Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH3:15])=[C:4]([O:13][CH3:14])[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]=2[C:11]=1[CH3:12].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:2]3[C:3]([CH3:15])=[C:4]([O:13][CH3:14])[C:5]4[O:9][CH:8]([CH3:10])[CH2:7][C:6]=4[C:11]=3[CH3:12])[CH2:26][CH2:25]2)=[CH:22][CH:23]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: COc1c(C)c(Br)c(C)c2c1OC(C)C2
Product: COc1ccc(N2CCN(c3c(C)c4c(c(OC)c3C)OC(C)C4)CC2)cc1
Yield: 54.9 %

Procedure:
By using 5-bromo-7-methoxy-2,4,6-trimethyl-2,3-dihydro-1-benzofuran (542 mg, 2.0 mmol) synthesized in Reference example 83 and 1-(4-methoxyphenyl)piperazine (768 mg, 4.0 mmol), the reaction was carried out in the same manner as Example 21 to synthesize the title compound 420 mg (yield 55%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[C:14]([C:16]4[CH:17]=[C:18]([C:21]([OH:23])=O)[S:19][CH:20]=4)[CH:13]=[N:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:27])=O>ClCCl>[C:1]1([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[C:14]([C:16]4[CH:17]=[C:18]([C:21]([Cl:27])=[O:23])[S:19][CH:20]=4)[CH:13]=[N:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(-c2cnc3c(-c4ccccc4)cnn3c2)cs1
Solvent: ClCCl
Product: O=C(Cl)c1cc(-c2cnc3c(-c4ccccc4)cnn3c2)cs1

Procedure:
A solution of 4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)thiophene-2-carboxylic acid (5-3, 1.0 g, 3.11 mmol, 1 equiv) and oxalyl chloride (2.17 mL, 24.9 mmol, 8.00 equiv) in dichloromethane (400 mL) was stirred at 23° C. for 72 hours. The reaction mixture was concentrated to give 4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)thiophene-2-carbonyl chloride (5-4) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.89 (d, 1H, J=2.4 Hz), 8.79 (d, 1H, J=2.2 Hz), 8.50 (s, 1H), 8.22 (d, 1H, J=1.6 Hz), 8.05 (br d, 2H, J=7.8 Hz), 8.00 (d, 1H, J=1.6 Hz), 7.48 (br t, 2H, J=7.7 Hz), 7.31 (t, 1H, J=7.5 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][N:27]2[CH2:28][CH2:29][CH:24]([C:20]3[CH:19]=[C:18]([NH:17][C:15](=[O:16])[CH:14]([CH3:13])[CH3:30])[CH:23]=[CH:22][CH:21]=3)[CH2:25][CH2:26]2)=[CH:4][CH:3]=1
Reactant: ClCCCOc1ccc(Br)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCOc3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-bromo-4-(3-chloropropoxy)benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.37 (d, 2H, J=7.6 Hz), 7.26 (m, 3H) 6.97 (d, 1H, J=7.7 Hz), 6.79 (d, 2H, J=7.7 Hz), 4.01 (t, 2H, J=5.6 Hz), 3.08 (d, 2H, J=9.4 Hz), 2.53 (m, 4H), 2.05 (m, 4H), 1.84 (m, 4H), 1.24 (d, 6H, J=5.9 Hz); Anal. Calcd for C24H31BrN2O2.HCl+0.34CHCl3: C, 54.5; H, 6.08; N, 5.22. Found: C, 54.5; H, 6.22; N, 5.22; ESMS m/e: 459.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH:18]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:23]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)C1CCCC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C4CCCC4)nc23)CC1
Yield: 83.6 %

Procedure:
Beginning with 0.080 gm (0.348 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.093 mL (0.766 mMol) cyclopentanecarbonyl chloride, 0.095 gm (84%) of the title compound was recovered as an amorphous solid essentially by the procedure described in Example 4.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=[CH:7][CH:6]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH:52]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH2:55][CH2:54][CH2:53]1>CN(C)C=O>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][N:8]=[CH:9][C:10]=1[C:11]([N:52]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH2:55][CH2:54][CH2:53]1)=[O:13]
Reactant: O=C(O)c1cnccc1Oc1cc(Cl)ccc1Cl
Reactant: c1ccc2c(c1)CCCN2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 23 h
Yield: 73 %

Procedure:
To a solution of 0.16 g (0.56 mmol) 4-(2,5-dichloro-phenoxy)-nicotinic acid in 3 mL N,N-dimethylformamide were added 0.225 g (0.59 mmol) O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1) and 0.29 mL (1.69 mmol) N,N-diisopropylethylamine. To the light yellow solution 0.07 mL (0.59 mmol) 1,2,3,4-tetrahydroquinoline (commercially available; CAS RN 635-46-1) was added and the resulting light yellow solution was stirred at room temperature for 23 hours. The reaction mixture was poured on water and extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The resulting powder was purified by silica gel chromatography using a MPLC system (20 g silica gel column, CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 50:50). The product-containing fractions were combined and evaporated to give 165 mg (73%) of the desired compound as a light brown solid. MS (ESI): m/z=399.06 [M+H]+.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:17])[NH:9][C:10]2[S:11][CH:12]=[C:13]([CH:15]=O)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:18]1[CH2:24][C:22](=[O:23])[N:21]([CH2:25][C:26]([OH:28])=[O:27])[C:19]1=[S:20].N1CCCCC1>C(O)C>[C:1]1([NH:7][C:8](=[O:17])[NH:9][C:10]2[S:11][CH:12]=[C:13]([CH:15]=[C:24]3[S:18][C:19](=[S:20])[N:21]([CH2:25][C:26]([OH:28])=[O:27])[C:22]3=[O:23])[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1csc(NC(=O)Nc2ccccc2)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C(O)CN1C(=O)C(=Cc2csc(NC(=O)Nc3ccccc3)n2)SC1=S
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
A mixture comprising 1 g of 2-(3-phenylureido)thiazole-4-carbaldehyde, 0.85 g of rhodanine-3-acetic acid, 0.76 g of piperidine and 15 ml of ethanol was stirred at room temperature for 2 hours, and the resulting mixture was left to stand overnight. The crystals which precipitated out were collected by filtration dispersed in dilute aqueous hydrochloric acid, and washed with stirring for 30 minutes. The resulting crystalline product was recrystallized from a mixture of acetic acid and ethyl acetate, giving 0.78 g of the desired compound as an orange powder.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:16]4[CH:17]=[N:18][CH:19]=[N:20][CH:21]=4)=[CH:9][CH:10]=3)[C:5]3([CH2:25][S:24][C:23]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[N:22]3)[C:4]=2[CH:3]=1.[CH3:31][C:32]([CH3:36])([CH3:35])[C:33]#[CH:34].C(NC(C)C)(C)C>[Cu]I.CN(C=O)C>[C:27]([NH:26][C:23]1[S:24][CH2:25][C:5]2([N:22]=1)[C:4]1[CH:3]=[C:2]([C:34]#[C:33][C:32]([CH3:36])([CH3:35])[CH3:31])[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:16]2[CH:21]=[N:20][CH:19]=[N:18][CH:17]=2)=[CH:9][CH:10]=1)([CH3:29])([CH3:28])[CH3:30]
Reactant: C#CC(C)(C)C
Reactant: CC(C)(C)NC1=NC2(CS1)c1cc(Br)ccc1Oc1ccc(-c3cncnc3)cc12
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC(C)(C)C#Cc1ccc2c(c1)C1(CSC(NC(C)(C)C)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A resealable tube was charged with (t-4)-tetrakis(triphenylphosphine)palladium (27.1 mg, 0.023 mmol), copper(i) iodide (8.94 mg, 0.047 mmol),2′-bromo-N-tert-butyl-7′-(pyrimidin-5-yl)-5H-spiro[thiazole-4,9′-xanthen]-2-amine (113 mg, 0.235 mmol), 3,3-dimethylbut-1-yne (144 μL, 1.174 mmol), diisopropylamine (669 μL, 4.69 mmol) and DMF (1.9 mL). The mixture was heated at 80° C. After 18 hrs, the mixture was cooled to RT, filtered through celite with EtOAc, and concentrated in vacuo. The residue was adsorbed onto silica gel and purified by silica gel chromatography using 30-75% Hexanes:EtOAc to afford N-tert-butyl-2′-(3,3-dimethylbut-1-ynyl)-7′-(pyrimidin-5-yl)-5H-spiro[thiazole-4,9′-xanthen]-2-amine as an off-white foam. MH+=483.2.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1>>[F:24][C:21]1[CH:22]=[CH:23][C:18]2[N:19]([CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=2)[CH:20]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Reactant: Nc1ccc(F)cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(F)ccc2n1
Yield: 13 %

Procedure:
As described for Example 2, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (112 mg, 0.4 mmol) was converted, using 2-amino-5-fluoropyridine instead of 2-amino-3-methylpyridine, to the title compound (15 mg, 13%) which was obtained as a yellow solid. MS: m/e=294.3 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[NH:7][CH2:8][C:2]1=2.[C:10](OC(NC1(C(O)=O)CC1)=O)(C)(C)[CH3:11]>>[NH:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[NH:7][C:8]3([CH2:11][CH2:10]3)[C:2]1=2
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: O=C1NCc2[nH]ccc21
Product: O=C1NC2(CC2)c2[nH]ccc21

Procedure:
This compound was prepared in a manner similar to that described for Intermediate 703, starting from 1-((tert-butoxycarbonyl)amino)cyclopropanecarboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.08 (1H, br.), 7.53 (1H, s), 6.82 (1H, s), 6.11 (1H, d, J=2.2 Hz), 1.3 (2H, m), 1.27 (2H, m). m/z (ESI, +ve) 149.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1I.[CH2:10]([O:12][C:13](OCC)([O:16]CC)[C:14]#[CH:15])[CH3:11]>C(#N)C.CCOC(C)=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:15]#[C:14][C:13]([O:12][CH2:10][CH3:11])=[O:16]
Reactant: C#CC(OCC)(OCC)OCC
Reactant: Clc1ccc(Br)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C#Cc1cc(Cl)ccc1Br
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 55.2 %

Procedure:
A suspension of 1-bromo-4-chloro-2-iodobenzene (5.4 g, 17.0 mmol), 3,3,3-triethoxyprop-1-yne (4.4 g, 25.6 mmol), copper(I) iodide (976 mg, 5.1 mmol), and trans-dichlorobis(triphenylphosphine)palladium(II) (1.19 g, 1.7 mmol) in ACN (60 mL) was degassed and backfilled with argon. The resulting mixture was treated with TEA (22.0 mL, 157.9 mmol). The reaction flask was capped with a septum and stirred at 23° C. After 90 minutes, the reaction was diluted with EtOAc (300 mL) and washed with water (150 mL). The aqueous layer was extracted with EtOAc (300 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, concentrated in vacuo, dissolved in EtOH (50 mL) and water (5 mL) and then treated with p-toluenesulfonic acid monohydrate (5 mg). After stirring at 23° C. for 60 minutes, the solution was concentrated, dissolved in diethyl ether (300 mL) and washed with saturated NaHCO3 solution (100 mL), water (100 mL) and brine (100 mL), dried over MgSO4, and concentrated in vacuo affording 2.7 g of ethyl 3-(2-bromo-5-chlorophenyl)propiolate.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([N:13]3[CH2:18][CH2:17][CH:16]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15][CH2:14]3)[CH:7]=[CH:8][CH:9]=2)[N:4]=1)=O.[NH:28]([C:30]1[CH:35]=[C:34]([I:36])[CH:33]=[CH:32][N:31]=1)[NH2:29]>>[I:36][C:34]1[CH:33]=[CH:32][N:31]=[C:30]([NH:28][N:29]=[CH:1][C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[C:6]([N:13]4[CH2:14][CH2:15][CH:16]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:26])[CH3:24])[CH2:17][CH2:18]4)[CH:7]=[CH:8][CH:9]=3)[N:4]=2)[CH:35]=1
Reactant: NNc1cc(I)ccn1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(C=O)nc23)CC1
Product: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(C=NNc4cc(I)ccn4)nc23)CC1

Procedure:
Prepared as described in Example 1, steps D-E, using tert-butyl (1-(2-formylquinolin-8-yl)piperidin-4-yl)methylcarbamate in place of 8-(tert-butyldimethylsilyloxy)quinoline-2-carbaldehyde, and 2-hydrazinyl-4-iodopyridine in place of 2-Hydrazinyl-4-(2-methoxyethoxy)pyridine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[C:3]([C:10]([OH:12])=[O:11])[CH:2]=1>C(OC(=O)C)(=O)C>[N:1]1[CH:6]=[CH:5][C:4]2[C:7]([O:12][C:10](=[O:11])[C:3]=2[CH:2]=1)=[O:9]
Reactant: O=C(O)c1ccncc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cnccc21
Yield: 75.5 %

Procedure:
A mixture of pyridine 3,4-dicarboxylic acid (15.0 g) and acetic anhydride (30 mL) is refluxed for two hours. The excess acetic anhydride is removed by distillation and the anhydride is collected and purified by sublimation (123° C. at 3 mm Hg) to yield pyridine 3,4-dicarboxylic acid anhydride as a white solid (10.1 g).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][C:13]3[S:14][C:15]([C:18](=[NH:21])[NH:19]O)=[CH:16][N:17]=3)[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:3]1.C(OC(=O)C)(=O)C>C(O)(=O)C.[Pd]>[C:18]([C:15]1[S:14][C:13]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]3[CH:4]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)=[N:17][CH:16]=1)(=[NH:19])[NH2:21]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ncc(C(=N)NO)s3)cc(C)c21
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3ncc(C(=N)N)s3)cc(C)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of crude ethyl 2-(1-hydroxy-6-(5-(N-hydroxycarbamimidoyl)thiazol-2-yloxy)-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (6.2 g crude) in 30 ml of acetic acid was added 400 ul of acetic anhydride. After the mixture was stirred at room temperature for one and half hour, it was treated with palladium (10% wet on charcoal, 1.8 g) and then hydrogenation on Parr-shaker for five hours. The mixture was filtered through a Celite pad and the filtrate was concentrated and dried under hi-Vac to give the crude product. The crude was used in subsequent steps without further purification.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]2[N:9]=[C:10]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[C:11]([C:12]([NH:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[O:21][CH3:22])=[O:13])=[C:5]2[N:4]=1.CN(C=O)C.O=S(Cl)[Cl:37]>C(Cl)Cl>[Cl:37][CH2:2][C:3]1[CH:8]=[CH:7][N:6]2[N:9]=[C:10]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[C:11]([C:12]([NH:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[O:21][CH3:22])=[O:13])=[C:5]2[N:4]=1
Reactant: COc1ccncc1NC(=O)c1c(NC(=O)C(F)(F)F)nn2ccc(CO)nc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccncc1NC(=O)c1c(NC(=O)C(F)(F)F)nn2ccc(CCl)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude 5-(hydroxymethyl)-N-(4-methoxy-3-pyridyl)-2-[(2,2,2-trifluoroacetyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxamide prepared in step 2 above (50 mg, 0.1219 mmol) and DMF (44.55 mg, 47.19 μL, 0.6095 mmol) were suspended in dry DCM (1.25 mL). SOCl2 (72.51 mg, 44.46 μL, 0.6095 mmol) was added dropwise and the resulting mixture was stirred at RT for ˜2 h. The bright yellow suspension was filtered and the collected solid was washed with DCM (1 mL) and ether (3×1 mL) to give a light yellow powder (49.6 mg). LC-MS (M+H)+ 429.1; 1H NMR (500 MHz, DMSO-d6) δ 11.78 (s, 1H), 10.60 (s, 1H), 9.63 (s, 1H), 9.50 (d, J=7.1 Hz, 1H), 8.71 (d, J=6.4 Hz, 1H), 7.80 (d, J=6.6 Hz, 1H), 7.62 (d, J=7.1 Hz, 1H), 5.07 (s, 2H), 4.34 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1)=[O:2].S(=O)(=O)([OH:31])N.Cl([O-])=O.[Na+]>O1CCCC1.O>[CH3:28][O:27][C:25]([CH2:24][CH2:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][C:11]2[CH:10]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]([OH:31])=[O:2])[CH:4]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:22][CH:21]=1)=[O:26]
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3cccc(C=O)c3)c2)cc1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OCc2cccc(-c3cccc(C(=O)O)c3)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.5 %

Procedure:
To a solution of methyl 4-[(3′-formyl-[1,1′-biphenyl]-3-yl) methoxy]benzenepropanoate (0.48 g, 1.3 mmol) in tetrahydrofuran (5 mL) and water (2 mL) was added sulfamic acid (0.15 g, 1.3 mmol), and a solution of sodium chlorite (0.17 g, 1.5 mmol) in water (1.5 mL) was added. The mixture was stirred at room temperature for 15 hrs., and water was added. The mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure to give the title compound 0.50 g (quantitative).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Br:12]N1C(=O)CCC1=O.O>C(O)(=O)C>[Br:12][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(Br)c(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 66.9 %

Procedure:
3-Chloro-2-nitroaniline (5.00 g, 29.0 mmol) was dissolved in glacial acetic Acid (258 mL). N-Bromosuccinimide (5.06 g, 28.4 mmol) was added and the resulting mixture was refluxed for 1 hour. The reaction was cooled to room temperature and poured into water to give a precipitate that was filtered, rinsed with water and dried to constant weight to give the title compound (4.78 g, 67%). 1H NMR (400 MHz, CDCL3) δ ppm 7.46 (d, J=9.0, 1H), 6.64 (d, J=9.0, 1H), 4.74 (s, 2H).
Reaction SMILES: [NH:1]([C:8]([CH3:10])=[O:9])[C@H:2]([C:5]([OH:7])=O)[CH2:3][OH:4].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[Cl:32][C:33]1[CH:34]=[C:35]([CH:40]([NH:43][C:44]([C:46]2[NH:47][CH:48]=[C:49]([C:51]3[C:55]([C:56]4[CH:61]=[CH:60][C:59]([CH2:62][NH2:63])=[C:58]([Cl:64])[CH:57]=4)=[CH:54][NH:53][N:52]=3)[CH:50]=2)=[O:45])[CH2:41][OH:42])[CH:36]=[CH:37][C:38]=1[F:39]>CN(C=O)C>[Cl:32][C:33]1[CH:34]=[C:35]([CH:40]([NH:43][C:44]([C:46]2[NH:47][CH:48]=[C:49]([C:51]3[C:55]([C:56]4[CH:61]=[CH:60][C:59]([CH2:62][NH:63][C:5](=[O:7])[CH:2]([NH:1][C:8](=[O:9])[CH3:10])[CH2:3][OH:4])=[C:58]([Cl:64])[CH:57]=4)=[CH:54][NH:53][N:52]=3)[CH:50]=2)=[O:45])[CH2:41][OH:42])[CH:36]=[CH:37][C:38]=1[F:39]
Reactant: CC(=O)N[C@@H](CO)C(=O)O
Reactant: NCc1ccc(-c2c[nH]nc2-c2c[nH]c(C(=O)NC(CO)c3ccc(F)c(Cl)c3)c2)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)NC(CO)C(=O)NCc1ccc(-c2c[nH]nc2-c2c[nH]c(C(=O)NC(CO)c3ccc(F)c(Cl)c3)c2)cc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of N—Ac-Ser-OH (0.2 mmol) in DMF (5 mL) was added HOBt (0.4 mmol) and EDCI (0.22 mmol) and stirred for 5 min. To the solution was added benzyl amine 11 (0.2 mmol) and TEA (0.3 mmol). The reaction mixture was stirred for 2 h at room temperature. The crude products were purified from preparatory HPLC to afford the desired product II-20 as a white solid. 1HNMR (CD3OD) 8.5 (br, 1H), 7.6 (s, 1H), 7.5 (m, 1H), 7.4 (s, 1H), 7.2-7.3 (m, 3H), 7.1 (t, 1H), 6.8-6.9 (m, 2H), 5.0 (t, 1H), 4.2-4.4 (m, 3H), 3.6-3.7 (m, 4H), 1.9 (s, 3H).
Reaction SMILES: [F-:1].[K+].[Cl-].[NH4+].[Cl:5][C:6]1[CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:10][C:11]=1Cl>C1(C)C(C)=CC=CC=1>[Cl:5][C:6]1[CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:10][C:11]=1[F:1]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: [F-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccc(F)c(Cl)c1
Yield: 71 %

Procedure:
In a 1-liter flange flask fitted with a distillation bridge and impeller stirrer, 240 g (4.1 mol) of potassium fluoride, 30 g (0.05 mol) of dimethyldi (ethoxypolyoxypropyl methyl ether)ammonium chloride and 30 g of xylene were introduced at 70° C. into the melt of 767 g (4.0 mol) of 3,4-dichloronitrobenzene, and the reaction suspension was azeotropically dried under reduced pressure up to 120° C. 498 g (2.84 mol) of 3-chloro-4-fluoronitrobenzene were isolated. Amount of 3-chloro-4-fluoronitrobenzene formed, according to GC analysis:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]2[C:10]([C:13]([NH:15][C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[CH:18]=[N:19][N:20]4[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:14])=[CH:11][N:12]=[C:6]2[CH:5]=1)(=O)[CH3:2].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[CH2:25]([N:20]1[C:21]2[C:17](=[C:16]([NH:15][C:13]([C:10]3[N:7]4[CH:8]=[CH:9][C:4]([CH:1]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH3:2])=[CH:5][C:6]4=[N:12][CH:11]=3)=[O:14])[CH:24]=[CH:23][CH:22]=2)[CH:18]=[N:19]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C1COCCN1
Reactant: CC(=O)c1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3ccccc3)cnc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(c1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3ccccc3)cnc2c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7-acetyl-N-(1-benzyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 146; 10.8 mg, 0.026 mmol) in DCM (0.6 mL) was added morpholine (3 equivalents). The resulting solution was stirred at ambient temperature for two hours, after which sodium triacetoxyborohydride (28 mg, 0.13 mmol, 5 equivalents) was added. The resulting suspension was stirred at ambient temperature for 100 hours. The reaction was quenched with excess saturated aqueous sodium bicarbonate, and the resulting suspension was extracted with EtOAc and DCM. The combined organic extracts were dried over anhydrous sodium sulfate, and concentrated to afford the crude product. The crude product was subjected to preparative thin-layer chromatography on silica with MeOH/DCM as eluent to afford 0.3 mg of the desired product as a white solid. MS (ES+APCI) m/z=481 (M+H) detected.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13](=[O:17])[NH:14][CH2:15][CH2:16][C:11]=3[NH:10][C:9]=2[CH:18]=O)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[NH:26][C:25](=[O:39])[CH2:24]2>>[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[NH:26][C:25](=[O:39])[C:24]2=[CH:18][C:9]1[NH:10][C:11]2[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C:12]=2[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=C1Cc2cc(F)c(NCc3ccc(F)cc3)cc2N1
Reactant: O=Cc1[nH]c2c(c1-c1ccc(F)cc1)C(=O)NCC2
Product: O=C1Nc2cc(NCc3ccc(F)cc3)c(F)cc2C1=Cc1[nH]c2c(c1-c1ccc(F)cc1)C(=O)NCC2
Yield: 43.5 %

Procedure:
The title compound was prepared under the same conditions as described in Example 46 with 3-(4-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-fluoro-6-(4-fluoro-benzylamino)-1,3-dihydro-indol-2-one as starting materials to give 2-[5-fluoro-6-(4-fluoro-benzylamino)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-(4-fluoro-phenyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (34 mg, 43.5%) as a red solid.