Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:31][CH:32](O)[CH3:33]>O1CCCC1>[Cl:31][CH2:32][CH2:33][O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1]
Reactant: CC(O)Cl
Reactant: Cc1c(O)cccc1[N+](=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(OCCCl)cccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a solution of 2-methyl-3-nitro-phenol (3.0 g, 19.6 mmol), triphenylphosphine (7.2 g, 27.4 mmol), and chloroethanol (1.89 g, 23.5 mmol) in anhydrous tetrahydrofuran (70 mL) was slowly added a solution of diethylazidodicarboxylate (4.78 g, 27.4 mmol). After 1 h the reaction was complete and the solvent was removed and the residue dissolved in 1:1 ethyl acetate-hexanes (150 mL). After 30 min the solid triphenylphosphine oxide was filtered and the solvent again removed. The crude product was purified by chromatography (20% ethyl acetate-hexanes) to afford 4.2 g (100%) of a light yellow solid: mp 58°-59° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][C@H:13]2[O:25][CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.C(OCC)(=O)C.C(N(C(C)C)CC)(C)C.ClC1[S:45][C:46]([CH3:54])=[C:47]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[N:48]=1.Cl>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:45][C:46]([CH3:54])=[C:47]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[N:48]=3)[CH2:14][C@H:13]2[O:25][CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1Cl
Reactant: CCOC(=O)c1nc(Cl)sc1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)sc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
tert-Butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1g) (80 mg, 0.21 mmol) was dissolved in methanol (1 mL). A 4 N hydrochloric acid/ethyl acetate solution (3 mL) was added, and the mixture was stirred at room temperature for one hour. Following concentration under reduced pressure, the residue was dissolved in DMF (2 mL). Diisopropylethylamine (0.16 mL, 0.92 mmol) and ethyl 2-chloro-5-methyl-1,3-thiazole-4-carboxylate obtained in Example (38a) (70 mg, 0.34 mmol) were added, and the mixture was stirred using a microwave reactor at 160° C. for three hours. Dilute hydrochloric acid was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, 1/1, ethyl acetate) to obtain 15.3 mg of the title compound as a pale yellow solid (16%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH2:24])[CH2:23][O:22][CH2:21]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1.[CH3:32][C:33]1[CH:37]=[C:36]([C:38](O)=[O:39])[O:35][N:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH:24][C:38]([C:36]4[O:35][N:34]=[C:33]([CH3:32])[CH:37]=4)=[O:39])[CH2:21][O:22][CH2:23]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(N)COC2)no1
Reactant: Cc1cc(C(=O)O)on1
Product: Cc1cc(C(=O)NC2(C(=O)N[C@H]3CCc4cc(-c5cc(Cl)cc(F)c5-c5noc(C)n5)ccc43)COC2)on1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B], 3-amino-oxetane-3-carboxylic acid{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-yl}-amide (example 49) was coupled with 3-methyl-isoxazole-5-carboxylic acid to yield the title compound as light yellow oil. MS: 552.1 (MH+, 1Cl).
Reaction SMILES: OCC(CO)([C:9]([O:11]CC)=[O:10])C(OCC)=O.Br.[C:17]([S:21][C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])(C)C.[K]>>[CH3:23][C:22]([CH:25]([C:22]([S:21][CH2:17][CH3:20])([CH3:24])[CH3:23])[C:9]([OH:11])=[O:10])([S:21][CH2:17][CH3:20])[CH3:24]
Reactant: CCOC(=O)C(CO)(CO)C(=O)OCC
Reactant: CC(C)(C)SC(C)(C)C
Agent: Br
Agent: [K]
Product: CCSC(C)(C)C(C(=O)O)C(C)(C)SCC

Procedure:
Synthesis analogous to Example 13. The bis-(1,1-dimethyl-ethylthiomethyl)-acetic acid was synthesized from diethyl bis-(hydroxymethyl)-malonate by reaction with hydrogen bromide and subsequent replacement of the resulting β,β'-dibromoisobutyric acid with potassium tert.-butylsulfide.
Reaction SMILES: [Si]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][C@@:25]([CH2:44][C:45]([OH:47])=[O:46])([CH3:43])[C:24]1=[O:48])[CH2:21][CH3:22])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:42][C:38]1[CH:37]=[C:36]([C@@H:27]2[C@@H:28]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[N:23]([C@@H:20]([CH2:21][CH3:22])[CH2:19][OH:18])[C:24](=[O:48])[C@:25]([CH2:44][C:45]([OH:47])=[O:46])([CH3:43])[CH2:26]2)[CH:41]=[CH:40][CH:39]=1
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC[C@@H](CO)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To an ice-cooled solution of 370 g (0.53 mmol) of 2-((3R,5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (Example 185, Step F) in THF (15 mL) was added 2.60 mL (2.60 mmol) of a 1 M solution of TBAF in THF. The yellow solution was warmed to rt and stirred for 5 h. At this time 2.60 mL (2.60 mmol) of a 1 M solution of TBAF in THF was added and the reaction was stirred for an additional 20 h. The reaction was partitioned between 1 N HCl and EtOAc (4×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by reverse phase prep. HPLC (Sunfire™ Prep C18 OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 40% MeCN in water to 80% MeCN in water over a 30 min period, where both solvents contain 0.1% TFA) provided the title compound as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:8])[CH:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:26]1[CH:31]=[CH:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1>[I:1][C:2]1[CH:7]=[N:6][N:5]([CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][O:26]2)[C:4](=[O:8])[CH:3]=1
Reactant: C1=COCCC1
Reactant: O=c1cc(I)cn[nH]1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: O=c1cc(I)cnn1C1CCCCO1
Yield: 98 %

Procedure:
A solution of 5-iodo-2H-pyridazin-3-one (66 g, 0.30 mol) in tetrahydrofuran (500 mL) was treated with pyridinium para-toluene sulfonate (14.3 g, 0.057 mol) and 3,4-dihydro-2H-pyran (52 mL). The reaction mixture was stirred at reflux for 5 h. At this time, the reaction was treated with another aliquot of 3,4-dihydro-2H-pyran (32.5 mL). The solution was stirred at reflux overnight. At this time, the solution was concentrated in vacuo. Chromatography (ethyl acetate/petroleum ether=1/2) afforded 5-iodo-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (89 g, 98%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([S:5]([C:8]2[CH:9]=[C:10]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=2)[C:11]([N:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[O:28][CH3:29])[CH3:14])=[O:12])(=[O:7])=[O:6])[CH2:2]1.CCN(C(C)C)C(C)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48].[NH4+].[Cl-]>C(Cl)Cl>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[N:13]([CH3:14])[C:11](=[O:12])[C:10]2[CH:30]=[C:31]([C:33]([F:34])([F:36])[F:35])[CH:32]=[C:8]([S:5]([CH:3]3[CH2:4][N:1]([S:47]([CH3:46])(=[O:49])=[O:48])[CH2:2]3)(=[O:7])=[O:6])[CH:9]=2)=[C:22]([O:28][CH3:29])[CH:23]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)C2CNC2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)C2CN(S(C)(=O)=O)C2)c1
Temperature: 0 °C
Reaction time: 1.75 h

Procedure:
To an ice-cold solution of 3-(azetidin-3-ylsulfonyl)-N-(4-(4-fluoro-2-methoxyphenyl)-pyridin-3-yl)-N-methyl-5-(trifluoromethyl)benzamide (0.05 g, 95.5 μmol, example 280) and DIPEA (24.7 mg, 33.4 μL, 191 μmol) in CH2Cl2 (1 mL) was added methanesulfonyl chloride (16.4 mg, 11.2 μL, 143 μmol) and stirring was continued in an ice-bath for 1.75 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and CH2Cl2 and the layers were separated. The aqueous layer was extracted twice with CH2Cl2. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 5 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless solid (0.044 g; 76%). MS (ESI): m/z=602.10 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:20]=[C:7]3[N:8]=[CH:9][CH:10]=[C:11]([S:12][C:13]4[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=4)[N:6]3[N:5]=2)[CH2:3][CH2:2]1.Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)=[N:24][N:23]=1>CC(O)(C)C.C(Cl)Cl>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:22]([NH:19][C:16]3[CH:15]=[CH:14][C:13]([S:12][C:11]4[N:6]5[N:5]=[C:4]([CH:1]6[CH2:3][CH2:2]6)[CH:20]=[C:7]5[N:8]=[CH:9][CH:10]=4)=[CH:18][CH:17]=3)=[N:23][N:24]=2)=[CH:37][CH:36]=1
Reactant: Clc1ccc(-c2nnc(Cl)c3ccccc23)cc1
Reactant: Nc1ccc(Sc2ccnc3cc(C4CC4)nn23)cc1
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: Clc1ccc(-c2nnc(Nc3ccc(Sc4ccnc5cc(C6CC6)nn45)cc3)c3ccccc23)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A resealable tube charged with a mixture of 4-(2-cyclopropylpyrazolo[1,5-a]pyrimidin-7-ylthio)benzenamine (100 mg, 0.354 mmol) and 1-chloro-4-(4-chlorophenyl)phthalazine (97 mg, 0.354 mmol) in tBuOH (2 mL) was heated to 100° C. After 3 hrs, the mixture was cooled to RT, diluted with CH2Cl2, and washed with water and brine. After drying the organic fraction with sodium sulfate, the solvent was removed in vacuo. The residue was purified by silica gel chromatography using 20-90% Hexanes:EtOAc to afford 4-(4-chlorophenyl)-N-(4-(2-cyclopropylpyrazolo[1,5-a]pyrimidin-7-ylthio)phenyl)phthalazin-1-amine. MS: Found M+H+=521.2.
Reaction SMILES: [C:1]([CH:4]([CH2:10][C:11](=O)[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].[Br:14][C:15]1[CH:20]=[C:19]([NH2:21])[CH:18]=[C:17]([Br:22])[C:16]=1[OH:23]>CCO>[Br:14][C:15]1[CH:20]=[C:19]([N:21]2[C:11]([CH3:12])=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:1]2[CH3:2])[CH:18]=[C:17]([Br:22])[C:16]=1[OH:23]
Reactant: Nc1cc(Br)c(O)c(Br)c1
Reactant: CCOC(=O)C(CC(C)=O)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2cc(Br)c(O)c(Br)c2)c1C

Procedure:
Utilizing the procedure outlined in Example 85, ethyl 2-acetyl-4-oxopentanoate (6.37 g, 34.2 mmol) was dissolved in 20 mL of EtOH. 2,6-dibromo-4-aminophenol (11.6g, 34.2mmol) were reacted to afford ethyl 1-(3,5-dibromo-4-hydroxyphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate was taken on without further purification. MS (ESI) 418 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([CH:8]=1)[NH2:7].[N:10]([O-])=O.[Na+]>Cl.O>[ClH:9].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([NH:7][NH2:10])[CH:8]=1
Reactant: O=N[O-]
Reactant: Nc1cc(Br)ccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(Br)ccc1Cl
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 248.8 %

Procedure:
A suspension of 5-bromo-2-chloroaniline (23 g, 0.11 mol) in concentrated hydrochloric acid (150 mL) and water (90 mL) was cooled in an ice/salt bath. A solution of sodium nitrite (8 g, 0.11 mol) in water (50 mL) was added dropwise to the reaction mixture while maintaining the temperature below 4° C. After stirring for 30 minutes the suspension was transferred via cannula to a solution of SnCl2 dihydrate in concentrated hydrochloric acid (170 mL) and cooled to 5° C. The resulting thick suspension was stirred for 2 h at 5° C. and the solid was isolated via filtration. The solid was air dried and then further dried by adding chlorobutane (500 mL) and refluxing using a Dean-Stark condenser. After cooling, the solid was isolated by filtration to afford the title compound as an off-white solid (35.3 g). 1H NMR (CD3COCD3): δ 10.25 (br s, 1H), 8.32 (br s, 2H) 7.38 (d, 1H), 7.30 (d, 1H), 7.16 (dd, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH2:16][CH3:17])=[C:5]([C:13](Cl)=[O:14])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]([CH2:34][CH2:35][CH:36]=[CH:37][CH2:38][CH2:39][CH3:40])[CH2:27][NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:22]=[CH:23][C:24]=1[Cl:25]>C(N(CC)CC)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]([CH2:34][CH2:35][CH:36]=[CH:37][CH2:38][CH2:39][CH3:40])[CH2:27][N:28]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:13]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:12]=[C:3]([C:1]#[N:2])[C:4]=2[CH2:16][CH3:17])=[O:14])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: CCCC=CCCC(CNCCC(=O)O)c1ccc(Cl)c(Cl)c1
Reactant: CCc1c(C#N)cc2ccccc2c1C(=O)Cl
Solvent: CCN(CC)CC
Product: CCCC=CCCC(CN(CCC(=O)O)C(=O)c1c(CC)c(C#N)cc2ccccc12)c1ccc(Cl)c(Cl)c1
Yield: 56.7 %

Procedure:
3-Cyano-2-ethyl-1-naphthoyl chloride (0.49 g) was combined with N-[2-(3,4-dichlorophenyl)-4-pentenylbutyl]-N-[(carboxymethyl)methyl]-amine (0.57 g) and triethyl amine under standard acylation conditions to afford N-[2-(3,4-dichlorophenyl)-4-pentenylbutyl]-N-[(carboxymethyl)methyl]-3-cyano-2-ethyl-1-naphthamide (0.51 g) as a solid after purification by chromatography (5:4:1 Hexane:DCM:EtOAc); MS: m/z 509 (M+); 1H NMR (CDCl3) δ 8.29 (s), 8.26 (s), 7.83 (d), 7.98-7.30 (m), 7.01 (d), 6.80 (s), 6.53 (d), 5.30-5.11 (m), 4.85-4.52 (m), 4.35-4.03 (m), 4.22 (s), 3.84 (s), 3.80 (s), 3.45 (dd), 3.32 (dd), 3.20-2.91 (m), 1.37 (t).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]([CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:4](=[O:22])[C:3]=1[C:23]([O:25]CC)=[O:24].[OH-].[Na+]>C(O)C.O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:14])([F:13])[F:15])=[CH:9][CH:10]=2)[N:5]([CH:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[C:4](=[O:22])[C:3]=1[C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)c1c(C)c2ccc(C(F)(F)F)cc2n(C2CCOCC2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)c(=O)n(C2CCOCC2)c2cc(C(F)(F)F)ccc12
Temperature: 80 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
To a solution of 330 mg (0.86 mmol) ethyl 4-methyl-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-7-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxylate in ethanol (6 ml) and water (0.6 ml) was added 140 mg (3.45 mmol) NaOH at RT. The reaction mixture was stirred at 80° C. for 16 h. Then the mixture was evaporated to dryness and the residue was diluted with water (5 ml) and acidified with 2N HCl to pH ˜3. The aq. part was extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with water (10 ml), brine (10 ml), dried over anhydrous Na2SO4 and concentrated in vacuum to give 280 mg (0.79 mmol, 91%) 4-methyl-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-7-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxylic acid which is used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]([F:16])([F:15])[F:14])[N:5]=[C:4]([NH:17][CH3:18])[N:3]=1.[C:19]([C:21]1[C:26]([F:27])=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[F:31])#[N:20].C([O-])(O)=O.[Na+]>O1CCOCC1.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>[F:27][C:26]1[CH:25]=[C:24]([C:2]2[CH:7]=[C:6]([N:8]3[CH2:12][CH2:11][CH2:10][C@H:9]3[C:13]([F:16])([F:15])[F:14])[N:5]=[C:4]([NH:17][CH3:18])[N:3]=2)[CH:23]=[C:22]([F:31])[C:21]=1[C:19]#[N:20]
Reactant: N#Cc1c(F)cc(B(O)O)cc1F
Reactant: CNc1nc(Cl)cc(N2CCC[C@H]2C(F)(F)F)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CNc1nc(-c2cc(F)c(C#N)c(F)c2)cc(N2CCC[C@H]2C(F)(F)F)n1
Temperature: 100 °C
Yield: 55.2 %

Procedure:
4-Chloro-N-methyl-6-[(2S)-2-(trifluoromethyl)-1-pyrrolidinyl]-2-pyrimidinamine (600 mg, 2.138 mmol) and (4-cyano-3,5-difluorophenyl)boronic acid (587 mg, 3.21 mmol) were dissolved in 1,4-dioxane (10 mL) in a 20 mL sealable vial. Saturated NaHCO3 solution (5 mL) was added, and N2 gas was bubbled through the mixture for 10 minutes. Then Pd(Ph3P)4 (371 mg, 0.321 mmol) was added, and N2 gas was bubbled through the mixture for an additional 5 minutes. The reaction vial was then capped and heated at 100° C. overnight. The reaction was diluted with water (10 mL) and then extracted with EtOAc (3×10 mL). Organic was then combined, dried over MgSO4, filtered and concentrated. The yellow oil was then purified on Biotage SNAP 50 g column with a gradient of 0 to 35% EtOAc in Hexane over 30 minutes to isolated the title compound (452 mg). LC-MS (ES) m/z=384 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[C:6]([O:10][C:11](=[O:24])[NH:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[NH:19][CH2:20][CH2:21][CH:22]=[CH2:23])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[C:6]([O:10][C:11](=[O:24])[NH:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[N:19]([C:1](=[O:4])[CH:2]=[CH2:3])[CH2:20][CH2:21][CH:22]=[CH2:23])([CH3:9])([CH3:8])[CH3:7]
Reactant: C=CC(=O)Cl
Reactant: C=CCCN[C@@H]1CCCC[C@H]1NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCN(C(=O)C=C)[C@@H]1CCCC[C@H]1NC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
Acryloyl chloride (47 mg, 0.50 mmol) was added at 0° C. to a solution of trans-(2-but-3-enylamino-cyclohexyl)-carbamic acid tert-butyl ester (123 mg, 0.46 mmol) and triethylamine (51 mg, 0.51 mmol) in dichloromethane (3 ml), and the reaction mixture was allowed to reach room temperature over 3 h. After partitioning between dichloro-methane and 10% aq. citric acid solution, the organic layer was washed with 1 M aq. sodium carbonate solution and brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded the title compound (103 mg, 70%). Light yellow solid, MS (ISP) 323.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[C:4]([F:11])[CH:3]=1.N1C=CC=CC=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>CC(C)=O>[F:11][C:4]1[CH:3]=[C:2]([NH:1][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][CH2:9][OH:10]
Reactant: Nc1ccc(CCO)c(F)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(CCO)c(F)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a stirred solution of 2-(4-amino-2-fluorophenyl)ethanol (1.3 g, 8.38 mmol, 1.0 eq) in acetone (50 mL) was added pyridine (1.32 g, 16.7 mmol, 2.0 eq) and phenyl chloroformate (1.45 g, 9.23 mmol, 1.1 eq) at 0° C. and the mixture was stirred at RT for 2 h. The solvent was evaporated, the residue diluted with EtOAc (50 mL), washed with water (100 mL) followed by brine and the solvent evaporated. The resulting residue was purified by CC using EtOAc/PE (1:4) to get phenyl 3-fluoro-4-(2-hydroxyethyl)phenylcarbamate (1.5 g, 65%, white solid). (TLC system: EtOAc/PE (1:1), Rf: 0.3).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1.[CH3:19][N:20]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][Cl:31])[CH:25]=1)[C:21](Cl)=[O:22].N1C=CC=CC=1>C1(C)C=CC=CC=1>[F:18][C:2]([F:1])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:21](=[O:22])[N:20]([CH3:19])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][Cl:31])[CH:25]=3)[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1
Reactant: CN(C(=O)Cl)c1cccc(CCl)c1
Reactant: CN1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CN1CCC(OC(=O)N(C)c2cccc(CCl)c2)N(c2nnc(C(F)(F)F)s2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), N-methyl-N-(3-chloromethylphenyl)carbamoyl chloride (0.06 mole), pyridine (0.06 mole) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 3 hours. After this time the reaction mixture is cooled to room temperature and is filtered to remove pyridine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvent leaving a residue. The residue is recrysallized to yield the desired product tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-[N-methyl-N-(3-chloromethylphenyl)carbamoyloxy]-2(1H)-pyrimidinone.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]([CH3:17])[S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].O.C(OCC)C>C(O)(=O)C>[F:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]([CH3:17])[S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)c2ccc(F)cc2)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(F)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 70 %

Procedure:
4′-Fluoro-N-methyl-p-toluenesulfonanilide (1.00 g (3.58 mmol) was dissolved in 5.0 ml of acetic acid. To this, was added with stirring at room temperature, 97% fuming nitric acid (0.35 ml (8.19 mmol)) dropwise, and the mixture was stirred at 100° C. for one hour, poured into water and extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude crystals. Diethyl ether was added to these crystals. The crystals were filtered and washed to give 0.81 g (70%) of the title compound as yellow crystals.