Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH2:6][CH2:7][O:8][CH2:9][C:4]=2[C:3]([C:10]([OH:12])=O)=[N:2]1.[NH2:13][C@@H:14]([CH3:31])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([Cl:30])[CH:22]=2)=[N:17]1>>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:3]3[C:4]4[CH2:9][O:8][CH2:7][CH2:6][C:5]=4[O:1][N:2]=3)=[O:12])[CH3:31])[N:17]=2)[CH:28]=[C:27]([F:29])[C:24]=1[C:25]#[N:26]
Reactant: O=C(O)c1noc2c1COCC2
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1noc2c1COCC2
Yield: 13.26 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 6,7-dihydro-4H-pyrano[3,4-d]isoxazole-3-carboxylic acid (0.174 g, 1.026 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.22 g, 0.789 mmol). The product was purified by LC/MS-trigger. Yield 13.26%. 1H-NMR (400 MHz; CDCl3): δ 1.23 (d, 3H), 2.93 (t, 2H), 3.91 (t, 2H), 4.27 (dd, 1H), 4.42 (dd, 1H), 4.50-4.60 (m, 1H), 4.89 (d, 2H), 6.63 (d, 1H), 7.37 (d, 1H), 7.50 (d, 1H), 7.59 (dd, 1H), 7.76-7.77 (m, 1H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>>[CH3:16][C:13]1([CH3:17])[N:12]([CH2:18][C:19]2[CH:26]=[CH:25][C:22]([CH3:23])=[CH:21][CH:20]=2)[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: Cc1ccc(CBr)cc1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: Cc1ccc(CN2N(C3C4CC5CC(C4)CC3C5)C(=O)C2(C)C)cc1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 4-methylbenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[C:3]=1[N+:11]([O-:13])=[O:12].C1(O)C=CC=CC=1.[CH3:21][O:22][C:23](=[O:27])[CH:24](Br)[CH3:25]>>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:24]([CH3:25])[C:23]([O:22][CH3:21])=[O:27])=[C:3]([N+:11]([O-:13])=[O:12])[C:4]=1[CH3:10])=[O:7]
Reactant: Cc1c(C=O)ccc(O)c1[N+](=O)[O-]
Reactant: COC(=O)C(C)Br
Solvent: Oc1ccccc1
Product: COC(=O)C(C)Oc1ccc(C=O)c(C)c1[N+](=O)[O-]

Procedure:
Using 4-hydroxy-2-methyl-3-nitrobenzaldehyde as the phenol and methyl-2-bromopropanoate as the alkylating agent in the general procedure for alkylation of substituted-2-nitrophenols gives the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51 (d, J=6.82 Hz, 3 H) 2.50 (s, 3H) 3.69 (s, 3H) 5.40 (q, J=6.82 Hz, 1H) 7.29 (d, J=9.09 Hz, 1H) 8.00 (d, J=8.84 Hz, 1H) 10.12 (s, 1H). ESI-MS: m/z 268.2 (M+H)+.
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[CH3:11].Cl.CS([O-])(=O)=O.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][C:20]=1[S:28](=[O:31])(=[O:30])[NH2:29]>>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][N:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH:3]2[CH3:11])=[O:24])=[CH:21][C:20]=1[S:28]([NH2:29])(=[O:31])=[O:30]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: CC1Cc2ccccc2N1N
Agent: CS(=O)(=O)[O-]
Agent: Cl
Product: CC1Cc2ccccc2N1NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
Process according to claim 1, characterised in that the 1-amino-2,3-dihydro-2-methyl-1H-indole is reacted in the form of a hydrochloride or a methanesulphonate with the 4-chloro-3-sulphamoylbenzoyl chloride.
Reaction SMILES: [CH:1]1([CH2:5][CH2:6][NH:7][C:8]([C:10]2[N:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=2)=[O:9])[CH2:4][CH2:3][CH2:2]1.[N:17]1([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[CH:1]1([CH2:5][CH2:6][NH:7][C:8]([C:10]2[N:11]=[N:12][C:13]([N:20]3[CH2:21][CH2:22][N:17]([C:23](=[O:24])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:32])[F:33])[CH2:18][CH2:19]3)=[CH:14][CH:15]=2)=[O:9])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(NCCC1CCC1)c1ccc(Cl)nn1
Product: O=C(NCCC1CCC1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-cyclobutylethyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (47% yield). 1H NMR (300 MHz, CDCl3) δ 8.02, 7.74, 7.73, 7.57, 7.35, 6.98, 4.03, 3.89-3.66, 3.40-3.31, 2.36, 2.09-2.00, 1.92-1.57. 13C NMR (75 MHz, CDCl3) δ 167.6, 134.3, 132.4, 129.5, 127.2, 127.0, 126.9, 126.8, 126.7, 125.5, 121.8, 112.6, 46.4, 44.6, 44.5, 41.3, 37.6, 36.5, 33.7, 28.3, 18.6. MS (ES+) m/z 462.3 (M+1).
Reaction SMILES: [OH-].[Na+].C([CH:8]1[CH:13]=[C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[CH2:19][CH:18]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:17]3)[NH:11][NH:10][C:9]1=[O:34])(OCC)=O>O.C(O)C>[C:30]1([CH3:33])[CH:31]=[CH:32][C:27]([S:24]([NH:23][CH:18]2[CH2:17][C:16]3[C:20](=[CH:21][CH:22]=[C:14]([C:12]4[CH2:13][CH2:8][C:9](=[O:34])[NH:10][N:11]=4)[CH:15]=3)[CH2:19]2)(=[O:26])=[O:25])=[CH:28][CH:29]=1
Reactant: CCOC(=O)C1C=C(c2ccc3c(c2)CC(NS(=O)(=O)c2ccc(C)cc2)C3)NNC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)NC2Cc3ccc(C4=NNC(=O)CC4)cc3C2)cc1

Procedure:
600 mg (15 mmol) of sodium hydroxide in 2 ml of water are added to 2.3 g (5 mmol) of 4-carbethoxy-6-(2-p-toluenesulfonamido-indan-5-yl)-dihydro-pyridazin-3(2H)-one in 40 ml of ethanol, and the mixture is stirred over night in order to achieve hydrolysis. The reaction product which is precipitated on acidifying is filtered off with suction and heated in glacial acetic acid for 10 minutes at the boil. The desired compound crystallises out on cooling.
Reaction SMILES: [CH3:1][C:2]1[C:20]([N:21]([C:23](=[O:40])[CH2:24][NH:25][C:26](=[O:39])[CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][C:32]([C:35](=[O:38])[NH:36][CH3:37])=[CH:31][CH:30]=2)[CH3:22])=[CH:19][CH:18]=[C:17]([CH3:41])[C:3]=1[CH2:4][O:5][C:6]1[C:14]2[N:13]=[C:12]([SH:15])[N:11]([CH3:16])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[C:42](=O)([O-])[O-].[K+].[K+].CN(C)C=O.CI>O>[CH3:1][C:2]1[C:20]([N:21]([C:23](=[O:40])[CH2:24][NH:25][C:26](=[O:39])[CH:27]=[CH:28][C:29]2[CH:30]=[CH:31][C:32]([C:35](=[O:38])[NH:36][CH3:37])=[CH:33][CH:34]=2)[CH3:22])=[CH:19][CH:18]=[C:17]([CH3:41])[C:3]=1[CH2:4][O:5][C:6]1[C:14]2[N:13]=[C:12]([S:15][CH3:42])[N:11]([CH3:16])[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(C)c(COc3cccc4c3nc(S)n4C)c2C)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(C)c(COc3cccc4c3nc(SC)n4C)c2C)cc1
Reaction time: 16 h
Yield: 59.3 %

Procedure:
To a mixture of 4-[2,6-dimethyl-3-[N-[4-(methylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzyloxy]-2-mercapto-1-methyl-1H-benzimidazole (34.9 mg), potassium carbonate (10.1 mg) and N,N-dimethylformamide (0.4 ml) was added methyl iodide (4 μl) at ambient temperature, and the mixture was stirred for 16 hours. The reaction mixture was poured into water, and extracted with chloroform. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (ethyl acetate:methanol=10:1, v/v) to give 4-[2,6-dimethyl-3-[N-[4-(methylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzyloxy]-1-methyl-2-methylthio-1H-benzimidazole (21.2 mg).
Reaction SMILES: CC([O:5][C:6]([C:8]1[NH:9][C:10](=[O:14])[NH:11][C:12]=1[CH3:13])=[O:7])(C)C.FC(F)(F)C(O)=O>>[CH3:13][C:12]1[NH:11][C:10](=[O:14])[NH:9][C:8]=1[C:6]([OH:7])=[O:5]
Reactant: Cc1[nH]c(=O)[nH]c1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]c(=O)[nH]c1C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2,3-Dihydro-5-methyl-2-oxo-1H-imidazole-4-carboxylic acid 1,1-dimethylethyl ester (110.1 g, 0.556 mol) is added in portions to stirred trifluoroacetic acid (500 g). After stirring the resulting mixture at room temperature for 20 minutes the suspension is evaporated in vacuo. The solid residue is mixed with water (700 mL), the mixture filtered, and the solid residue washed with an additional portion of water (700 mL). The filter cake is then dried for 1.5 hr. at ca. 105° C., then overnight at room temperature to produce the title compound.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]4[O:33][C:32]5[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=5[C:13]=4[N:14]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]5[O:28][CH2:29][O:30][C:24]=5[CH:23]=4)[C:15](=[O:20])[C:16]=3[C:17](O)=[O:18])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.CN(C1C=CC=CN=1)C.S(Cl)(Cl)=O.[C:51]1([S:57]([NH2:60])(=[O:59])=[O:58])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>N1C=CC=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]4[O:33][C:32]5[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=5[C:13]=4[N:14]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]5[O:28][CH2:29][O:30][C:24]=5[CH:23]=4)[C:15](=[O:20])[C:16]=3[C:17]([NH:60][S:57]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)(=[O:59])=[O:58])=[O:18])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1c(-c2ccc3c(c2)OCCO3)c2oc3ccccc3c2n(Cc2ccc3c(c2)OCO3)c1=O
Reactant: NS(=O)(=O)c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(NS(=O)(=O)c1ccccc1)c1c(-c2ccc3c(c2)OCCO3)c2oc3ccccc3c2n(Cc2ccc3c(c2)OCO3)c1=O
Reaction time: 10 h

Procedure:
A solution of 4.85 g of 4-(1,4-benzodioxan-6-yl)-1,2-dihydro-1-(3,4-methylenedioxybenzyl)-2-oxobenzofuro-[3,2-b]pyridine-3-carboxylic acid and 0.2 g of dimethylaminopyridine in 50 ml of pyridine is treated with 5 ml of thionyl chloride and 1.57 g of phenylsulfonamide. The mixture is stirred for 10 hours and worked up in the customary manner, and 4-(1,4-benzodioxan-6-yl)-1,2-dihydro-1-(3,4-methylenedioxybenzyl)-2-oxo-3-(phenylsulfonamidocarbonyl)benzofuro[3,2-b]pyridine is obtained.
Reaction SMILES: [CH2:1]([O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH:2]1[O:4][CH2:3]1.O>CC(O)=O.C1COCC1>[CH2:1]([O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:7])[CH3:8])[C@H:2]1[O:4][CH2:3]1
Reactant: CC(C)(C)[Si](C)(C)OCC1CO1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CO1
Yield: 48.3 %

Procedure:
Using the (R,R)-(salen)Co(II) precatalyst of 1 (91 mg, 0.15 mmol, 0.005equiv), (+/−)-(tert-butyldimethylsilyl) glycidyl ether (5.64 g, 30.0 mmol), AcOH (32 mL, 0.6 mmol, 0.02 equiv), 0.3 mL THF, and H2O (297 mL, 16.5 mmol, 0.55 equiv) and a procedure analogous to the one outlined for 5b, (S)-(tert-butyldimethylsilyl) glycidyl ether 5c (2.72 g, 14.5 mmol, 48%) was obtained as a clear oil by vacuum distillation of the reaction mixture (30° C., 0.5 Torr). The product was determined to be present in >99% ee by derivatization through ring opening with 2-napthalenethiol in methanol using 1 equiv TEA at 0° C. and direct analysis of the 2-napthylsulfide thus obtained (Chiralcel OD, 99.25:0.75 hexanes:EtOH, 1 mL/min, 230 nm).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:17][C:16]3[CH2:15][CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12][C:11]=3[C:9]=2[CH:10]=1)(=[O:4])=[O:3].[CH3:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1>>[CH3:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([S:2]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][C:16]4[CH2:15][CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12][C:11]=4[C:9]=3[CH:10]=2)(=[O:4])=[O:3])[CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)Cl)cc3c2C1
Reactant: Cc1c[nH]c2ccccc12
Product: Cc1cn(S(=O)(=O)c2ccc3oc4c(c3c2)CN(C(=O)OC(C)(C)C)CC4)c2ccccc12
Yield: 32 %

Procedure:
The product of Example 41, step B was reacted with 3-methylindole following the procedure of Example 41, step C providing tert-butyl 8-(3-methyl-1H-indol-1-ylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (36 mg, 32%) as a clear oil: 1H NMR (CDCl3, 300 MHz) δ 8.02 (m, 2H), 7.74 (d, J=8.7 Hz, 1H), 7.42 (t, J=8.4 Hz, 2H), 7.34 (s, 1H), 7.30 (dd, J=8.4, 1.3 Hz, 1H), 7.21 (dt, J=3.7, 1.0 Hz, 1H), 4.53 (br s, 2H), 3.80 (br s, 2H), 2.84 (br s, 2H), 2.22 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.[NH2:13][CH:14]([CH2:22][CH3:23])[C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16]>>[CH2:18]([O:17][C:15](=[O:16])[CH:14]([NH:13][C:10](=[O:12])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:22][CH3:23])[CH:19]([CH3:20])[CH3:21]
Reactant: COc1cccc(CC(=O)O)c1
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1cccc(OC)c1)C(=O)OCC(C)C

Procedure:
Following General Procedure I above and using 3-methoxyphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared frollowing General Procedure J above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: C(O)C.[CH2:4]=[C:5]1[CH2:13][CH2:12][C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]1=O.O.[NH2:16][NH2:17]>O>[N:16]1[NH:17][CH2:4][CH:5]2[C:6]=1[C:7]1[CH:11]=[CH:10][S:9][C:8]=1[CH2:12][CH2:13]2
Reactant: C=C1CCc2sccc2C1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: c1cc2c(s1)CCC1CNN=C21

Procedure:
To 20 mL of anhydrous ethanol was added 1.2 g of the product from Step A and 0.40 g of hydrazine hydrate. The reaction mixture was heated at reflux for 2 h, cooled, poured into cold water and extracted with ether. The ether extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered and utilized without concentration or purification in Step C.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH3:4].[CH2:6]([NH:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:7]([CH3:9])[CH3:8].O>C1(C)C=CC=CC=1>[CH:1](/[N:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:6][CH:7]([CH3:9])[CH3:8])=[CH:2]\[CH2:3][CH3:4]
Reactant: CCCC=O
Reactant: CC(C)CNCC(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CC/C=C/N(CC(C)C)CC(C)C
Temperature: 130 °C
Yield: 73.8 %

Procedure:
Butanal (68 mL, 0.75 mol) was added dropwise over 20 minutes to a solution of diisobutylamine (87 mL, 0.50 mol) in toluene (100 mL) at room temperature under a nitrogen atmosphere. After installation of a Dean-Stark tube, the mixture was warmed to 130° C. and refluxed. 50 mL of distillate containing water was extracted twice. The reaction mixture was cooled to room temperature and then distilled under reduced pressure (0.25 mmHg, 51-55° C.) to obtain the title compound (67.67 g, yield: 74%) as a colorless oil substance.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][Si:35]([C:38]#[CH:39])([CH3:37])[CH3:36]>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.CN(C)C=O>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([N:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH2:39][CH2:38][Si:35]([CH3:37])([CH3:36])[CH3:34])=[CH:3][CH:4]=3)=[CH:9][C:10]([C:23]([F:26])([F:25])[F:24])=[N:11]2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)cc2)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.4 %

Procedure:
To a mixture of 5-(4-bromophenyl)-1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole (670 mg, 1.5 mmol, from step 1), triethylamine (10 mL) and dimethylformamide (2 mL) was added copper(I) iodide (15 mg, 0.08 mmol), bis(triphenylphosphine)palladium(II)chloride (105 mg, 0.15 mmol) and (trimethylsilyl)acetylene (221 mg, 2.25 mmol) at room temperature. The mixture was stirred for 4 hours at room temperature and concentrated. The concentrate was diluted with water (30 mL) and extracted with ethyl acetate (20 mL×3), dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:4) to give title compound (353 mg, 52%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16](B(O)O)=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Br[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[Cl:27].C(=O)([O-])[O-].[Na+].[Na+]>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.CCO.COCCOC.O>[Cl:27][C:26]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[CH:10][C:11]=12
Reactant: OB(O)c1ccnc2c1cnn2-c1ccc(F)cc1
Reactant: Clc1ccncc1Br
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: CCO
Solvent: COCCOC
Solvent: O
Product: Fc1ccc(-n2ncc3c(-c4cnccc4Cl)ccnc32)cc1
Temperature: 105 °C
Yield: 11.3 %

Procedure:
Example 10 was prepared according to the general procedure of Example 1, except that the reaction mixture was heated at 105° C. for 2 h, and using the following materials: Intermediate 5A (40 mg, 0.156 mmol), 3-bromo-4-chloropyridine (53.6 mg, 0.279 mmol), sodium carbonate (61.3 mg, 0.578 mmol), degassed EtOH:DME:H2O (1.2:2.5:1.0 ratio) (1.5 mL) and tetrakis(triphenylphosphine)palladium(0) (25.3 mg, 0.022 mmol). Example 10 was isolated as an off-white solid (5.7 mg, 11%). Purification was done by preparative HPLC (Condition A) using a Phenomenex Luna Axia 30×100 mm S10 column from 35% Solvent B to 100% Solvent B over 12 min, ret. T=11.8 min. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.78-8.86 (2 H, m), 8.74 (1 H, d, J=5.19 Hz), 8.37 (1 H, s), 8.26-8.34 (2 H, m), 7.86 (1 H, d, J=5.19 Hz), 7.43-7.55 (3 H, m). LC/MS (Condition B): ret. T=3.8 min, (M+H)+ 325.00, 326.98. Analytical HPLC: (Condition A): >98%, ret. T=24.69 min, (Condition B): >98%, ret. T=24.45 min, (Condition C): >98%, ret. T=18.88 min, (Condition D): >98%, ret. T=15.00 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](O[C@H](C4C=CC=CC=4)[C@@H](N)C)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.IC1C=CC=C2C=1C=NN2C1C=CC(F)=CC=1.[CH3:45][C@H:46]([NH2:55])[C@H:47]([OH:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[C:12]([O:54][C@H:47]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C@@H:46]([NH2:55])[CH3:45])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Agent: Fc1ccc(-n2ncc3c(I)cccc32)cc1
Product: C[C@H](N)[C@H](Oc1cccc2c1cnn2-c1ccc(F)cc1)c1ccccc1

Procedure:
Prepared according to the protocol described for 1a starting from 4-iodo-1-(4-fluorophenyl)indazole (3b, 332 mg, 0.98 mmol) and (1R,2S)-norephedrine (742 mg, 4.9 mmol). Yield: 150 mg (42%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.F[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1>CN(C)C=O>[O:3]=[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]1[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1
Reactant: Oc1ccccn1
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(-n2ccccc2=O)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 51.8 %

Procedure:
4.4 g of 60% sodium hydride was suspended into 150 ml of N,N-dimethylformamide, to which 10.78 g of 2-hydroxypyridine was added little by little at a room temperature. 30 min after, 12.4 g of 4-fluorobenzaldehyde was added and stirred at 120° C. for 3 hours. The reaction solution was concentrated under a reduced pressure and iced water was added, which was extracted with chloroform. After drying with anhydrous magnesium sulfate, the solvent was distilled off. Resultant crystals were washed with ethyl acetate to obtain 10.3 g of the above-captioned compound as fine gray powder (yield: 52%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](Cl)=[N:6][CH:7]=1.Cl.[CH3:11][C:12]1([C:18]([O:20][CH2:21]C)=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(C(C)C)C(C)C)C.CN1CCCC1=O>O>[Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([N:15]2[CH2:16][CH2:17][C:12]([CH3:11])([C:18]([O:20][CH3:21])=[O:19])[CH2:13][CH2:14]2)=[N:6][CH:7]=1
Reactant: Fc1cc(Br)cnc1Cl
Reactant: CCOC(=O)C1(C)CCNCC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)C1(C)CCN(c2ncc(Br)cc2F)CC1
Temperature: 210 °C
Yield: 47.7 %

Procedure:
5-Bromo-2-chloro-3-fluoropyridine (100 mg, 0.475 mmol), ethyl 4-methyl-piperidine-4-carboxylate hydrochloride (118 mg, 0.57 mmol), ethyldiisopropylamine (248 uL, 1.426 mmol) and 1-methyl-pyrrolidin-2-one (0.5 mL) were transferred to a microwave reaction vial. The vial was sealed and heated at 210° C. for 15 minutes. A further portion of ethyl 4-methyl-piperidine-4-carboxylate hydrochloride (118 mg, 0.57 mmol) was added and the reaction mixture heated for a further 15 min at 210° C. The reaction mixture was diluted with water (25 mL), the pH adjusted to 3 using 1 M HCl, before extraction with DCM (3×25 mL). The organic fractions were combined, dried (cotton wool plug) and concentrated in vacuo to give a crude brown oil. Flash chromatography on silica gel, eluting with DCM (0-100% gradient) in n-hexane gave an impure mixture which was further purified using flash chromatography on silica gel, eluting with 0-4% EtOAc gradient, 4% isocratic, then 4-10% EtOAc in n-hexane to obtain the desired product (75 mg, clear oil). 1H NMR (Acetone) δ 8.05 (dd, J=2.0, 1.1 Hz, 1H), 7.60 (dd, J=12.6, 2.0 Hz, 1H), 4.17 (q, J=7.1 Hz, 1H), 3.83-3.75 (m, 1H), 3.16-3.07 (m, 1H), 2.19-2.11 (m, 1H), 1.60-1.50 (m, 1H), 1.25 (t, J=7.1 Hz, 3H), 1.22 (s, 3H). m/z 345.0, 346.9 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH3:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH:27]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH3:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=2)[CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1Cl
Product: Cc1cc(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)c(NC(=O)OC(C)(C)C)cc1Cl

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-methyl-phenyl)-carbamic acid tert-butyl ester (Example J21) (257 mg, 1.0 mmol) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) (297 mg, 1.0 mmol) according to the general procedure M. Obtained as an off-white foam (370 mg, 77%).
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][C:4]1[CH:5]=[C:6]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O>CCO>[F:19][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[CH:7]=[CH:8][C:9]=1[NH2:10]
Reactant: Cn1cc(-c2ccc([N+](=O)[O-])c(OC(F)F)c2)cn1
Solvent: CCO
Product: Cn1cc(-c2ccc(N)c(OC(F)F)c2)cn1

Procedure:
The title compound was prepared according to the method described for Preparation 158 using 4-(3-(difluoromethoxy)-4-nitrophenyl)-1-methyl-1H-pyrazole (Preparation 214) in EtOH for 40 minutes. The residue was purified by elution through an SCX-2 column using 50% methanol in chloroform followed by 50% chloroform in 7N NH3/MeOH.