Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(CC)CC.Br[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:19][C:18]2=[O:34])[CH3:16])=[CH:11][CH:10]=1.CN(C)[CH:37]=[O:38].[CH3:40][OH:41]>CC#N>[CH3:40][O:41][C:37](=[O:38])[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:29][C:30]([OH:33])([CH3:31])[CH3:32])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:19][C:18]2=[O:34])[CH3:16])=[CH:11][CH:10]=1
Reactant: CO
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CN(C)C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
NEt3 (0.47 mL) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)dichloromethane complex (0.15 g) were added to a solution of 3-[(S)-1-(4-bromo-phenyl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one (1.04 g) in MeCN (2.5 mL), methanol (20 mL), and N,N-dimethylformamide (5 mL). The resulting mixture was sparged with argon for 5 min and then transferred to a pressure-resistant vessel that was filled with CO (5.5. bar). The mixture was heated to 70° C. and stirred at this temperature for 18 h before another portion of [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)dichloromethane complex (0.15 g) was added. After stirring at 70° C. for another 4 h, the mixture was cooled to ambient temperature, filtered, and concentrated under reduced pressure. The residue was taken up in ethyl acetate and the resulting mixture was washed with water and brine and dried (MgSO4). The solvent was removed and the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 40:60→0:100) to afford the title compound as an oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:36]=[CH:35][C:9]([O:10][CH2:11][CH2:12][S:13][C:14]2[CH:34]=[CH:33][C:17]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.C(=O)([O-])[OH:38].[Na+]>>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:18][C:17]1[CH:33]=[CH:34][C:14]([S:13]([CH2:12][CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:6]([F:5])=[CH:36][C:35]=2[N+:1]([O-:4])=[O:2])=[O:38])=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])O
Reactant: O=C([O-])O
Reactant: COc1cc2nccc(Oc3ccc(SCCOc4ccc(F)cc4)cc3)c2cc1OC
Agent: [Na+]
Product: COc1cc2nccc(Oc3ccc(S(=O)CCOc4ccc(F)cc4[N+](=O)[O-])cc3)c2cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
Nitric acid (0.5 ml) was added to 4-(4-{[2-(4-Fluorophenoxy)ethyl]sulfanyl}phenoxy)-6,7-dimethoxyquinoline (20 mg), and the mixture was stirred at 0° C. for 30 min. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform, followed by washing with saturated brine. The extract was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development to give the title compound (13 mg, yield 58%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][C@@H:12]1[CH2:17][O:16][CH2:15][CH2:14][NH:13]1>CO>[CH3:11][C@@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: C[C@@H]1COCCN1
Solvent: CO
Product: C[C@@H]1COCCN1c1ccc([N+](=O)[O-])cn1
Temperature: 150 °C
Yield: 77.6 %

Procedure:
A mixture of 1 g (6.18 mmol) of 2-chloro-5-nitropyridine and 1.31 g (12.36 mmol) of (R)-3-methylmorpholine is heated in a Biotage microwave machine for 1 hour at 150° C. The reaction medium is taken up in MeOH and then evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/MeOH mixture from (100/0 v/v) up to (95/5 v/v) to give 1.07 g of (R)-3-methyl-4-(5-nitro-pyridin-2-yl)-morpholine.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[CH3:16])=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]#N.[OH-:17].[K+].[OH2:19]>>[CH3:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[CH3:16])=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]([OH:19])=[O:17]
Reactant: [OH-]
Reactant: Cc1cc(C#N)cnc1N1CCCCC1C
Reactant: O
Agent: [K+]
Product: Cc1cc(C(=O)O)cnc1N1CCCCC1C

Procedure:
A solution of 5-methyl-6-(2-methylpiperidin-1-yl)nicotinonitrile obtained in step 1 (1.0 g; 4.64 mmol) and KOH (1.3 g; 23.22 mmol) in water (60 mL) was heated at reflux for 16 hours. After this time, reaction mixture was acidified to pH 3 and extracted with EtOAc to give the title compound as a yellow solid (1.1 g, quantitative). 1H NMR (DMSO-d6) δ 12.82 (bs, 1H), 8.58 (d, J=2.3 Hz, 1H), 7.88 (d, J=2.3 Hz, 1H), 3.85-3.82 (m, 1H), 3.19-3.10 (m, 2H), 2.24 (s, 3H), 1.75-1.44 (m, 6H), 1.04 (d, J=6.2 Hz, 3H). HPLC (Method B) Rt 1.96 min (Purity: 92.2%). LC/MS (Method A): 235.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([OH:20])=O)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[C:26]([NH:31][C:32]([C@@H:34]([NH2:45])[CH2:35][C:36]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[NH:38][CH:37]=3)=[O:33])[CH:27]=[CH:28]2)=[CH:23][CH:22]=1.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>ClCCl.CN(C1C=CN=CC=1)C>[NH:38]1[C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:36]([CH2:35][C@H:34]([NH:45][C:18]([C@@H:13]2[CH2:14][CH2:15][CH2:16][CH2:17][N:12]2[S:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:10])=[O:11])=[O:20])[C:32](=[O:33])[NH:31][C:26]2[CH:27]=[CH:28][C:29]3[C:24](=[CH:23][CH:22]=[CH:21][CH:30]=3)[CH:25]=2)=[CH:37]1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1ccc2ccccc2c1
Reactant: COc1cccc(S(=O)(=O)N2CCCC[C@H]2C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1cccc(S(=O)(=O)N2CCCC[C@H]2C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)Nc2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a solution of 0.78 g (2.60 mmol) of (S)-1-(3-methoxy-benzenesulfonyl)-piperidine-2-carboxylic acid and 1.03 g (3.12 mmol) of (S)-2-amino-3-(1-indol-3-yl)-naphthalen-2-yl-propionamide in dichloromethane (100 ml) was added 0.16 g (1.30 mmol) DMAP followed by addition of 4-methylmorpholine 1.37 g (13.54 mmol), HOBT 0.84 g (6.25 mmol) and EDCI 1.39 g (7.29 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was then washed with water, dried (sodium sulfate). Chromatography on silica gel eluting with 50% ethyl acetate/heptane proved 1.2 g (1.96 mmol) of the title compound. 1H NMR (300 MHz, CDCl3): 1.34-1.01 (m, 5H); 2.07 (bd, 1H); 2.21 (dd, 1H); 3.43-3.48 (m, 3H); 3.83 (s, 3H); 4.34 (b, 1H); 4.98 (q, 1H); 6.98 (d, 1H); 7.09-7.47 (m, 11H); 7.68-7.80 (m, 4H); 8.15 (s, 1H); 8.21 (s, 1H); 8.40 (s, 1H).
Reaction SMILES: [Cl:1][S:2]([N:5]=[C:6]=O)(=[O:4])=[O:3].[CH2:8]([C:11]1(C=[CH:16][CH:15]=[CH:14][CH2:13]1)[NH2:12])[CH:9]=[CH2:10].C([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])C.[S:25](Cl)(=[O:28])(=[O:27])N>C(#N)C.O>[S:2]([Cl:1])(=[O:4])(=[O:3])[NH2:5].[CH3:10][CH2:9][CH2:8][CH:11]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:24][C:23]=2[N:20]([CH2:21][CH:22]=[CH2:6])[S:25](=[O:28])(=[O:27])[NH:12]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCN(CC)CC
Reactant: C=CCC1(N)C=CC=CC1
Agent: NS(=O)(=O)Cl
Solvent: CC#N
Solvent: O
Product: C=CCN1c2ccccc2C(CCC)NS1(=O)=O
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
Sulfamoyl chloride was prepared in situ by cautiously adding to a solution of chlorosulfonyl isocyanate (7.05 g, 0.05 mol) in acetonitrile (50 ml) cooled to 0-5° C., water (0.9 ml) in acetonitrile (5 ml) keeping the temperature below 10° C., whilst stirring for 1 hour. A solution of 1-(prop-2-en-1-yl) aniline (6.65 g, 0.05 mol) and triethylamine (5.05 g, 0.05 mol) was stirred at 0-5° C. and the sulfamoyl chloride prepared above was added slowly keeping the temperature below 10° C., stirring overnight. The reaction was poured into ice-water(100 ml) and the product, 1-phenyl-1-(prop-2-en-1-yl) sulfamide was collected by filtration. This was treated with 2-methylpropionaldehyde and methane sulfonic acid as described previously to give 3,4-dihydro-4-(2-methylethyl)-1-(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine-2,2-dioxide. This compound was converted to 3,4-dihydro-4-(2-methylethyl)-1-(2-oxoethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide by methods discussed previously.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)(=[O:22])=[O:21])[CH:15]=3)[CH:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)Cl)c3)c2)n1
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)N4CCOCC4)c3)c2)n1
Temperature: 25 °C
Yield: 68 %

Procedure:
The title compound was prepared from the above described solution of 3-[6-methyl-4-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl-2′-yl]-benzenesulfonyl chloride (ca. 0.2 g, 0.41 mmol) by treatment with excess morpholine in THF (5 mL) at 50° C. for 16 h. Cooled to rt, diluted with EtOAc, washed with 1 N HCl, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with n-heptane/EtOAc followed by trituration with n-heptane/diethyl ether to give the title compound (0.150 g, 68%) as a white solid. MS (ISP) 539.9 [(M+H)+]; mp 115° C.
Reaction SMILES: C1(NC(N)=S)C=CC=CC=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=2[Cl:29])=[S:20])=[C:14]([OH:30])[C:13]=1[S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32].[Si:37](Cl)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38].N1C=CN=C1>>[Cl:29][C:23]1[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:19]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[C:13]([S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])[C:14]=1[O:30][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])=[S:20]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2cccc(F)c2Cl)c1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: NC(=S)Nc1ccccc1
Agent: c1c[nH]cn1
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2cccc(F)c2Cl)c1O[Si](C)(C)C(C)(C)C
Yield: 50.3 %

Procedure:
Following the general procedure for protected phenyl thiourea formation outlined in example 12, N-[4-chloro-2-hydroxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]-N′-(2-chloro-3-fluorophenyl)thiourea (575 mg, 1.32 mmol), tert-butyldimethylsilyl chloride (991 mg, 6.6 mmol) and imidazole (179 mg, 2.64 mmol) were reacted to form the desired product (367 mg, 50%). LC-MS m/z 552.2 (M+).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=[C:11]2[CH:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=[C:11]2[CH:10]=1
Reactant: CCOC(=O)c1nc2cc(NC(=O)OC(C)(C)C)ccn2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nc2cc(N)ccn2n1
Yield: 75.5 %

Procedure:
A solution of ethyl 7-(tert-butoxycarbonylamino)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (1.07 g, 3.49 mmol) in dichloromethane (5 ml) and trifluoroacetic acid (5.38 ml, 69.9 mmol) is stirred for 3 hours at 25° C. The mixture is made basic using sat. aqueous sodium carbonate solution and extracted with ethyl acetate. The organic layer is washed with water and brine, dried with magnesium sulfate and the solvent is removed in vacuo affording ethyl 7-amino-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (543 mg, 75.4%) as a light yellow solid. mp.: 150-171° C. MS: m/z=207.0 (M+H+).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:24]=[CH:23][C:9]([O:10][CH2:11][C:12]2[N:16]=[C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[O:14][N:13]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(OC(N1[CH2:37][CH2:36][CH:35]([C:38]2O[N:41]=[C:40](COC3C=CC(S(C)(=O)=O)=CC=3)[N:39]=2)[CH2:34]C1)=O)(C)(C)C.CCN(C(C)C)C(C)C.ClC1N=CC(CC)=CN=1>O1CCOCC1.CC(O)C>[CH2:36]([C:35]1[CH:38]=[N:39][C:40]([N:20]2[CH2:21][CH2:22][CH:17]([C:15]3[O:14][N:13]=[C:12]([CH2:11][O:10][C:9]4[CH:8]=[CH:7][C:6]([S:3]([CH3:2])(=[O:5])=[O:4])=[CH:24][CH:23]=4)[N:16]=3)[CH2:18][CH2:19]2)=[N:41][CH:34]=1)[CH3:37]
Reactant: CS(=O)(=O)c1ccc(OCc2noc(C3CCNCC3)n2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(COc3ccc(S(C)(=O)=O)cc3)no2)CC1
Agent: CCc1cnc(Cl)nc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCc1cnc(N2CCC(c3nc(COc4ccc(S(C)(=O)=O)cc4)no3)CC2)nc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To the crude HCl salt (0.18 g, ˜0.5 mmol) of 4-[3-(4-methanesulfonyl-phenoxymethyl)-[1,2,4]oxadiazol-5-yl]-piperidine, prepared by treatment of 4-[3-(4-methanesulfonyl-phenoxymethyl)-[1,2,4]oxadiazol-5-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 81) in dioxane with 4N HCl, was added 2-propanol (3 mL), followed by DIPEA (0.13 g, 1 mmol) and 2-Chloro-5-ethyl-pyrimidine (0.14 g, 1 mmol). The resulting mixture was stirred at 70° C. overnight. After concentration in vacuo, the residue was purified by silica column chromatography with EtOAc/hexanes to afford the desired product. 1H NMR (CDCl3): δ 8.18 (2H, s), 7.89 (2H, d, J=8.8 Hz), 7.15 (2H, d, J=8.8 Hz), 5.24 (2H, s), 4.75˜4.65 (2H, m), 3.3˜3.2 (1H, m), 3.2˜3.1 (2H, m), 3.03 (3H, s), 2.47 (2H, q, J=7.6 Hz), 2.22˜2.16 (2H, m), 1.96˜1.84 (2H, m), 1.19 (3H, t, J=7.6 Hz).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[C:13]3=[C:14]([F:22])[CH:15]=[N:16][C:17]4[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:4][C@H:3]1[F:23].[O:24]1[C:33]2[CH:32]=[C:31]([CH:34]=O)[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1.[Cl:36]CCl.CO>>[ClH:36].[O:24]1[C:33]2[CH:32]=[C:31]([CH2:34][NH:1][C@H:2]3[CH2:7][CH2:6][N:5]([CH2:8][CH:9]4[C:13]5=[C:14]([F:22])[CH:15]=[N:16][C:17]6[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=65)[CH2:10]4)[CH2:4][C@H:3]3[F:23])[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: N[C@H]1CCN(CC2Cn3c(=O)ccc4ncc(F)c2c43)C[C@H]1F
Reactant: ClCCl
Solvent: CO
Product: Cl
Product: O=c1ccc2ncc(F)c3c2n1CC3CN1CC[C@H](NCc2cc3c(cn2)OCCO3)[C@H](F)C1
Yield: 82 %

Procedure:
The free base of the title compound was prepared from 4-{[cis-4-amino-3-fluoro-1-piperidinyl]methyl}3-fluoro-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c)) according to the general method of Example 2(h), chromatographing with dichloromethane/methanol/0.88 ammonia 95:5:0.5, in 82% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[Cl:16])=[O:6]
Reactant: Nc1ccccc1Cl
Reactant: Cc1cccc(N)c1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: Cc1cccc(N)c1C(=O)Nc1ccccc1Cl
Yield: 50.9 %

Procedure:
Prepared according to Procedure A using 2-amino-6-methylbenzoic acid (2.5 g, 16.5 mmol) and SOCl2 (3.0 mL, 41.3 mmol) in benzene (75 mL), followed by 2-chloroaniline (3.5 mL, 33.0 mmol) and CHCl3 (75 mL). The product was chromatographed in CH2Cl2 to provide 2.19 g of a brown oil (51%). 1H NMR (CDCl3) δ: 8.58 (d, J=8.1 Hz, 1H); 7.99 (br s, 1H); 7.40 (dd, J=1.4, 8.0 Hz, 1H); 7.34 (t, J=7.7 Hz, 1H); 7.11 (t, J=7.8 Hz, 1H); 7.09 (dt, J=1.5, 7.7 Hz, 1H); 6.64 (d, J=7.5 Hz, 1H); 6.59 (d, J=8.1 Hz, 1H); 4.29 (br s, 2H); 2.45 (s, 3H). MS (ES) m/z 283.0 (M+22).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:14]N1C(=O)CCC1=O>CC#N>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][C:11]=2[Cl:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(Br)ccc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CC(=O)N1CCc2cc(Br)cc(Cl)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.4 %

Procedure:
Part A: 1-Acetyl-5-bromoindoline (2.47 g, 10.29 mmol) was heated at reflux with N-chlorosuccinimide (1.56 g, 10.40 mmol) in CH3CN for 30 min and an additional amount NCS (1 g, 7.47 mmol) was added while hot and the reaction was stirred at 25° C. for 16 h. The solvent was stripped in vacuo and the residue was chromatographed on silica gel using 20% EtOAc/hexanes as eluent to give 1-acetyl-5-bromo-7-chloroindoline (1.17 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[CH2:20](N(CC)CC)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OCC)(=O)C>O1CCCC1>[CH2:20]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([F:14])([F:12])[F:13])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:34]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)c1[nH]c2cc(C(F)(F)F)ccc2c1N
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2cc(C(F)(F)F)ccc2c1NCC(=O)c1ccccc1
Yield: 55.6 %

Procedure:
Suspend the 3-amino-2-carbethoxy-6-trifluoromethylindole (290 mg, 1.06 mmol) in tetrahydrofuran (30 mL) and add triethylamine (0.150 mL, 1.17 mmol). Add benzoyl chloride (0.136 mL, 1.17 mmol) and stir for 30 minutes at room temperature. Dilute the reaction with ethyl acetate (mL), rinse with 1M HCl, water, dry over magnesium sulfate, filter and concentrate in vacuo. Recrystallize from hot ethyl acetate/hexane to yield 3-[(phenacyl)amino]-2-carbethoxy-6-trifluoromethylindole (230 mg, 56%); mp 237°-239° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[H-].[Na+].I[CH2:14][CH3:15]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:14][CH3:15])[N:6]=[CH:5]2
Reactant: CCI
Reactant: Brc1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1ncc2cc(Br)ccc21
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
To a solution of 5-bromo-1H-indazole (1 g, 5.10 mmol) in tetrahydrofuran (30 mL) was added sodium hydride (330 mg, 8.25 mmol) at 0° C. with stirring for 30 min, iodoethane (1.72 g, 11.04 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature. The reaction was then quenched with water (50 mL), extracted with ethyl acetate (3×80 mL) and the organic layers combined, dried over anhydrous magnesium sulfate and concentrated under vacuum to give the residue, which was purified by a silica gel column with 1% to 5% ethyl acetate in petroleum ether to afford 5-bromo-1-ethyl-1H-indazole as yellow oil (598 mg, 52%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]#[N:14])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].FC(F)(F)C(O)=O.[CH3:22][C:23]([CH3:25])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:13]([C:3]1[C:2]([NH:1][CH:23]([CH3:25])[CH3:22])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:12])[CH:4]=1)#[N:14]
Reactant: CC(C)=O
Reactant: COC(=O)c1cc(N)c(C#N)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COC(=O)c1cc(NC(C)C)c(C#N)cc1C
Temperature: 25 °C
Yield: 76.2 %

Procedure:
Methyl 5-amino-4-cyano-2-methylbenzoate (synthesized in reagent preparation 41, step 4) (240 mg, 1.26 mmol) was dissolved in 1,2-dichloroethane (7 mL) and was treated with trifluoroacetic acid (0.6 mL, 7.57 mmol), acetone (0.28 mL, 3.79 mmol), and sodium triacetoxyborohydride (802 mg, 3.78 mmol) at 45° C. for 20 min. The reaction mixture was cooled to ambient temperature and quenched with saturated aqueous sodium bicarbonate and was partitioned with dichloromethane. The aqueous portion was extracted with dichloromethane. The combined organic portion was washed with brine, dried over sodium sulfate, then filtered and concentrated to afford a yellow oil which was purified by column chromatography (silica gel, 10% dichloromethane in hexanes) to afford methyl 4-cyano-5-(isopropylamino)-2-methylbenzoate (224 mg, 0.96 mmol, 76% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.25 (s, 1H), 7.16 (s, 1H), 4.28 (d, 1H), 3.91 (s, 3H), 3.77-3.74 (m, 1H), 2.40 (s, 3H), 1.27 (s, 3H), 1.26 (s, 3H); MS (EI) for C14H16N2O2: 233 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13](OS(C(F)(F)F)(=O)=O)[C:12]([C:27]2[N:28]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[N:29]=[CH:30][CH:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:45](B1OC(C)(C)C(C)(C)O1)=[CH2:46].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:41]([O:40][C:38]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH:45]=[CH2:46])[C:12]([C:27]2[N:28]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[N:29]=[CH:30][CH:31]=2)=[CH:11][CH:10]=1)=[O:39])([CH3:43])([CH3:44])[CH3:42]
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(-c2ccnn2C2CCCCO2)c1OS(=O)(=O)C(F)(F)F
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1c(-c2ccnn2C2CCCCO2)ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1C(=O)OC
Temperature: 80 °C

Procedure:
A mixture of methyl 6-[bis-(tert-butoxycarbonyl)amino]-3-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-2-trifluoromethanesulfonyloxybenzoate (Intermediate 11, 4.35 g), vinylboronic acid pinacol ester (1.9 mL), bis(triphenylphosphine)palladium (II) dichloride (0.255 g) and cesium carbonate (7.1 g) in dioxane (300 mL) and water (47 mL) was de-gassed and purged with nitrogen. The mixture was then heated to 80° C. for 4 hours. After cooling, the mixture was diluted with ether and the organic layer was separated, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-60% to give methyl 6-[bis-(tert-butoxycarbonyl)amino]-3-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-2-vinylbenzoate (2.84 g) as a gum.
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[C:41]([S:51]([CH3:54])(=[O:53])=[O:52])[CH:40]=1>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[C:41]([S:51]([CH3:54])(=[O:52])=[O:53])[CH:40]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CS(=O)(=O)c1cc(Br)ccc1-c1ccccc1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc(-c2ccccc2)c(S(C)(=O)=O)c1

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 4-bromo-2-(methylsulfonyl)biphenyl (Intermediate 203), the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.