Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:33]=[C:32]5[C:27]([CH2:28][CH2:29][N:30]([CH3:34])[CH2:31]5)=[CH:26][CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[CH2:40][C:41](Cl)=[O:42]>>[CH3:34][N:30]1[CH2:29][CH2:28][C:27]2[C:32](=[CH:33][C:24]([NH:23][C:19]3[N:18]=[C:17]([C:16]4[C:8]([C:4]5[CH:3]=[C:2]([NH:1][C:41](=[O:42])[CH2:40][C:36]6[S:35][CH:39]=[CH:38][CH:37]=6)[CH:7]=[CH:6][CH:5]=5)=[N:9][N:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=45)[CH:22]=[CH:21][N:20]=3)=[CH:25][CH:26]=2)[CH2:31]1
Reactant: O=C(Cl)Cc1cccs1
Reactant: CN1CCc2ccc(Nc3nccc(-c4c(-c5cccc(N)c5)nn5ccccc45)n3)cc2C1
Product: CN1CCc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)Cc6cccs6)c5)nn5ccccc45)n3)cc2C1
Yield: 89 %

Procedure:
The title compound was prepared from N-{4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-2-methyl-1,2,3,4-tetrahydro-7-isoquinolinamine and 2-thiopheneacetyl chloride using acylation conditions described in Example 1, Step F to generate the product in 89% yield. 1H NMR (400 MHz, DMSO-d6): δ 2.31 (s, 3H), 2.57 (t, 2H, J=5.7 Hz), 2.74 (t, 2H, J=5.6 Hz), 3.38 (s, 2H), 3.88 (s, 2H), 6.47 (d, 1H, J=5.3 Hz), 6.97 (m, 3H), 7.13 (t, 1H, J=6.8 Hz), 7.27 (d, 1H, J=7.5 Hz), 7.38-7.50 (m, 5H), 7.75 (d, 1H, J=8.1 Hz), 7.90 (s, 1H), 8.23 (d, 1H, J=5.3 Hz), 8.46 (d, 1H, J=8.6 Hz), 8.83 (d, 1H, J=7.0 Hz), 9.43 (s, 1H), 10.36 (s, 1H). ES-LC/MS m/z=572 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH3:12][C:13]([CH3:17])([CH3:16])[C:14]#[CH:15]>C(N(CC)CC)C.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:15]#[C:14][C:13]([CH3:17])([CH3:16])[CH3:12])[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: C#CC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)C#Cc1ccc(C(=O)O)c(Cl)n1
Yield: 5 %

Procedure:
2,6-dichloropyridine-3-carboxylic acid (2.0 g, 10.42 mmol), 3,3-dimethylbut-1-yne (1.4 mL, 11.46 mmol), copper(I) iodide (0.198 g, 1.04 mmol) and bis(triphenylphosphine) palladium(II) chloride (1.46 g, 2.08 mmol) were stirred in 40 mL triethylamine at room temperature for 24 h. The solvent was removed in vacuo and the residue was purified by column chromatography using 10-50% MeOH/EtOAc to furnish 125 mg (5%) of the title compound as an orange solid. m/z=236 (M−1).
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([C:26]([OH:28])=O)[CH:21]=2)=[N:11][NH:10]1.Cl.[CH:30]1([O:35][CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:34][CH2:33][CH2:32][CH2:31]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CC(N(C)C)=O>[CH:30]1([O:35][CH:36]2[CH2:41][CH2:40][N:39]([C:26]([C:22]3[CH:21]=[C:20]([CH2:19][C:12]4[C:13]5[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=5)[C:9](=[O:8])[NH:10][N:11]=4)[CH:25]=[CH:24][N:23]=3)=[O:28])[CH2:38][CH2:37]2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: C1CCC(OC2CCNCC2)C1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccn1)N1CCC(OC2CCCC2)CC1
Temperature: 20 °C
Reaction time: 72 h
Yield: 8.3 %

Procedure:
Triethylamine (0.452 ml, 3.24 mmol) was added in one portion to 4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)picolinic acid (5) (304 mg, 1.08 mmol), 4-(cyclopentyloxy)piperidine hydrochloride (183 mg, 1.08 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (533 mg, 1.41 mmol) in DMA (3 ml) at 20° C. under air. The resulting mixture was stirred at 20° C. for 3 days. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white solid (39 mg, 8.3% yield); 1H NMR (400.132 MHz, DMSO) δ 1.28-1.74 (11H, m), 1.82-1.88 (1H, m), 3.08-3.14 (1H, m), 3.20-3.27 (1H, m), 3.44-3.49 (1H, m), 3.53-3.59 (1H, m), 3.96-4.05 (2H, m), 4.40 (2H, s), 7.39 (1H, d), 7.49 (1H, s), 7.83-7.96 (3H, m), 8.28 (1H, d), 8.47 (1H, d), 12.60 (1H, s); m/z (LC-MS, ESI+), RT=1.88 (M+H 433.1).
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:10][C:11]1[CH:12]=[C:13]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=1)=[O:15]>C(O)(C(F)(F)F)=O.C(O)(C)C>[C:4]([C:3]1[C:2]([NH:10][C:11]2[CH:12]=[C:13]([CH:26]=[CH:27][C:28]=2[CH3:29])[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=2)=[O:15])=[N:9][CH:8]=[CH:7][CH:6]=1)#[N:5]
Reactant: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1N
Reactant: N#Cc1cccnc1Cl
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1Nc1ncccc1C#N
Temperature: 130 °C

Procedure:
To 2-chloronicotinonitrile (140 mg, 1.00 mmol) and 3-amino-N-(3-isopropyl-phenyl)-4-methyl-benzamide (80 mg, 0.30 mmol) was added isopropanol (0.8 mL) and TFA (12 drops). The mixture was heated to 130° C. for 16 hours in a sealed tube. The cooled mixture was purified by silica gel chromatography (25% EtOAc/hexanes) to yield 3-(3-cyanopyridin-2-ylamino)-N-(3-isopropylphenyl)-4-methylbenzamide. MS m/z [M+H]+=371; Calc'd for C23H22N4O: 370.46.
Reaction SMILES: [C:1]1([C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][N:9]=[C:10]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[C:11]([O-])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([NH+](CC)CC)C.C(Cl)(=O)C([Cl:41])=O.CN(C)C=O>C(Cl)Cl>[C:1]1([C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][N:9]=[C:10]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[C:11]([Cl:41])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C([O-])C(=NOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1cccs1
Agent: CC[NH+](CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C(=NOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1cccs1
Reaction time: 2 h
Yield: 103 %

Procedure:
A solution of triethylammonium 2-triphenylmethoxyimino-2-(thien-2-yl)-acetate (syn isomer) (2.30 g, 4.46 mmole) in dry methylene chloride (50 ml) was cooled to 0° to +5° and stirred whilst oxalyl chloride (0.38 ml, 4.46 mmole) was added. N,N-Dimethylformamide (ca 0.1 ml) was added and the mixture was stirred at 0° to +5° for 21/2 hours. The solvent was evaporated and the residue was stirred with ether (100 ml) for 1 hour, and the suspension then filtered. The filtrate and ether washings (100 ml) were evaporated to give the title compound as a white crystalline solid (1.985 g, quantitative). This acid chloride was used without further purification.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])C=2OC)[CH2:10][CH2:9]1)=O)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].C[CH2:34][O:35]CC>>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[CH3:22][O:21][C:17]1[C:18]([O:35][CH3:34])=[CH:19][CH:20]=[CH:15][C:14]=1[C:11]1([CH:28]=[O:30])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CCOCC
Reactant: COc1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1OC
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(C2(C=O)CCNCC2)c1OC
Reaction time: 0.75 h

Procedure:
4-(2,3-Dimethoxybenzoyl)-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (7.75 g, 22.2 mmol) was dissolved in trifluoroacetic acid (50 mL, 650 mmol) and stirred for 45 minutes. The entire solution was poured into ether (900 mL) and allowed to stand overnight. Filtration yielded 4-(2,3-dimethoxyphenyl)-4-piperidinylmethanone trifluoroacetate as fine white needles, m.p. 123° C. Anal. Calcd for C14H19NO3.CF3CO2H: C, 52.89; H, 5.55; N, 3.86. Found: C, 52.77; H, 5.62; N, 3.82.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([SH:13])[CH2:10][C@H:9]1[CH2:14][N:15]([C:25](=[O:27])[CH3:26])[CH2:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[F:24])=[O:7])[CH2:2][CH2:3][CH3:4].[C:28](Cl)(=[O:30])[CH3:29]>N1C=CC=CC=1.C(Cl)Cl>[CH2:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][C:28](=[O:30])[CH3:29])[CH2:10][C@H:9]1[CH2:14][N:15]([C:25](=[O:27])[CH3:26])[CH2:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[F:24])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)Cl
Reactant: CCCCOC(=O)N1C[C@H](S)C[C@H]1CN(Cc1cc(F)ccc1F)C(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCOC(=O)N1C[C@H](SC(C)=O)C[C@H]1CN(Cc1cc(F)ccc1F)C(C)=O
Temperature: 25 °C
Yield: 82.2 %

Procedure:
130 mg (0.325 mmol) [2S,4R]-2-{[acetyl-(2,5-difluoro-benzyl)-amino]-methyl}-4-mercapto-pyrrolidine-1-carboxylic acid butyl ester in 3 ml pyridine were treated with 120 μl (1.68 mmol, 5.1 eq) acetyl chloride at 0° C. The resulting suspension was diluted with 8 ml CH2Cl2, and the mixture was stirred at RT over night, concentrated in vacuo and the oil was redissolved in EtOAc/1M HCl. The inorganic phase was extracted with CH2Cl2 and the organic phases were washed with 1M HCl and brine, dried over Na2SO4. The crude product was purified by flash column chromatography with EtOAc/hexane 1:1 as eluent yielding 118.2 mg (82%) [2S,4R]-2-{[acetyl-(2,5-difluoro-benzyl)-amino]-methyl}-4-acetylsulfanyl-pyrrolidine-1-carboxylic acid butyl ester as light yellow oil, MS: 443 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][CH:3]=1.[BH3-]C#[N:15].[Na+]>C(O)(C)C>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[NH2:15])=[CH:4][CH:3]=1
Reactant: Cc1c(Cl)ccc2c1C(=O)CC2
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1c(Cl)ccc2c1C(N)CC2

Procedure:
6-Chloro-7-methyl-1-indanone (2.50 g, 14.00 mmol), NaBH3CN (6.00 g, 95.48 mmol) and NH4OAc (32.04 g, 0.42 mol) in isopropanol were reacted according to the protocols as outlined in general procedure C to give the title indanamine. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ 1.5 (br s, 2H), 1.84-1.93 (m, 1H), 2.30-2.45 (m, 4H), 2.72-2.88 (m, 1H), 3.02-3.16 (m, 1H), 4.40-4.50 (m, 1H), 7.0 (d, 1H, J=7.9 Hz), 7.2 (d, 1H, J=8.2 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([B:7]([OH:9])[OH:8])[S:5][CH:6]=1.O[C:11]([C:14](O)([CH3:16])[CH3:15])([CH3:13])[CH3:12]>>[CH3:12][C:11]1([CH3:13])[C:14]([CH3:16])([CH3:15])[O:9][B:7]([C:4]2[S:5][CH:6]=[C:2]([CH3:1])[CH:3]=2)[O:8]1
Reactant: CC(C)(O)C(C)(C)O
Reactant: Cc1csc(B(O)O)c1
Product: Cc1csc(B2OC(C)(C)C(C)(C)O2)c1
Yield: 54 %

Procedure:
The title compound (54%, oil) was prepared from 4-methylthiophen-2-yl-boronic acid and pinacol.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.O.[Pd]>[CH3:21][O:20][CH:17]1[CH2:18][CH2:19][N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:15][CH2:16]1
Reactant: COC1CCN(C2CCN(Cc3ccccc3)CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COC1CCN(C2CCNCC2)CC1
Reaction time: 8 h

Procedure:
A suspension of 2.1 (5.87 mmol) 1′-benzyl-4-methoxy-[1,4′]bipiperidinyl and 1.0 g 10% Pd/C in 50 mL MeOH and 20 mL water was hydrogenated for 8 h at RT and 3 bar hydrogen pressure. The catalyst was removed by suction filtering, the filtrate was concentrated by evaporation i.vac., the residue was triturated with diethyl ether, suction filtered and dried.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][C:29]3[CH:33]=[CH:32][N:31]([CH:34]([CH3:36])[CH3:35])[N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.[C:37]([CH2:39][C:40](O)=[O:41])#[N:38].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[C:37]([CH2:39][C:40]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][C:29]3[CH:33]=[CH:32][N:31]([CH:34]([CH3:36])[CH3:35])[N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1)=[O:41])#[N:38]
Reactant: N#CCC(=O)O
Reactant: CC(C)n1ccc(Nc2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ccc(Nc2cc(N[C@H]3CC[C@H](NC(=O)CC#N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of Example 48 and 2-cyanoacetic acid (4.01 mg, 0.047 mmol) in DCM (1 mL) was added DIEA (0.035 mL, 0.200 mmol) and BOP (20.87 mg, 0.047 mmol). The mixture was stirred at room temperature for 30 minutes and then concentrated. The crude reaction mixture was purified by reversed-phase preparative HPLC to give the title compound (8.1 mg, 61%) as white solid. HPLC Rt=2.981 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm), [M+H]=560.
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8]P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)([O-])=O>O1CCCC1>[CH:33]1[CH:40]=[CH:39][C:36](/[CH:37]=[CH:8]/[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:29][CH:28]=2)=[CH:35][CH:34]=1
Reactant: O=[N+]([O-])c1ccc(C[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In an embodiment of the invention, a method for preparing the aforesaid alignment film in a laboratory level is illustrated as an example. 10 g of 4-nitrobenzyl bromide is mixed with 12 g of triphenylphosphine and dissolved in 150 ml of a dry tetrahydrofuran solution, heated to 75° C. and agitated under reflux for 48 hours, to obtain 8.2 g of a dry white p-nitrobenzyl triphenylphosphine. The p-nitrobenzyl triphenylphosphine is mixed with 2.6 g of p-nitrobenzaldehyde in a 150 ml tetrahydrofuran solution, and agitated under room temperature for about 24 hours to obtain 4.2 g of p-nitrostilbene. The resultant p-nitrostilbene is mixed with 14.7 g of tin dichloride, dissolved in a mixed solution of 30 ml/40% hydrochloride acid and 100 ml acetone, agitated under the room temperature for about 2 hours and refluxed for 8 hours to obtain p-aminostilbene. The p-aminostilbene is mixed with 9,9′-bianthracyl tetracarboxylic dianhydride in a dry NMP (N-methyl-pyrrolidone) solution under agitation for 24 hours, under protection of nitrogen gas, to obtain the precursor of the polyimide alignment film involved in the embodiment. The precursor is heated to 230° C. to obtain the final alignment film, which is a light sensitive alignment film.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[NH2:12][NH2:13].CCN(C(C)C)C(C)C>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6]([NH2:7])=[N:12][NH:13]2)=[C:8]([F:10])[CH:9]=1
Reactant: N#Cc1c(F)cc(Br)cc1F
Reactant: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1n[nH]c2cc(Br)cc(F)c12
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 410.7 %

Procedure:
Five batches of the below reaction were run in sequence in a microwave reactor: To a 5-mL microwave vial was added 4-bromo-2,6-difluorobenzonitrile (3 g, 13.76 mmol), hydrazine (0.864 mL, 27.5 mmol), Hunig's base (4.81 mL, 27.5 mmol) and ethanol (10 mL). The vial was capped and stirred for 10 minutes at 150° C. in a microwave reactor. The reaction mixture was cooled (ice-water bath) and a yellow precipitate formed. The yellow precipitates were collected, combined and the solids were washed with cold ethanol to yield pale yellow rods of the title compound (13.0 g). LC-MS (ES) m/z=230 and 232 (1:1 intensity) [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:12][C:13]([O-])(C)C.[K+].ICC>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:11])=[N:7][N:8]2[CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(I)n[nH]c2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCn1nc(I)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
To a solution of 6-chloro-3-iodo-1H-indazole (913 mg, 3.28 mmol) in THF (12 ml) at 0° C. was added KOt-Bu (429 mg, 3.82 mmol). The reaction mixture was stirred at 0° C. for 30 min then added iodoethane (0.37 ml, 4.6 mmol). Stirred at 0° C. for 30 min then warmed to room temperature and stirred for 48 h. The reaction was quenched with water and extracted with EtOAc (2×). The combined organics were washed with brine then dried over MgSO4 and concentrated. The crude residue was purified by silica gel chromatography with 10% to 50% EtOAc/heptane to afford 622 mg (62%) of 6-chloro-1-ethyl-3-iodo-1H-indazole as a white powder. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.37-7.43 (m, 2H), 7.17 (dd, J=8.7, 1.1 Hz, 1H), 4.41 (q, J=7.2 Hz, 2H), 1.51 (t, J=7.2 Hz, 3H). Also isolated 174 mg (17%) of 6-chloro-2-ethyl-3-iodo-2H-indazole as a more polar, minor regioisomer. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.66-7.70 (m, 1H), 7.35 (d, J=9.1 Hz, 1H), 7.04-7.12 (m, 1H), 4.56 (q, J=7.2 Hz, 2H), 1.58 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[O:12][C:11]1[C:2]([CH3:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][N:5]=2
Reactant: Cc1nc2ncccc2cc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc4cccnc4nc3C)c2cc1OC
Temperature: 140 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
2-Methyl-[1,8]naphthyridin-3-ol (20 mg), 4-chloro-6,7-dimethoxyquinoline (84 mg), and 4-dimethylaminopyridine (46 mg) were suspended in o-dichlorobenzene (2 ml), and the suspension was stirred at 140° C. for 3 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (41 mg, yield 100%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[CH:15]=[CH:16][CH:17]=[C:8]([C:9]=23)[S:7]1(=[O:19])=[O:18].Br.Br.[OH:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1>[OH:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:14]5[CH:15]=[CH:16][CH:17]=[C:8]([C:9]=45)[S:7]3(=[O:19])=[O:18])[CH2:31][CH2:30]2)=[CH:27][CH:28]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCCl
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCCN1CCN(c2ccc(O)cc2)CC1
Temperature: 20 °C
Yield: 69.9 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(4-chlorobutyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (3 g), 4-(4-hydroxyphenyl)piperazine dihydrobromide (3.8 g) and sodium bicarbonate (2.8 g) in a mixture of dimethylformamide (30 cc) and tetrahydrofuran (20 cc). The mixture is heated for 5 hours at boiling point, then cooled to a temperature of about 20° C. After purification by recrystallization from boiling acetone (215 cc), 2-{4-[4-(4-hydroxyphenyl)-1-piperazinyl]butyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (3.1 g) is obtained, m.p. 195° C.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C:12]1[C:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][N:14]([CH3:25])[N:13]=1.O.NN>CO>[NH2:3][C:12]1[C:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:15][N:14]([CH3:25])[N:13]=1
Reactant: Cn1cc(NC(=O)OC(C)(C)C)c(N2C(=O)c3ccccc3C2=O)n1
Agent: NN
Solvent: CO
Solvent: O
Product: Cn1cc(NC(=O)OC(C)(C)C)c(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
To a solution of tert-butyl (3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-methyl-1H-pyrazol-4-yl)carbamate (1.8 g) in methanol (26 mL) was added hydrazine monohydrate (0.38 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.1 g).
Reaction SMILES: [CH2:1]([C@H:8]([NH:37][C:38](=[O:48])[O:39][C@@H:40]1[C@H:47]2[C@H:43]([O:44][CH2:45][CH2:46]2)[O:42][CH2:41]1)[C@H:9]([OH:36])[CH2:10][N:11]([O:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)[S:12]([C:15]1[CH:20]=[CH:19][C:18](OCCN2CCOCC2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:49]([O:52][CH2:53][CH3:54])(=O)[CH3:50]>>[CH2:1]([C@H:8]([NH:37][C:38](=[O:48])[O:39][C@@H:40]1[C@H:47]2[C@H:43]([O:44][CH2:45][CH2:46]2)[O:42][CH2:41]1)[C@H:9]([OH:36])[CH2:10][N:11]([O:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35]1)[S:12]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([O:36][CH2:9][CH2:8][N:37]2[CH2:54][CH2:53][O:52][CH2:49][CH2:50]2)[CH:20]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCC1)S(=O)(=O)c1ccc(OCCN2CCOCC2)cc1)O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: CCOC(C)=O
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCC1)S(=O)(=O)c1cccc(OCCN2CCOCC2)c1)O[C@H]1CO[C@H]2OCC[C@H]21

Procedure:
This compound was prepared from Example 44 under the same conditions used for the preparation of Example 98 (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-[(1S,2R)-1-benzyl-3-((cyclopentyloxy)[4-(2-morpholinoethoxy) phenyl]sulfonylamino)-2-hydroxypropyl]carbamate. Rf=0.15 (ethyl acetate); H1-NMR (CDCl3): δ7.44-7.14 (10H,m), 5.62 (1H,s), 5.00 (1H,m), 4.79 (2H,m), 4.16 (2H,m), 3.98-3.60 (10H,m), 3.12 (1H,bs), 3.02-2.71 (8H,m), 2.58 (4H,m), 1.90-1.72 (4H,m), 1.72-1.42 (4H,m); MS (ESI): M+H=690.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH:6]=O)#[N:2].Cl.[OH:13][NH2:14]>C(O)C.N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH:6]=[N:14][OH:13])#[N:2]
Reactant: NO
Reactant: N#Cc1cc(C=O)ccc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: N#Cc1cc(C=NO)ccc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 91.4 %

Procedure:
3-Cyano-4-fluorobenzaldehyde (5.00 g) and hydroxyamine hydrochloride (2.90 g, 1.25 Eq) were dissolved in ethanol (100 mL) and pyridine (100 mL). The mixture was stirred at RT under N2 for 45 minutes. The solvents were removed and the brown oil was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, and concentrated to give 3-cyano-4-fluorobenzaldehydeoxime (5.03 g). CI mass spectrum z (rel. intensity) 165 (M+H, 100).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[N:12]1([C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][N:25]=2)[C:21]#[N:22])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:12]1([C:18]2[CH:19]=[C:20]([C:21]3[S:4][C:3]4[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=4[C:1](=[O:10])[N:22]=3)[CH:23]=[CH:24][N:25]=2)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: N#Cc1ccnc(N2CCOCC2)c1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2ccnc(N3CCOCC3)c2)sc2ccccc12
Yield: 24.6 %

Procedure:
Methyl thiosalicylate (0.49 g, 2.9 mmol) and 2-morpholinylisonicotinonitrile (0.38 g, 2.0 mmol) were dissolved in toluene (2.0 ml), and triethylamine (0.48 ml, 3.4 mmol) was added thereto. The reaction mixture was refluxed for 14 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol. The obtained crystals were recrystallized from ethyl acetate again to give the titled compound (0.16 g, 25%) as white crystals.