Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1C(=O)N(C)CCC1.[F:10][C:11]([F:24])([F:23])[C:12]1[CH:13]=[C:14]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:16][CH:17]=1.Br[CH2:26][N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37].Cl>C1COCC1>[O:37]=[C:28]1[C:29]2[C:30](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](=[O:32])[N:27]1[CH2:26][CH:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([F:23])([F:24])[F:10])[CH:13]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)Cc1cccc(C(F)(F)F)c1
Reactant: O=C1c2ccccc2C(=O)N1CBr
Agent: Cl
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C(CN1C(=O)c2ccccc2C1=O)c1cccc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
Over about 5 min, a solution of n-butyllithium (1.6 M in hexane, 18.75 ml, 30 mmol) was added dropwise to a solution, pre-cooled to −20° C., of 4.91 ml (35 mmol) of diisopropylamine in 50 ml of THF. The LDA solution obtained in this manner was cooled to −78° C., and 15.1 ml of DMPU (1,3-dimethyltetrahydro-2(1H)-pyrimidinone, 125 mmol) were added. After 20 min at −78° C., a solution of 5.45 g (25 mmol) of methyl [3-(trifluoromethyl)phenyl]acetate in 35 ml of THF was slowly added dropwise. After a further 20 min at −78° C., a solution of 7.20 g (30 mmol) of N-bromomethylphthalimide in 50 ml of THF was added dropwise. Stirring of the reaction mixture was continued initially at −78° C. for 1 h, then without cooling bath at RT overnight. After addition of 100 ml of 1 N hydrochloric acid, the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulphate and freed from the solvent on a rotary evaporator. The residue was dissolved in 50 ml of DMSO and purified in several portions by preparative HPLC [Method 8]. This gave 2.20 g (22% of theory) of the title compound.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[CH2:15][CH2:14][CH2:13][N:4]1[C@@H](C(Cl)(Cl)Cl)[O:6][C:7]2=O.[NH3:16].CO>>[OH:1][CH2:2][C@@:3]1([C:7]([NH2:16])=[O:6])[CH2:15][CH2:14][CH2:13][NH:4]1
Reactant: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@]12CO
Reactant: N
Solvent: CO
Product: NC(=O)[C@]1(CO)CCCN1
Temperature: 75 °C

Procedure:
(3R,7aR)-7a-Hydroxymethyl-3-trichloromethyl-tetrahydro-pyrrolo[1,2-c]oxazol-1-one (Stage J.1, 308 mg, 1.122 mmol) was added to 7 M ammonia in MeOH (8.014 mL, 56.1 mmol) under argon and heated at 75° C. in a sealed vessel for 72 h and then evaporated to give the title compound as a viscous pale brown oil which was used without further purification.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:5]([C:7]1[CH:11]=[CH:10][O:9][C:8]=1[CH3:12])=O.Cl.[CH3:21][CH:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28](=[NH:30])[NH2:29])[CH2:23]1.CC(C)([O-])C.[K+]>C(O)C.O>[CH3:12][C:8]1[O:9][CH:10]=[CH:11][C:7]=1[C:5]1[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:3][N:29]=[C:28]([N:24]2[CH2:25][CH2:26][CH2:27][CH:22]([CH3:21])[CH2:23]2)[N:30]=1
Reactant: CC1CCCN(C(=N)N)C1
Reactant: Cc1occc1C(=O)C(=CN(C)C)c1ccccn1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1occc1-c1nc(N2CCCC(C)C2)ncc1-c1ccccn1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
A mixture of 3-(dimethylamino)-1-(2-methyl-3-furanyl)-2-(2-pyridinyl)-2-propen-1-one (256 mg, 1 mmol) and 3-methyl-1-piperidinecarboximidamide hydrochloride (267 mg, 1.5 mmol) in ethanol (5 ml) was stirred at room temperature. Potassium tert-butoxide (224 mg, 2 mmol) was added and the mixture was heated at reflux for 45 minutes. After cooling to room temperature the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were combined, washed with water and brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 25% ethyl acetate and isohexane followed by mass-directed automated HPLC to give 4-(2-methyl-3-furanyl)-2-(3-methyl-1-piperidinyl)-5-(2-pyridinyl)pyrimidine (223 mg, 67%).
Reaction SMILES: [CH:1]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C@H:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:6]([NH:21]C(=O)OC(C)(C)C)[C:5]1=[O:29])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[NH2:21][C@@H:6]1[C:5](=[O:29])[N:4]([CH:1]([CH3:3])[CH3:2])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C@@H:7]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](c2ccccc2)Oc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N1C(=O)[C@@H](N)[C@@H](c2ccccc2)Oc2ccccc21
Yield: 98.6 %

Procedure:
tert-Butyl [(2R,3S)-5-isopropyl-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]carbamate (69a) (80 mg, 0.202 mmol) was dissolved in 5:1 (v/v) dichloromethane:trifluoroacetic acid (3 mL) and kept at ambient temperature for 30 min. The solution was evaporated and the residue was dissolved in ethyl acetate and extracted with saturated aqueous sodium bicarbonate. The organic solution was dried and evaporated to afford the title compound (59 mg, 99%) as a white solid. MS APCI, m/z=297 (M+1). LC/MS: 1.79 min
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][O:25][CH2:26][C:27](O)=[O:28]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:27](=[O:28])[CH2:26][O:25][CH3:24])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: COCC(=O)O
Product: COCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and methoxy-acetic acid to yield (3aR,4S,7aR)-4-(2-methoxy-acetoxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 296 (ester elimination ion); RT=7.930 min; HPLC Method I
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@H:5]([CH2:7][C:8]([OH:10])=O)[C:4](=[O:11])[O:3]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.Cl.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>C(Cl)Cl>[F:29][C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH2:41][CH2:40][N:39]([C:8](=[O:10])[CH2:7][C@H:5]3[O:6][C:2]([CH3:1])([CH3:12])[O:3][C:4]3=[O:11])[CH2:38][CH2:37]2)=[CH:34][CH:35]=1
Reactant: CC1(C)OC(=O)[C@@H](CC(=O)O)O1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC1(C)OC(=O)[C@@H](CC(=O)N2CCN(c3ccc(F)cc3)CC2)O1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.1 %

Procedure:
To a solution of [(4R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic acid (3.48 g; 20.0 mmol; 1.0 eq.), TEA (6.07 g; 60.0 mmol; 3.0 eq.) in DCM (60 mL) was added HOBt (2.97 g; 22.0 mmol; 1.1 eq.) and the mixture was chilled to 0° C. EDC (4.6 g; 24.0 mmol; 1.2 eq.) was then added and the resulting reaction mixture was stirred for 15 min at 0° C. 1-(4-fluorophenyl)piperazine dihydrochloride (5.57 g; 22.0 mmol; 1.1 eq.) was added and the resulting reaction mixture was stirred at RT over night. Purification by flash chromatography (AcOEt/c-Hex: 50/50) gave the title compound as a colorless oil (5.12 g, 76%). M+ (ESI): 337.2. HPLC (Condition A): Rt: 2.5 min (HPLC purity: 97.4%).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:21]2[C:24]([CH2:29]Cl)=[C:25]([Cl:28])[CH:26]=[CH:27][C:20]=2[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CN(C=O)C.[I-].[K+]>[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:21]2[C:24]([CH2:29][O:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[C:25]([Cl:28])[CH:26]=[CH:27][C:20]=2[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCl)c2CC1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(COc3ccccc3)c2CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.8 %

Procedure:
Add sodium hydride (22 mg, 0.54 mmol, 60% dispersion in mineral oil) to phenol (42 mg, 0.04 mL, 0.45 mmol) in anhydrous DMF (2 mL). Stir the mixture under nitrogen for 5 min and then add 3-tert-butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (175 mg, 0.45 mmol) in anhydrous DMF (2 mL) followed by catalytic potassium iodide (1 mg). Stir the reaction at 45° C. for 12 h then cool to room temperature and partition between EtOAc/water. Wash the organic phase with brine. Dry the organic phase over MgSO4, filter and concentrate in vacuo to give a yellow oil. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give 3-tert-butoxycarbonyl-7-chloro-6-phenoxymethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil (59 mg, 36%).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:11]=[C:12]2[CH:18]=[N:17][NH:16][C:13]2=[N:14][CH:15]=1>ClC(Cl)C.C1COCC1>[Br:9][C:10]1[CH:11]=[C:12]2[C:18]([I:1])=[N:17][NH:16][C:13]2=[N:14][CH:15]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Brc1cnc2[nH]ncc2c1
Solvent: CC(Cl)Cl
Solvent: C1CCOC1
Product: Brc1cnc2[nH]nc(I)c2c1
Temperature: 25 °C
Yield: 74.8 %

Procedure:
N-Iodosuccinimide (8.1 g, 34.1 mmol) was added to a solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine (4.5 g, 22.7 mmol) in dichloroethane (100 mL), and the reaction mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature and diluted with THF (300 mL). The organic layers were washed with saturated Na2S2O3 (100 mL) and brine (100 mL). The organic layers were dried, filtered and concentrated to a solid. The crude product was triturated with DCM and ethyl acetate to give 5-bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine (5.5 g, 75%) as a solid.
Reaction SMILES: [CH3:1][N:2]([CH2:18][C@:19]1([CH3:30])[O:23][C:22]2=[N:24][C:25]([N+:27]([O-:29])=[O:28])=[CH:26][N:21]2[CH2:20]1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11](OC(C)(C)C)=O)[CH2:7][CH2:6]1.FC(F)(F)C(O)=O.[F:38][C:39]([F:49])([F:48])[C:40]1[CH:47]=[CH:46][C:43](C=O)=[CH:42][CH:41]=1.[B-]C#N.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:1][N:2]([CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:43]2[CH:46]=[CH:47][C:40]([C:39]([F:49])([F:48])[F:38])=[CH:41][CH:42]=2)[CH2:7][CH2:6]1)[CH2:18][C@:19]1([CH3:30])[O:23][C:22]2=[N:24][C:25]([N+:27]([O-:29])=[O:28])=[CH:26][N:21]2[CH2:20]1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CN(CCN1CCN(C(=O)OC(C)(C)C)CC1)C[C@@]1(C)Cn2cc([N+](=O)[O-])nc2O1
Agent: O=C([O-])O
Agent: [B-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(CCN1CCN(Cc2ccc(C(F)(F)F)cc2)CC1)C[C@@]1(C)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.7 %

Procedure:
Tert-butyl (S)-4-[2-(N-methyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethylamino)-ethyl]piperazine-1-carboxylate prepared in Example 173 (400 mg, 0.94 mmol) was dissolved in methylene chloride (5 ml). To the solution, trifluoroacetic acid (5 ml) was added followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and added methylene chloride (2 ml) and triethylamine (2 ml). After stirring for 5 minutes at room temperature, the solution was concentrated under reduced pressure. The residue was dissolved in methanol (10 ml). To the solution, 4-(trifluoromethyl)benzaldehyde (0.4 ml, 2.83 mmol), sodium cyanotrihydroborate (178 mg, 2.83 mmol) and acetic acid (0.2 ml) were added followed by stirring at room temperature for 30 minutes. To the solution, a saturated sodium hydrogencarbonate solution and methylene chloride were added followed by stirring, and the mixture was extracted with methylene chloride. The organic phase was dried over magnesium sulfate. After filtration, the resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=200/1) and crystallized from methylene chloride-isopropyl ether to afford (S)-N-methyl-N-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-2-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]ethylamine (307 mg, yield 68%) as a white powder.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([N:28](S(C4C=CC=CC=4[N+]([O-])=O)(=O)=O)[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:52])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]4[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][C:41]=4[N+:49]([O-:51])=[O:50])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C([O-])([O-])=O.[K+].[K+].C1(S)C=CC=CC=1>CN(C)C=O>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([NH:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:52])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]4[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][C:41]=4[N+:49]([O-:51])=[O:50])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](N(CCCNC(=O)CCCCCNc5ccc([N+](=O)[O-])cc5[N+](=O)[O-])S(=O)(=O)c5ccccc5[N+](=O)[O-])CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](NCCCNC(=O)CCCCCNc5ccc([N+](=O)[O-])cc5[N+](=O)[O-])CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 23 °C
Reaction time: 18 h
Yield: 59.2 %

Procedure:
To a slurry of N-(3-{(3β)-cholest-5-en-3-yl[(2-nitrophenyl)sulfonyl]amino}propyl)-6-[(2,4-dinitrophenyl)amino]hexanamide (19, 164 mg, 0.180 mmol) and K2CO3 (270 mg, 1.954 mmol) in N,N-dimethylformamide (20 mL) was added thiophenol (80 μL, 0.777 mmol). After stirring at 23° C. for 18 h, the mixture was filtered and solvent was removed in vacuo. The crude product was purified by flash column chromatography (MeOH /triethylamine/CH2Cl2, 2:5:100) to afford 4 (77 mg, 59%) mp 165-166° C.; 1H NMR (500 MHz, CDCl3) δ 9.11 (d, J=2.6 Hz, 1H), 8.53 (br s, 1H), 8.25 (dd, J=2.5 Hz, J=9.5 Hz, 1H), 6.99 (t, J=4.3, 1H), 6.90 (d, J=9.5 Hz, 1H), 5.29 (d, J=4.8 Hz, 1H), 3.42-3.38 (m, 2H), 3.34 (dt, J=5.8 Hz, J=5.9 Hz, 2H), 2.74 (t, J=6.1 Hz, 2H), 2.39-2.34 (m, 1H), 2.23-2.17 (m, 3H), 2.04-1.92 (m, 4H), 1.84-0.98 (m, 32H), 0.95 (s, 3H), 0.90 (d, J=6.5 Hz, 3H), 0.85 (d, J=2.1 Hz, 3H), 0.84 (d, J=2.1 Hz, 3H), 0.65 (s, 3H); 13C NMR (75.5 MHz, CDCl3) δ 172.5, 148.5, 141.5, 136.2, 130.5 (×2), 124.5, 121.2, 114.7, 58.4, 56.9, 56.3, 50.4, 45.5, 43.6, 42.5, 40.3, 39.9, 39.7, 39.3, 38.1, 37.2, 36.6, 36.4, 36.0, 32.1, 32.0, 29.7, 29.2, 28.7, 28.4, 28.2, 26.8, 25.3, 24.4, 24.0, 23.0, 22.7, 21.2, 19.6, 18.9, 12.0; IR (film) νmax 3362, 3295, 2934, 2867, 1622, 1336 cm−1; CI m/z 722.5229 (MH+, C42H68N5O5 requires 722.5220).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>C(Cl)Cl>[CH3:22][S:23]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]1)(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To N-Boc-4-hydroxypiperidine (2200 g, 10.95 mol) in anhydrous DCM (8 L) was added triethylamine (2284 mL, 16.42 mol) in one portion at 0° C., then MsCl (1316 g, 11.49 mol) was added drop wise into the mixture at 0° C. The mixture was stirred at room temperature for 2 h. Water (2 L) was added to the mixture and the organic phase was separated, and then the organic phase was washed with 1 M hydrochloride solution (4 L), saturated NaHCO3 solution (4 L), brine (1 L), and dried over anhydrous Na2SO4. The organic layer was concentrated to afford tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate, which was used for the next step without further purification.
Reaction SMILES: [N:1]1([CH2:6][CH:7]=[CH:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11](OS(C(F)(F)F)(=O)=O)[CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>[N:1]1([CH2:6]/[CH:7]=[CH:8]/[C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([C:31]3[CH:30]=[CH:29][C:28]([F:27])=[CH:33][C:32]=3[F:34])[CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1ccc(C=CCn2ccnc2)cc1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccc(F)cc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1ccc(/C=C/Cn2ccnc2)cc1-c1ccc(F)cc1F

Procedure:
A mixture of methyl 4-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(trifluoromethylsulphonyloxy)benzoate (1.17 g; 3 mmol), 2,4-difluorophenylboronic acid (0.52 g; 3.3 mmol), tetrakis(triphenylphosphine) palladium (0.14 g; 0.12 mmol), 2M aqueous sodium carbonate solution (4.5 ml), lithium chloride (0.25 g; 6 mmol) and ethanol (13 ml) in toluene (120 ml) was refluxed, under an argon atmosphere, for 8 hours. The mixture was extracted with ethyl acetate and purified by flash chromatography eluting with isopropanol/dichloromethane (3/97) to give methyl 4-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(2,4-difluorophenyl)benzoate as a mixture of E and Z isomers.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Br[CH2:10][CH:11]1[CH2:13][C:12]1([F:15])[F:14].C([O-])([O-])=O.[K+].[K+]>C(#N)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH:11]2[CH2:13][C:12]2([F:15])[F:14])=[CH:4][N:3]=1
Reactant: Oc1ccc(Br)nc1
Reactant: FC1(F)CC1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: FC1(F)CC1COc1ccc(Br)nc1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
The mixture of 5.00 g (28.7 mmol) of 2-bromo-5-hydroxypyridine, 6.14 g (35.9 mmol) of 1-bromomethyl-2,2-difluorocyclopropane and 9.93 g (71.8 mmol) of K2CO3 in 100 ml ACN is stirred at 70° C. for 14 h. The reaction mixture is diluted with EtOAc, washed with water and 1N aq. NaOH, dried over MgSO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1.[C:12](Cl)(=[O:17])[CH2:13][CH2:14][CH:15]=[CH2:16].C(O)(=O)CCC=C.S(Cl)(Cl)=O>C(Cl)Cl.N1C=CC=CC=1>[C:12]([NH:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([O:2][CH3:1])=[O:11])(=[O:17])[CH2:13][CH2:14][CH:15]=[CH2:16]
Reactant: COC(=O)c1cccc(N)c1
Reactant: C=CCCC(=O)Cl
Agent: C=CCCC(=O)O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: C=CCCC(=O)Nc1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
Methyl(3-amino)benzoate (4.5 g, 29.8 mmol) was taken up in DCM (10 ml) and pyridine (1 ml) at 0° C. 4-Pentenoyl chloride (freshly prepared from 4-pentenoic acid (3.0 g, 29.97 mmol) and thionyl chloride (6.6 ml) at r.t. for 1 h, evaporated and azeotroped with DCM) was added dropwise in DCM (3 ml). The mixture was allowed to warm to r.t. and stirred overnight. The mixture was evaporated and partitioned between EtOAc and 1M HCl. The organic portion was washed with 5% KHCO3 and brine, filtered (Whatman® 1PS, phase separator), and evaporated. The residue was chromatographed (eluant 30% EtOAc in hexanes) to provide a colourless oil (2.20 g, 32%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH2:22].Cl.[OH-].[Na+]>O.C(O)C>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: COc1ccc(OC)c(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(OC)c(Nc2cc(C(F)(F)F)nc(-c3ccccc3)n2)c1
Temperature: 25 °C
Yield: 49.7 %

Procedure:
A mixture of 4-chloro-2-phenyl-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol), 2,5-dimethoxyaniline (44 mg, 0.290 mmol) and aqueous 2N HCl (150 μl) in water:ethanol (1:1, 10 ml) was refluxed for 48 h. The mixture was cooled to room temperature and then basified with aqueous 2N NaOH to pH 10-12. The resulting precipitate was filtered, washed with water, water:ethanol (2:1) and dried under vacuo to give a gray solid (36 mg, 50%). 1H NMR (CDCl3): 8.51-8.48 (m, 2H), 8.14 (s, 1H), 7.51-7.48 (m, 4H), 6.89 (s, 1H), 6.88 (d, J=9.3 Hz, 1H), 6.66 (dd, J=3.0, 8.7 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=[O:13].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>CN(C)C=O>[CH2:14]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCc2c(O)cccc21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C1CCc2c(OCc3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a suspension of 60% sodium hydride (0.18 g) in dimethylformamide (22 mL), 4-hydroxy-2,3-dihydro-1H-inden-1-one (1.0 g) was added and the resultant reaction mixture was stirred at room temperature for 1 hour. Then, into the reaction mixture, a solution of benzyl bromide (1.3 g) in DMF (15 mL) was added dropwise at 80° C. and at the same temperature, the resultant reaction mixture was heated with stirring for 30 minutes. Further, to the reaction mixture, sodium hydride (0.09 g) and benzyl bromide (0.30 g) were further added and the resultant reaction mixture was heated with stirring for 2 hours. To the reaction mixture, a saturated aqueous solution of ammonium chloride was added and the resultant reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated saline and was dried over sodium sulfate anhydride. From the organic phase, the solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=5:1) to obtain 4-benzyloxy-2,3-dihydro-1H-inden-1-one (1.2 g) as a white solid. The obtained white solid was subjected to a reaction according to the method of (Example 124) <Step 2> to obtain the subject compound (1.1 g) as a white solid.
Reaction SMILES: [C:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=2)(=[O:3])[NH2:2].[OH-].[K+]>O1CCCC1.C(O)CO.O>[C:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2)(=[O:3])[NH2:2]
Reactant: COC(=O)c1ccc2[nH]c(C(N)=O)cc2c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: OCCO
Product: NC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a suspension of methyl 2-carbamoyl-1H-indole-5-carboxylate (300 mg, 1.38 mmol) in tetrahydrofuran (4.5 mL) and ethylene glycol (4.5 mL) was added potassium hydroxide (3.16 g, 56.4 mmol). The mixture was heated to reflux and stirred for 2 hours. The reaction was cooled to room temperature and diluted with water. The tetrahydrofuran was removed under reduced pressure. The solids were filtered off and the filtrate was acidified to pH 4 with concentrated hydrochloric acid. The resulting precipitate was collected by filtration and dried under vacuum to give 2-carbamoyl-1H-indole-5-carboxylic acid (230 mg, 82%). 1H NMR (400 MHz, DMSO-d6, δ): 12.53 (br. s., 1 H), 11.88 (br. s., 1 H), 8.28 (s, 1 H), 8.04 (br. s., 1 H), 7.77 (d, J=8.6 Hz, 1 H), 7.46 (m, J=8.6 Hz, 2 H), 7.25 (s, 1 H).