:55])[C:35](=[O:54])[N:36]([C:45]6[CH:46]=[C:47]([Cl:53])[C:48]([F:52])=[C:49]([Cl:51])[CH:50]=6)[C:37]5=[N:41][CH:40]=4)=[O:43])[CH2:18][CH2:17]3)=[O:15])[CH2:12][CH2:11]2)=[N:6][CH:5]=1
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(C(=O)Cl)n21
Reactant: NC1(C(=O)NC2(c3ncc(I)cn3)CC2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5ncc(I)cn5)CC4)CC3)n21
Reaction time: 2 h
Yield: 101.7 %

Procedure:
To 1-amino-cyclopropanecarboxylic acid[1-(5-iodo-pyrimidin-2-yl)-cyclopropyl]-amide dihydrochloride (400 mg, 0.96 mmol) was added 1 mL of dry THF and triethylamine (0.71 ml, 3.98 mmol). Crude (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl chloride (476 mg, 1.0 mmol) was dissolved in 2 mL of dry THF and transferred to the reaction flask. After 2 h, the solvent was removed at 55° C. under a stream of N2. The resulting slurry was diluted with EtOAc (75 mL) and washed with 10% aq citric acid (75 mL) and saturated aq NaHCO3 (75 mL). The organic layer was dried over Na2SO4 and concentrated to give a light orange foam. This solid was purified by normal phase flash chromatography on silica gel (1→3% MeOH/CH2Cl2) to give 767 mg of the title compound as a tan powder, m/z 785.5.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:18][CH:17]3[CH2:19][CH:14]2[CH2:15][N:16]3[CH:20]([CH3:22])[CH3:21])[CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[C:6](=[O:31])[N:7]2[C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:30].[F:41][C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=1B(O)O>>[Cl:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([Cl:29])[C:23]=1[N:7]1[C:8]2[C:3](=[C:2]([C:45]3[CH:44]=[CH:43][C:42]([F:41])=[CH:47][C:46]=3[F:48])[CH:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH:17]4[CH2:19][CH:14]3[CH2:15][N:16]4[CH:20]([CH3:21])[CH3:22])[CH:9]=2)[CH2:4][N:5]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[C:6]1=[O:31]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: COc1ccc(CN2Cc3c(Br)cc(CN4CC5CC4CN5C(C)C)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Product: COc1ccc(CN2Cc3c(-c4ccc(F)cc4F)cc(CN4CC5CC4CN5C(C)C)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1

Procedure:
The 1-(2,6-dichlorophenyl)-5-(2,4-difluorophenyl)-7-[(5-isopropyl-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one was prepared from 5-bromo-1-(2,6-dichlorophenyl)-7-[(5-isopropyl-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (EXAMPLE AAA16, STEP C) and 2,4-difluorobenzene boronic acid as described in EXAMPLE AAA16, STEP D. 1H NMR (CDCl3, 500 MHz): δ 1.03 (s, 3H), 1.08 (s, 3H), 1.59 (brs, 2H), 2.40 (m, 2H), 2.56 (brs, 1H), 2.83 (m, 1H), 2.90 (brs, 1H), 3.15 (s, 1H), 3.58 (abq, 3H, J=14.5 Hz), 3.81 (s, 3H), 4.20 (brs, 2H), 4.58 (brs, 2H), 6.23 (s, 1H), 6.85 (m, 3H), 6.91 (m, 2H), 7.14 (q, 1H, J=7.1 Hz), 7.23 (d, 2H, J=8.5 Hz), 7.39 (t, 1H, J=8.0 Hz), 7.54 (d, 2H, J=8.1 Hz). MS (API-ES+): 677 (M+H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9](=[O:19])[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1.[C:20]([NH:23][NH2:24])(=[O:22])[CH3:21].CCN(CC)CC>C(Cl)Cl.O>[CH3:7][O:8][C:9](=[O:19])[C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:24][NH:23][C:20](=[O:22])[CH3:21])=[O:16])=[CH:17][CH:18]=1
Reactant: CC(=O)NN
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)NNC(C)=O)cc1
Reaction time: 4 h
Yield: 76.3 %

Procedure:
Oxalyl chloride (1.05 g, 8.3 mmol) was added to a stirred solution of terephthalic acid monomethyl ester (1 g, 5.55 mmol) in DCM (12 mL) and stirring was continued at ambient temperature for 4 hr. The reaction mixture was concentrated under reduced pressure to afford the residue. The residue was dissolved in DCM (4 mL) and to the resulting solution was added, acetic acid hydrazide (490 mg, 6.66 mmol), Et3N (670 mg, 6.66 mmol) and stirring was continued at temperature overnight. The reaction mixture was diluted with water and extracted with ethylacetate, dried over sodium sulfate and concentrated under reduced pressure to afford 1 g (76.39% Yield) of 4-(N′-acetyl-hydrazinocarbonyl)-benzoic acid methyl ester. A stirred solution of 4-(N′-acetyl-hydrazinocarbonyl)-benzoic acid methyl ester (500 mg, 5.55 mmol) in POCl3 (12 mL) was heated at 100° C. for 3 hr. The reaction mixture was concentrated under reduced pressure to afford the residue. The residue was diluted with cold water, extracted with ethyl acetate, washed the organic layer with sodium bicarbonate solution, saturated brine solution and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to 350 mg (75.92% Yield) of afford 4-(5-methyl-[1,3,4]oxadiazol-2-yl)-benzoic acid methyl ester. LiOH.H2O (330 mg, 8 mmol) was added to a solution of 4-(5-methyl-[1,3,4]oxadiazol-2-yl)-benzoic acid methyl ester (350 mg, 1.6 mmol) in the mixture of methanol (4 mL), THF (10 mL) and H2O (4 mL). The resulting reaction mixture was stirred at ambient temperature for 2 hrs. The reaction mixture was concentrated The residue was diluted with water, acidified with aqueous citric acid solution, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to afford 280 mg (87.46% Yield) of 4-(5-methyl-[1,3,4]oxadiazol-2-yl)-benzoic acid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH3:18])([CH3:17])[C:15]#N)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1[CH:24]=[CH:23]C=[CH:21][CH:20]=1.[Cl-].[NH4+]>C(OCC)C>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([CH3:17])([C:15]2[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=2)[CH3:18])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C#N)N1CCN(Cc2ccccc2)CC1
Reactant: c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(c1ccccc1)N1CCN(Cc2ccccc2)CC1
Reaction time: 3.5 h

Procedure:
In an atmosphere of argon and at room temperature, 2-(4-benzyl-piperazin-1-yl)-2-methyl-propionitrile (820 mg, 3.4 mmol) dissolved in diethyl ether (1.2 ml) and benzene (2.5 ml) was added dropwise to phenylmagnesium bromide ether solution (3.0 M, 2.0 ml, 6.0 mmol), and the mixture after completion of the dropwise addition was stirred for 3.5 hours. The reaction solution was mixed with 10% ammonium chloride aqueous solution (18 ml) and separated into water layer and organic layer. The reaction product was extracted from the organic layer with dilute hydrochloric acid, and then the water layer was neutralized with aqueous ammonia and the reaction product was again extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, the solvent was removed by evaporation under a reduced pressure, and then the thus obtained material was separated and purified by a silica gel column chromatography to obtain 300 mg (1.0 mmol, 30% in yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:9]([C:13]([NH:15][NH2:16])=[O:14])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][O:7]2.C(N(CC)CC)C.[CH:24]1([N:27]2[CH2:32][CH2:31][CH:30]([C:33](Cl)=[O:34])[CH2:29][CH2:28]2)[CH2:26][CH2:25]1>ClCCl.O>[CH:24]1([N:27]2[CH2:28][CH2:29][CH:30]([C:33]([NH:16][NH:15][C:13]([C:9]3[CH:10]=[C:11]([Cl:12])[C:2]([NH2:1])=[C:3]4[C:8]=3[O:7][CH2:6][CH2:5][CH2:4]4)=[O:14])=[O:34])[CH2:31][CH2:32]2)[CH2:26][CH2:25]1
Reactant: NNC(=O)c1cc(Cl)c(N)c2c1OCCC2
Reactant: O=C(Cl)C1CCN(C2CC2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1c(Cl)cc(C(=O)NNC(=O)C2CCN(C3CC3)CC2)c2c1CCCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.7 %

Procedure:
To a stirred solution of 5-amino-6-chloro chroman-8-carboxylic acid hydrazide (8.0 grams, 33.1 mmol, obtained in preparation 1) in dichloromethane (200 mL) cooled at 0° C., was added triethylamine (13.9 mL, 99.9 mmol) and a solution of 1-cyclopropylpiperidine-4-carbonyl chloride (11.0 grams) in dichloromethane (200 mL). The reaction mixture was warmed to room temperature and stirred for 16 hours before diluting it with water (160 mL). The two layers were separated, the organic layer was dried over anhydrous sodium sulphate and the volatiles were removed under reduced pressure to obtain the title compound (10.5 grams).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([C:8]2[N:12]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[N:11]=[CH:10][C:9]=2[N+:18]([O-])=O)[CH:7]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([C:8]2[N:12]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[N:11]=[CH:10][C:9]=2[NH2:18])[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1c([N+](=O)[O-])cnn1CCC(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cl)cc1-c1c(N)cnn1CCC(C)C
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A mixture of 5-(5-Chloro-2-methoxyphenyl)-1-isopentyl-4-nitro-1H-pyrazole (632 mg, 1.95 mmol, 1.00 eq), iron (642.5 mg, 11.50 mmol, 5.90 eq), and ammonium chloride (500.7 mg, 9.36 mmol, 4.80 eq) in 5.0 mL ethanol and 10 mL water was stirred at 75° C. for 2 hours. The reaction mixture was concentrated, 10 mL of saturated bicarbonate solution was added, and the aqueous layer was extracted with dichloromethane (20 mL*3). The combined dichloromethane layers were dried with magnesium sulfate, filtered and concentrated. The reddish yellow oil was used as is for the next step LCMS (ESI) m+H=293.8.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[CH:6][C:5]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Li+].[OH-]>CO>[N:22]1[CH:21]=[CH:20][C:19]([CH:10]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:14])[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:31])=[O:2])=[C:5]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:6]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(C(O[Si](C)(C)C(C)(C)C)c2ccncc2)cc1-c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC(c1ccncc1)c1ccc(C(=O)O)c(-c2ccccc2)c1
Reaction time: 8 h
Yield: 27 %

Procedure:
4-(4-Pyridyl-t-butyldimethylsilyloxymethyl)-2-phenylbenzoic acid methyl ester (0.97 g, 2.24 mmol), prepared as in Example 297B, was dissolved in methanol. Saturated aqueous LiOH (1 mL) was added, and the solution was reluxed overnight. The reaction was evaporated to dryness and partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4 to provide the title compound in 27% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][OH:13])[C:5]#[N:6].[C:14]([O:18][C:19]([N:21]1[CH2:25][CH2:24][CH:23]([O:26][C:27]2[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33](O)=[O:34])=[CH:29][CH:28]=2)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>C(Cl)(Cl)Cl>[C:14]([O:18][C:19]([N:21]1[CH2:25][CH2:24][CH:23]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33](=[O:34])[NH:1][C:2]3[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=3[NH:10][CH2:11][CH2:12][OH:13])=[CH:36][CH:37]=2)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: N#Cc1ccc(NCCO)c(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCC(=O)O)cc2)C1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCC(=O)Nc3cc(C#N)ccc3NCCO)cc2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75.6 %

Procedure:
To a solution of 3-amino-4-(2-hydroxyethylamino)benzonitrile (1.21 g) and 4-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)phenoxyacetic acid (2.30 g) in chloroform (50 ml) was added 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline (2.19 g), and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:4) to give the title compound (2.56 g).
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][N:8]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])(C)(C)C>C(O)=O>[F:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][C:23]2[CH:22]=[CH:21][C:20]([S:17]([N:8]([CH2:7][C:6]([OH:34])=[O:5])[CH2:9][C:10]([OH:12])=[O:11])(=[O:19])=[O:18])=[CH:25][CH:24]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Solvent: O=CO
Product: O=C(O)CN(CC(=O)O)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{[4-(4-Fluoro-phenoxy)-benzenesulphonyl]-tert-butoxycarbonyl methyl-amino}-acetic acid tert-butyl ester (4b) (1.00 g, 2.03 mmol) was dissolved in formic acid (10 mL) and stirred overnight at room temperature.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.[CH3:17][OH:18]>>[CH3:17][O:18][CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1
Reactant: CO
Reactant: Cc1cccc(C(C)(C)C)c1
Agent: O=S(=O)(O)O
Product: COCc1cccc(C(C)(C)C)c1

Procedure:
For the electrochemical methoxylation of 3-tert-butyltoluene of the formula (II), an electrolyte consisting of 105 g of the compound of the formula (II), 1.9 g of sulfuric acid (96-98%) as conductive salt and 593.1 g of methanol was electrolyzed at 45° C. and at a current density of 34 mA/cm2 in an undivided capillary gap cell having 10 round graphite electrodes (A=32 cm2) until an amount of charge of 15 F/mol of the compound of the formula (II) was reached. Work-up by distillation gave 33.3 g of the compound of the formula (I) and 7.5 g of 3-tert-butylbenzyl methyl ether, corresponding to a total yield of acetal and ether of 30%.
Reaction SMILES: [C:1]([CH:5]1[CH2:9][S:8][CH:7]([CH2:10][CH2:11][CH3:12])[C:6]1=O)([O:3][CH3:4])=[O:2].Cl.[NH2:15][OH:16]>N1C=CC=CC=1>[C:1]([CH:5]1[CH2:9][S:8][CH:7]([CH2:10][CH2:11][CH3:12])[C:6]1=[N:15][OH:16])([O:3][CH3:4])=[O:2]
Reactant: CCCC1SCC(C(=O)OC)C1=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCCC1SCC(C(=O)OC)C1=NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of 94.0 g (0.465 mole) of 4-carbomethoxy-3-keto-2-propyl-tetrahydrothiophene in 250 ml of dry pyridine was treated with 40.0 (0.576 mole) of hydroxylamine hydrochloride at 25°. The reaction was stirred overnight at room temperature. The solvent was evaporated and the residue was partitioned between 1 N HCl and methylene chloride. The organic phase was dried over sodium sulfate and evaporated to afford 100 g (0.461 mole, 99%) of pure 4-carbomethoxy-3-keto-2-propyl-tetrahydrothiophene oxime as a colorless oil.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[Cl:9][C:10]1[C:29](I)=[CH:28][C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)=[O:15])=[CH:12][N:11]=1.[CH3:31][C:32]1[CH:33]=[N:34][N:35]([CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[C:36]=1B1OC(C)(C)C(C)(C)O1>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:9][C:10]1[C:29]([C:36]2[N:35]([CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][O:47]3)[N:34]=[CH:33][C:32]=2[CH3:31])=[CH:28][C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)=[O:15])=[CH:12][N:11]=1
Reactant: Cc1cnn(C2CCCCO2)c1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(I)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cnn(C2CCCCO2)c1-c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1Cl
Temperature: 110 °C
Reaction time: 18 h

Procedure:
K3PO4 (127 mg, 0.6 mmol) was added to a solution of 6-chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 4.2, 89 mg, 0.2 mmol) and 4-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (58.4 mg, 0.2 mmol) in dioxane (1 mL) in a vial which was flushed with argon, heated to 110° C. and then PdCl2(dppf) (7.32 mg, 0.01 mmol) was added. The vial was sealed and the RM was stirred under argon at 110° C. for 18 h. The RM was cooled to RT, dissolved in EtOAc and washed with brine. The organic phase was dried over Na2SO4 and the solvent was evaporated off under reduced pressure. and the residue was purified by flash chromatography (RediSep® Silica gel column, n-heptane/EtOAc form 50% to 100% EtOAc) to afford the title compound as a white foam. HPLC (Condition 4) tR=6.24 min, UPLC-MS (Condition 3) tR=1.22 min, m/z=481.2 [M+H]+.
Reaction SMILES: C([O-])=O.[NH4+].[F:5][C:6]1[CH:7]=[CH:8][C:9]([N+:19]([O-])=O)=[C:10]([CH:18]=1)[O:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>[Pd].CO>[F:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:19])=[C:10]([O:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:18]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1OC1CCOCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1ccc(F)cc1OC1CCOCC1
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
Ammonium formate (1.11 g, 17.6 mmol) was added into a suspension of 4-(5-fluoro-2-nitrophenoxy)tetrahydro-2H-pyran (1 g, 4.14 mmol) and palladium on carbon (5%, 0.250 g) in MeOH (10 mL) at ambient temperature. The solution was stirred for 0.5 hours, filtered through Celite and washed with MeOH. The filtrate was concentrated in vacuo and triturated from diethyl ether to remove the ammonium formate by-products. The sample was purified by flash column chromatography (5:1 petroleum ether (40-60° C.)/EtOAc→1:1 petroleum ether (40-60° C.)/EtOAc) to yield yellow oil (0.666 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:38]([O:40][C:41](=[O:46])[CH2:42][CH2:43][CH2:44]Br)[CH3:39]>CN(C=O)C>[CH2:38]([O:40][C:41](=[O:46])[CH2:42][CH2:43][CH2:44][O:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([N:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:12]([N:8]([C:9](=[O:11])[CH3:10])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:13][C@@H:14]2[CH3:31])=[O:30])=[CH:28][CH:27]=1)[CH3:39]
Reactant: CCOC(=O)CCCBr
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Temperature: 80 °C

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide was dissolved in DMF at room temperature and K2CO3 was added. Ethyl-4-bromobutyrate was added and the reaction was allowed to heat to 80° C. overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (50% EtOAc/50% Hexane) to afford the product.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[S:14][C:13]([C:15]([NH2:17])=O)=[N:12][N:11]=2)[CH:5]=[C:4]([O:18][CH2:19][C@H:20]2[CH2:22][C@@H:21]2[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=2)[N:3]=1.CCN(CC)CC.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C1COCC1>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[S:14][C:13]([C:15]#[N:17])=[N:12][N:11]=2)[CH:5]=[C:4]([O:18][CH2:19][C@H:20]2[CH2:22][C@@H:21]2[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=2)[N:3]=1
Reactant: Cc1ccc([C@H]2C[C@@H]2COc2cc(NCc3nnc(C(N)=O)s3)nc(C)n2)nc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc([C@H]2C[C@@H]2COc2cc(NCc3nnc(C#N)s3)nc(C)n2)nc1
Reaction time: 1 h
Yield: 67.8 %

Procedure:
To the solution of 5-((2-methyl-6-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-4-ylamino)methyl)-1,3,4-thiadiazole-2-carboxamide (17-11) (116 mg, 0.15 mmol) in THF was added NEt3 (0.1 mL, 0.7037 mmol) and TFAA (74 mg, 0.35 mmol) at 0° C. The mixture was brought to rt and stirred for 1 h. Then it was concentrated under reduced pressure and purified on silica gel (eluent PE/EA/NEt3=10/1/1%-5/1/1%) to give the product as a pale red solid (40 mg, 70%). 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.38 (dd, J=7.9, 1.7 Hz, 1H), 7.04 (d, J=7.9 Hz, 1H), 5.62 (s, 1H), 5.37 (t, J=5.9 Hz, 1H), 5.05 (d, J=6.2 Hz, 2H), 4.29 (ddd, J=27.7, 11.2, 7.0 Hz, 2H), 2.49 (s, 3H), 2.28 (s, 3H), 2.16-2.03 (m, 1H), 1.96-1.70 (m, 1H), 1.41-1.17 (m, 1H), 1.17-0.94 (m, 1H); LRMS (ESI) calculated M+H for C19H20N7OS: 394.4. Found: 394.1.