Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:14])([Cl:13])[CH2:3][O:4][C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6].[C:15]([C:19]1[CH:20]=[C:21]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[C:22]([O:40][CH3:41])=[C:23]([NH:25][C:26]([C:28]2[N:29]([CH3:39])[C:30]3[C:35]([CH:36]=2)=[CH:34][CH:33]=[CH:32][C:31]=3[CH:37]=O)=[O:27])[CH:24]=1)([CH3:18])([CH3:17])[CH3:16]>>[Cl:14][C:2]([Cl:1])([Cl:13])[CH2:3][O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:37][C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:30]=2[N:29]([CH3:39])[C:28]([C:26](=[O:27])[NH:25][C:23]2[CH:24]=[C:19]([C:15]([CH3:18])([CH3:16])[CH3:17])[CH:20]=[C:21]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[C:22]=2[O:40][CH3:41])=[CH:36]3)[CH2:9][CH2:8]1)=[O:6]
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCNCC1
Reactant: COc1c(NC(=O)c2cc3cccc(C=O)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)OCC(Cl)(Cl)Cl)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Piperazine-1-carboxylic acid 2,2,2-trichloro-ethyl ester and 7-formyl-1-methyl-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide were reacted under the reductive amination conditions described in Example 2 to provide the desired 4-[2-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-ylmethyl]-piperazine-1-carboxylic acid 2,2,2-trichloro-ethyl ester.
Reaction SMILES: [Br:1][CH:2]([CH3:10])[CH:3](OCC)OCC.Cl.C([O-])(O)=O.[Na+].[NH2:17][C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][N:19]=1>CO>[Br:1][C:2]1[CH:3]=[CH:23][C:18]2[N:17]([C:21]([CH3:22])=[CH:20][N:19]=2)[CH:10]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CCOC(OCC)C(C)Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1cnc2ccc(Br)cn12
Temperature: 90 °C
Reaction time: 8 h

Procedure:
2-Bromo-1,1-diethoxypropane (5g) was added to a stirring solution of aq. 1N HCl (15 mL) and heated at 90° C. for 1 h. The clear reaction mixture was cooled to room temperature and treated with solid NaHCO3 till pH 7.0. 2-amino-5-bromopyridine (1.8 G) and MeOH (25 mL) were transferred successively to the above reaction mixture and heated at 90° C. After 8 h, the reaction mixture was concentrated under vacuum by rotary evaporator. The resulting solid concentrate was stirred in CH2Cl2/water (200 mL/75 ml). Organic layer was separated, dried over MgSO4, filtered and concentrated. The crude concentrate was stirred in EtOAc (30 mL) and the solid was collected by filtration to obtain 6-bromo-3-methylimidazo[1,2-a]pyridine as a tan solid (1.6 g). 1H NMR (300 MHz, DMSO-d6): δ 8.55 (s, 1H), 7.50 (d, J=9.5 Hz, 1H), 7.37 (s, 1H), 7.28 (d, J=9.5 Hz, 1H), 2.44 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)(O)[CH3:13])[C:8]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>O=S(Cl)Cl.O>[Cl:1][C:2]1[C:10]2[N:9](/[CH:11]=[C:12](/[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)\[CH3:13])[C:8]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCc2c(c3cccc(Cl)c3n2CC(C)(O)c2ccncc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=S(Cl)Cl
Product: C/C(=C\n1c2c(c3cccc(Cl)c31)CN(C)CC2)c1ccncc1
Temperature: 100 °C

Procedure:
1-(6-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-4-yl)propan-2-ol (650 mg, 1.8 mmol) in SOCl2 (6.5 mL) was stirred at RT for 2 h. The progress of reaction was monitored by TLC and 1H NMR. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in N-methyl-2-pyrrolidone (3 mL), KOH (737 mg, 13.1 mmol) was added and the reaction mixture was heated at 100° C. for 2 h. After it was cooled to RT, the reaction mixture was diluted with water and extracted with EtOAc. Organic was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent 5% MeOH-DCM). 1H NMR (CD3OD, HCl salt) δ (ppm): 8.70 (d, 2H), 7.80 (d, 2H), 7.56 (s, 1H), 7.45 (d, 1H), 7.25 (d, 1H), 7.10 (t, 1H), 4.80 (m, 2H), 3.90 (m, 1H), 3.20 (m, 1H), 3.15 (s, 3H), 1.95 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([Cl:19])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([Cl:19])[CH:13]=2)=[N:28][OH:29])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C(CC(=O)c1cc(Cl)ncc1F)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(CC(=NO)c1cc(Cl)ncc1F)c1ccc(Br)cc1

Procedure:
In analogy to example 74, step 7, from 3-(4-bromo-phenyl)-1-(2-chloro-5-fluoro-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (1.6:1) as a colorless oil, MS (ESI+): m/z=447.733 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][C:9]=1[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([CH3:4])([CH3:3])[CH3:2].Cl[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39]([C:42]([F:45])([F:44])[F:43])(=[O:41])=[O:40].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[C:27]([O:26][C:24](=[O:25])[NH:23][C:9]1[CH:10]=[C:11]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[S:39]([C:42]([F:43])([F:44])[F:45])(=[O:40])=[O:41])[CH:12]=[CH:13][C:8]=1[NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:31])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1NC(=O)OC(C)(C)C
Reactant: O=S(=O)(c1ccccc1Cl)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2S(=O)(=O)C(F)(F)F)cc1NC(=O)OC(C)(C)C
Temperature: 90 °C
Yield: 74.8 %

Procedure:
A mixture of [2-tert-butoxycarbonylamino-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamic acid tert-butyl ester (0.213 g, 0.490 mmol), 1-chloro-2-trifluoromethanesulfonyl-benzene (0.100 g, 0.409 mmol), sodium carbonate (0.260 g, 2.45 mmol), and 1,1′-[bis(di-tert-butylphosphino)ferrocene]-palladium dichloride (0.027 g, 0.0409 mmol) in DME (2 mL) and H2O (0.5 mL) was heated at 90° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography (silica, hexanes: EtOAc, 1:1) to afford the title compound as a yellow solid (0.158 g, 75%).
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][N:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:23].C(N(CC)CC)C>C(O)C>[C:15]1(=[O:23])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][N:14]1[CH2:13][CH2:12][S:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Sc1cccc2nccn12
Reactant: O=C1c2ccccc2CN1CCBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2CN1CCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.9 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (150 mg, 1 mmole) and 2-[2-(bromo)ethyl]isoindolin-1-one (240 mg, 1 mmole) in ethanol (15 ml) was added triethylamine (0.21 ml, 1.5 mmoles) and the mixture was stirred at room temperature for 12 hours and heated at reflux for 2 hours. After the solvent was distilled off, chloroform was added to the residue which was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography [eluent: ethyl acetate/ethanol (15:1)] to obtain 238 mg of the desired product (77.0%, light brown solid).
Reaction SMILES: [F:1][C:2]([CH3:18])([CH3:17])[C@@H:3]([CH:13]1[CH2:16][NH:15][CH2:14]1)[C:4]1[CH:9]=[C:8]([S:10][CH3:11])[CH:7]=[C:6]([F:12])[CH:5]=1.Br[CH:20]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25].C([O-])([O-])=O.[Cs+].[Cs+]>>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C@H:20]([N:15]2[CH2:16][CH:13]([C@@H:3]([C:4]3[CH:9]=[C:8]([S:10][CH3:11])[CH:7]=[C:6]([F:12])[CH:5]=3)[C:2]([F:1])([CH3:18])[CH3:17])[CH2:14]2)[C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])=[CH:34][CH:33]=1
Reactant: CSc1cc(F)cc([C@H](C2CNC2)C(C)(C)F)c1
Reactant: N#Cc1cccc(C(Br)c2ccc(Cl)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CSc1cc(F)cc([C@H](C2CN([C@@H](c3ccc(Cl)cc3)c3cccc(C#N)c3)C2)C(C)(C)F)c1

Procedure:
A sample of 0.233 mg (0.86 mmole) of 3-{(1S)-2-fluoro-1-[3-fluoro-5-(methylthio)phenyl]-2-methylpropyl}azetidine was alkylated with 263 mg (0.86 mmole) of 3-[bromo(4-chlorophenyl)methyl]benzonitrile and 0.975 mg (3 mmole) of Cs2CO3 as described in Step 2 of Example 79 to afford the title compound; Mass Spectrum: m/e=497 (M+1, 35Cl); 499 (M+1, 37Cl)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[CH3:34][C:35]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[CH:37][C:36]=1[N:50]1[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH2:51]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:39]4[CH:38]=[CH:37][C:36]([N:50]5[CH2:51][CH2:52][N:53]([C:56]([O:58][C:59]([CH3:61])([CH3:60])[CH3:62])=[O:57])[CH2:54][CH2:55]5)=[C:35]([CH3:34])[CH:40]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:25])=[O:26])[CH:9]=2)[CH:12]=[N:13]1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)c(C)c4)cnc32)cc1
Yield: 77.4 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of Step-i of example 9) (200 g, 0.380 mmol) was coupled with tert-butyl 4-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (intermediate 69A) (280 mg, 0.694 mmol) using sodium carbonate (121 mg, 1.142 mmol) and Pd(PPh3)2Cl2 (14 mg, 0.019 mmol) in DME/water (15/4 mL). This afforded 212 mg (77.3% yield) of the titled compound after purification by column (Silica gel 60/120) using 15% ethyl acetate in hexane as eluent. MS: m/z=721.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[N:27][CH:28]=[C:29]([CH:33]=2)[C:30](O)=[O:31])[N:21]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:30](=[O:31])[C:29]3[CH:33]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=4)[CH:26]=[N:27][CH:28]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CN)c1csc(-c2ccc(Cl)cc2)n1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Product: CC(C)(CNC(=O)c1cncc(-c2noc(C(F)(F)F)n2)c1)c1csc(-c2ccc(Cl)cc2)n1
Yield: 51 %

Procedure:
This compound was synthesized from 2-(2-(4-chlorophenyl)thiazol-4-yl)-2-methylpropan-1-amine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (50 mg, yield 51%). 1H NMR (400 MHz, CDCl3) δ 9.46 (d, J=1.5 Hz, 1H), 9.24 (d, J=1.8 Hz, 1H), 8.79 (m, 1H), 8.22 (t, J=4.5 Hz, 1H), 7.85-7.83 (d, J=8.5 Hz, 2H), 7.38-7.36 (d, J=8.5 Hz, 2H), 7.09 (s, 1H), 3.72 (d, J=5.5 Hz, 2H), 1.50 (s, 6H). MS (ESI) m/z: Calculated for C22H17ClF3N5O2S: 507.07. found: 508.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[N:30]1([CH2:36][B-](F)(F)F)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.[K+]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:36][N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: F[B-](F)(F)CN1CCCCC1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Agent: [K+]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCCCC3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and potassium piperidin-1-ylmethyltrifluoroborate following a procedure analogous to that described for Intermediate 3. LC (method 5): tR=1.15 min; Mass spectrum (ESI+): m/z=490 [M+H]+.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][N:11]([CH3:16])[CH2:12][CH2:13][CH2:14][NH2:15]>COC(C)(C)C.C(O)(C)C>[CH3:10][N:11]([CH3:16])[CH2:12][CH2:13][CH2:14][NH:15][C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[S:9]
Reactant: S=C=Nc1ccccc1
Reactant: CN(C)CCCN
Solvent: CC(C)O
Solvent: COC(C)(C)C
Product: CN(C)CCCNC(=S)Nc1ccccc1
Reaction time: 2 h
Yield: 70.1 %

Procedure:
Phenyl isothiocyanate (5.283 g, 39.1 mmole) in 30 mL t-butyl methyl ether was added to a solution of 3-(dimethylamino)propylamine (3.993 g, 39.1 mmole) in 10 mL isopropanol. After stirring 2 hr at room temp., the solid which separated was filtered out and washed with t-butyl methyl ether to afford 6.51 g of 1-[3-(dimethylamino)propyl]-3-phenylthiourea (mp 112–114° C.), part of which (2.374 g, 10 mmole) was dissolved in ethanol (20 mL) containing conc. HCl (1.67 mL, 20 mmole) and added to 2-methylnaphthoquinone dissolved in warm ethanol (35 mL). After 4 days in a stoppered flask at room temp., the mixture was concentrated, and dissolved in ethyl acetate. The solid which separated after 16 hr was filtered out, but became sticky on the filter and was discarded. The filtrate was stored another 12 days at room temp. The powder which separated was filtered out to give 600 mg of pinkish-buff powder. Of this, 325 mg was recrystallized from 10 mL methanol+60 mL ethyl acetate containing a few drops of water to give 260 mg of the title compound, mp 238–240° C.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].C(OP(O[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C:15]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28])(OCC)=O)C.[NH4+].[Cl-]>C1COCC1.[Cu]I>[CH2:1]([C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:16][C:15]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:2]
Reactant: CCOC(=O)C1=C(OP(=O)(OCC)OCC)CCN(C(=O)OC(C)(C)C)C1
Reactant: CC[Mg]Br
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(CC)CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
To a slurry of CuI (4.21 g, 22.12 mmol) in THF (61.4 mL) at about 0° C. was added ethylmagnesium bromide (1.0 M in THF, 44.2 mL, 44.2 mmol) dropwise. After about 30 min, the reaction mixture was cooled to about −78° C. and a solution of 1-tert-butyl 3-ethyl 4-(diethoxyphosphoryloxy)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (7.51 g, 18.43 mmol) in THF (61 mL) was added slowly. The reaction mixture was stirred at about −78° C. for about 1 h then warmed to about 0° C. The reaction mixture was stirred at about 0° C. for about 1.5 h, then warmed to ambient temperature and stirred for about 1 h. The reaction mixture was cooled to about −78° C. and saturated aqueous NH4Cl (100 mL) was slowly added. The reaction mixture was allowed to warm to ambient temperature and stirred for about 16 h. The mixture was extracted with Et2O (100 mL). The aqueous layer was further extracted with Et2O (2×50 mL). The organic layers were combined, washed with saturated aqueous NH4Cl (50 mL), dried over anhydrous Na2SO4, filtered, concd under reduced pressure and purified by silica gel chromatography eluting with a gradient of 0-30% EtOAc in heptane to yield 1-tert-butyl 3-ethyl 4-ethyl-5,6-dihydropyridine-1,3(2H)-dicarboxylate (0.785 g, 15%) as a clear oil: 1H NMR (CDCl3) δ 4.23 (d, J=7.1 Hz, 2H), 4.12 (s, 2H), 3.48 (t, J=5.8 Hz, 2H), 2.52 (q, J=7.5 Hz, 2H), 2.28 (t, J=5.8 Hz, 2H), 1.51 (s, 9H), 1.32 (t, J=7.1 Hz, 3H), 1.09 (t, J=7.5 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([O:32][CH3:33])=[C:21]([NH:23][C:24](=[O:31])[CH2:25][C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH3:34][N:35]([CH3:46])[CH:36]1[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[C:41]([NH2:45])[CH:42]=2)[CH2:37]1.Cl>CC(O)C>[CH3:34][N:35]([CH3:46])[CH:36]1[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[C:41]([NH:45][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[CH:19][C:20]([O:32][CH3:33])=[C:21]([NH:23][C:24](=[O:31])[CH2:25][C:26]6[S:27][CH:28]=[CH:29][CH:30]=6)[CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:42]=2)[CH2:37]1
Reactant: CN(C)C1Cc2ccc(N)cc2C1
Reactant: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)Cc1cccs1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CC(N(C)C)C4)n2)cc1NC(=O)Cc1cccs1
Temperature: 180 °C
Yield: 23.1 %

Procedure:
To a solution of N-{5-[3-(2-chloropyrimidin-4-yl)pyrazolo[1,5-a]pyridin-2-yl]-2-methoxyphenyl}-2-(2-thienyl)acetamide (90 mg, 0.19 mmol) in anhydrous i-PrOH (3 mL) was added N2,N2-dimethylindane-2,5-diamine (37 mg, 0.21 mmol) followed by catalytic 12M HCl. After heating for 10 min. in the microwave at 180° C., the reaction was quenched with saturated NaHCO3 (25 mL) and the solvent was removed by rotary evaporation. The aqueous layer was extracted with DCM (25 mL), the organic layer-concentrated, and purified by column chromatography (1-10% MeOH in DCM) to provide the product (27 mg, 24%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 2.18 (s, 6H), 2.65-2.71 (m, 2H), 2.88-2.97 (m, 2H), 3.89 (s, 3H), 3.98 (s, 2H), 6.51 (d, 1H, J=5.3 Hz), 6.94-6.96 (m, 2H), 7.02-7.14 (m, 3H), 7.26-7.28 (m, 1H), 7.35-7.43 (m, 3H), 7.63 (s, 1H), 8.20 (d, 1H, J=5.3 Hz), 8.31 (s, 1H), 8.43 (d, 1H, J=8.9 Hz), 8.79 (d, 1H, J=7.0 Hz) 9.38 (s, 1H), 9.45 (s, 1H) ppm. ES-LC/MS m/z=616 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1Br.[Li]CCCC.Cl[SiH:15]([CH3:17])[CH3:16]>C1COCC1.CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SiH:15]([CH3:17])[CH3:16]
Reactant: Brc1ccccc1Br
Reactant: C[SiH](C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[SiH](C)c1ccccc1Br
Reaction time: 0 h
Yield: 68 %

Procedure:
A microsystem composed of three T-shaped micromixers (M1, M2 and M3) and two microtube reactors (R1 and R2) was used. The whole microsystem was dipped in a cooling bath (−78° C.). A solution of o-dibromobenzene (0.27 M) in THF (flow rate: 6 mL/min, 1.62 mmol/min) and a solution of n-BuLi (1.5 M) in n-hexane (flow rate: 1.2 mL/min, 1.8 mmol/min) were introduced to the first T-shaped mixer M1 (inner diameter: 250 μm) by using syringe pumps. The resulting solution was passed through the tube reactor R1 and was mixed with chlorodimethylsilane (HMe2SiCl) (0.65 M) in THF (flow rate: 3 mL/min, 1.95 mmol/min) in the second T-shaped mixer M2 (inner diameter: 500 μm). The solution was introduced to the third T-shaped mixer M3 (inner diameter: 500 μm), where the solution was quenched with methanol (neat, flow rate=3.0 mmol/min). The residence time of the tube reactor R1 (inner diameter: 500 μm, length=50 cm) was 0.82 second. The residence time of the tube reactor R2 (inner diameter: 1,000 μm, length=50 cm) was 2.31 second. After finishing the reaction, an aliquot of the product solution was taken (15 sec) and was analyzed by GC (column, CBP1; 0.25 mm×25 m; initial oven temperature, 50° C.; rate of temperature increase, 10° C./min). As a result, 2-bromophenyldimethylsilane (GC retention time: 14.9 min) was obtained in 68% yield. 1H NMR (400 MHz, CDCl3) δ: 0.40-0.43 (m, 6H), 4.47-4.53 (m, 1H), 7.14-7.27 (m, 2H), 7.42-7.50 (m, 2H); 13C NMR (100 MHz, CDCl3) δ: −3.5, 126.4, 130.6, 130.9, 132.2, 136.4, 139.1. HRMS (EI) m/z: calcd. for C8H11BrSi 213.9813, found 213.9816.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[C:13]1[CH:21]=[C:17]([C:18]([OH:20])=[O:19])[C:16]([OH:22])=[C:15]([I:23])[CH:14]=1.[CH2:24](O)[CH3:25]>>[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[C:13]1[CH:21]=[C:17]([C:18]([O:20][CH2:24][CH3:25])=[O:19])[C:16]([OH:22])=[C:15]([I:23])[CH:14]=1
Reactant: CCO
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)cc(I)c1O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(-c2ccc(F)cc2F)cc(I)c1O
Reaction time: 0.25 h

Procedure:
11.5 ml of ethyl alcohol and 2.9 ml of thionyl chloride (SOCl2) were placed in a flask under an inert atmosphere. It was stirred for 15 min and 1.67 g (4.56 mmol) of 5-(2,4-difluorophenyl)-3-iodo-salicylic acid was added. It was stirred continuously at room temperature until no evolution was observed by HPLC. The solvent was evaporated at low pressure and extracted with ethyl acetate. A crude of 97% purity was obtained and then purified by chromatography on silica gel.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14].[CH:16](=O)/[CH:17]=[CH:18]/[CH3:19]>>[N+:13]([C:9]1[CH:10]=[N:11][N:12]2[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH:16]2[CH:17]=[CH:18][CH3:19])([O-:15])=[O:14]
Reactant: C/C=C/C=O
Reactant: Nc1ccccc1-c1[nH]ncc1[N+](=O)[O-]
Product: CC=CC1Nc2ccccc2-c2c([N+](=O)[O-])cnn21
Yield: 83 %

Procedure:
5-(o-Aminophenyl)-4-nitropyrazole is reacted with crotonaldehyde as described in Example 11 to give 1-nitro-5-propenyl-5,6-dihydropyrazolo[1,5-c]quinazoline. M.p.: 115°-117° C. Yield: 83%.
Reaction SMILES: Cl[C:2]1C(=O)N[C:5]([C:9](OCC)=O)=[CH:4][CH:3]=1.C(OC([N:21]([C:29]1[CH:34]=[C:33](Cl)[N:32]=[CH:31][N:30]=1)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[CH:4]1(/[CH:3]=[CH:2]/[C:33]2[N:32]=[CH:31][N:30]=[C:29]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH:34]=2)[CH2:5][CH2:9]1
Reactant: CCOC(=O)c1ccc(Cl)c(=O)[nH]1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cc(/C=C/C2CC2)ncn1

Procedure:
A mixture of [(E)-2-cyclopropylvinyl]boronic acid (1, 1.0 g, 8.93 mmol), tert-butyl N-tert-butoxycarbonyl-N-(6-chloropyrimidin-4-yl)carbamate (2, 3.24 g, 9.83 mmol), sodium carbonate (2.84 g, 26.8 mmol), 1,4-dioxane (10 mL) and water (3 mL) in a microwave vial was degassed with argon for 10 minutes. To this mixture 1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.73 g, 0.89 mmol) was added and purged with argon for 5 minutes. After sealing, the vial was irradiated in a microwave reactor at 130° C. for 45 minutes. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×30 mL). The organics were washed with water (2×10 mL) and saturated brine solution (1×10 mL). The organics were then separated, dried with sodium sulfate, and filtered before concentration to dryness. The crude residue was purified by column chromatography (silica, ethyl acetate/hexanes=25%) to obtain tert-butyl N-[6-[(E)-2-cyclopropylvinyl]pyrimidin-4-yl]carbamate (3) as a light brown solid. Yield: 370 mg, 16%; MS (ESI) m/z 262.22 [M+1-Boc]+; 1H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.60 (s, 1H), 7.63 (s, 1H), 6.50 (m, 2H), 1.48 (s, 9H), 0.91 (m, 2H), 0.64 (m, 2H)