Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:14]=[CH:13][C:12]([C:15]3[C:23]4[C:22]([NH:24][C@H:25]([C:27]5[N:32]([C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)[C:31](=[O:39])[C:30]6=[C:40]([CH3:43])[CH:41]=[CH:42][N:29]6[N:28]=5)[CH3:26])=[N:21][CH:20]=[N:19][C:18]=4[N:17]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[CH:16]=3)=[N:11]2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.C(N(CC)CC)C.[CH3:59][S:60](Cl)(=[O:62])=[O:61]>N1C=CC=CC=1>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([NH:1][S:60]([CH3:59])(=[O:62])=[O:61])[CH:3]=[C:4]([N:10]2[CH:14]=[CH:13][C:12]([C:15]3[C:23]4[C:22]([NH:24][C@H:25]([C:27]5[N:32]([C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)[C:31](=[O:39])[C:30]6=[C:40]([CH3:43])[CH:41]=[CH:42][N:29]6[N:28]=5)[CH3:26])=[N:21][CH:20]=[N:19][C:18]=4[N:17]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:49])[CH3:50])[CH:16]=3)=[N:11]2)[CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(N)cc(-n2ccc(-c3cn(COCC[Si](C)(C)C)c4ncnc(N[C@@H](C)c5nn6ccc(C)c6c(=O)n5-c5ccccc5)c34)n2)c1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COc1cc(NS(C)(=O)=O)cc(-n2ccc(-c3cn(COCC[Si](C)(C)C)c4ncnc(N[C@@H](C)c5nn6ccc(C)c6c(=O)n5-c5ccccc5)c34)n2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
(S)-2-(1-((5-(1-(3-Amino-5-methoxyphenyl)-1H-pyrazol-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (15.3 mg, 0.02 mol) was dissolved in 2 ml pyridine and triethylamine (5 μl, 0.04 mol). The mixture was submitted to three vacuum-argon cycles and was cooled at 0° C. with an ice bath. Methanesulfonyl chloride (2 μl, 0.03 mol) was added dropwise and the reaction mixture was stirred for 2 h. The solvent was concentrated and the residue was partitioned between ethyl acetate and a saturated sodium bicarbonate solution. The organic phase was dried over sodium sulphate and evaporated under reduced pressure, to obtain 16.6 mg (94% yield) of the title compound. Purity 72%.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH:6]=[C:7]([S:22](Cl)(=[O:24])=[O:23])[N:8]3[S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[CH:4][C:3]=2[O:2]1.[OH-].[NH4+:27]>CC(C)=O>[CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH:6]=[C:7]([S:22](=[O:24])(=[O:23])[NH2:27])[N:8]3[S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[CH:4][C:3]=2[O:2]1
Reactant: O=S(=O)(Cl)c1cc2cc3c(cc2n1S(=O)(=O)c1ccccc1)OCO3
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Product: NS(=O)(=O)c1cc2cc3c(cc2n1S(=O)(=O)c1ccccc1)OCO3
Temperature: 25 °C

Procedure:
A solution of 5,6-methylenedioxy-1-benzenesulfonylindole-2-sulfonyl chloride (3.66 gm, 9.15 mmol) in acetone (35 ml) was added dropwise to a solution of concentrated ammonium hydorxide (5 ml) in acetone (20 ml) which was cooled in an ice bath. After 1 hour the reaction was warmed to room temperature and the solvent was evaporated. The residue was suspended in cold water and crystalline solid was collected by filtration. This solid was dissolved in ethyl acetate, dried (anhydrous Na2SO4), evaporated, and the residue was triturated with diethyl ether to give crystalline product (1.75 gm), mp 229°-232° C.
Reaction SMILES: N(C(OC(C)C)=O)=NC([O:5][CH:6]([CH3:8])C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:34]1C=CC=C1CC(O)=O.[CH2:43]([O:45][C:46](=[O:67])[C:47]([CH2:52][C:53]1[CH:54]=[N:55][C:56]([NH:59][C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])=[CH:57][CH:58]=1)([CH2:50]O)[CH2:48][CH3:49])[CH3:44]>C1COCC1>[CH2:43]([O:45][C:46](=[O:67])[C:47]([CH2:50][S:34][C:6](=[O:5])[CH3:8])([CH2:52][C:53]1[CH:54]=[N:55][C:56]([NH:59][C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])=[CH:57][CH:58]=1)[CH2:48][CH3:49])[CH3:44]
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: O=C(O)Cc1cccs1
Reactant: CCOC(=O)C(CC)(CO)Cc1ccc(NC(=O)OC(C)(C)C)nc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)(CSC(C)=O)Cc1ccc(NC(=O)OC(C)(C)C)nc1
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
Diisopropyl azodicarboxylate (296 μL, 1.53 mmol) was added dropwise to a solution of triphenylphosphine (402 mg, 1.53 mmol) in THF (4 mL) at 0° C. under argon and the reaction was stirred for 30 min. A solution of thiolacetic acid (109 μL, 1.53 mmol) and 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-2-hydroxymethyl-butyric acid ethyl ester (0.27 g, 0.77 mmol) in THF (2 mL) was added dropwise during 10 min. The reaction was stirred for 60 min. at 0° C. and then for 16 h at room temperature. Concentration under reduced pressure followed by chromathography (heptane/EtOAc, 10:1→1:1) gave 2-acetylsulfanylmethyl-2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-butyric acid ethyl ester (193 mg, 61%).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2].Cl.C[CH:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)[CH3:17].[CH:33]1[CH:34]=[CH:35]C2N(O)N=N[C:37]=2[CH:38]=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([CH2:3][NH:4][C:5]([C:7]1([NH:13][C:28](=[O:30])[C:27]2[CH:26]=[CH:25][C:24]([N:21]3[CH2:20][CH2:19][N:18]([CH2:16][C:17]4[CH:35]=[CH:34][CH:33]=[CH:38][CH:37]=4)[CH2:23][CH2:22]3)=[CH:32][CH:31]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2]
Reactant: N#CCNC(=O)C1(N)CCCCC1
Reactant: CC(C)N1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: On1nnc2ccccc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCNC(=O)C1(NC(=O)c2ccc(N3CCN(Cc4ccccc4)CC3)cc2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Amino-cyclohexanecarboxylic acid cyanomethyl-amide (0.84 mmol), 4-[4-(2-propyl)-piperazin-1-yl]-benzoic acid hydrochloride (0.84 mmol), HOBT (0.84 mmol), WSCD (0.84 mmol) and triethylamine (0.84 mmol) are dissolved in DMF (2 ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure slightly basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is suspended in methanol and the solid filtered of and dried (vacuum). A pale powder with mp. 210-212° C., Rf=0.20 (CH2Cl2/MeOH=95:5) is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([O:25][C:26]([NH:28][C@@H:29]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:30]=O)=[O:27])([CH3:24])([CH3:23])[CH3:22].C([BH3-])#N.[Na+].C(O)(=O)C>C(O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:10][NH:11][CH2:30][CH:29]([NH:28][C:26]([O:25][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:27])[CH2:32][O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)COCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)COCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(CNC[C@@H](COCc1ccccc1)NC(=O)OC(C)(C)C)COCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.1 %

Procedure:
The product from Example 17B (0.35 g, 1.25 mmol) and the product from Example 17A (0.36 g, 1.29 mmol) in absolute ethanol (12 mL) were treated with sodium cyanoborohydride (94 mg, 1.50 mmol) and a catalytic amount of acetic acid. The resulting mixture was stirred at ambient temperature overnight. The mixture was partitioned between water (40 mL) and ethyl acetate (3×40 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexanes:ethyl acetate, 1:1) to provide the title compound (0.15 g, 22%).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[O:12])=[CH:9][O:10][C:6]=2[C:5]([Cl:21])=[CH:4][C:3]=1[OH:22].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:25]>CS(C)=O>[Cl:21][C:5]1[C:6]2[O:10][CH:9]=[C:8]([C:11](=[O:12])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:7]=2[C:2](=[O:25])[C:3](=[O:22])[CH:4]=1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: COc1ccc(C(=O)c2coc3c(Cl)cc(O)c(Cl)c23)cc1
Solvent: CS(C)=O
Product: COc1ccc(C(=O)c2coc3c2C(=O)C(=O)C=C3Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of compound 10e (100 mg, 0.29 mmol) in DMSO (1.5 mL) was added Dess-Martin periodinane (253 mg, 0.59 mmol) at 0° C. The resulting mixture was stirred at room temperature for 20 min and poured into ice-water (2 mL). The resulting precipitate was filtered, washed with water, and dried under high vacuum to obtain compound SKC-BF-03 (50 mg, 53%) as an orange solid. TLC Rf=0.5 (petroleum ether-EtOAc, 6:4); 1H NMR (CDCl3) δ 7.90-7.84 (m, 3H), 6.95 (d, J=8.6 Hz, 2H), 6.53 (s, 1H), 3.88 (s, 3H); MS (ES) m/z 317 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[CH2:9][N:8]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:35])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH3:34])=[CH:22][CH:21]=3)=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[I-].C[CH:38]=[N+:39]=[CH:40]C.O1CCC[CH2:43]1>CCOCC>[CH:3]1[C:13]2[CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[CH2:9][N:8]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([N:26]([CH2:38][N:39]([CH3:40])[CH3:43])[C:27](=[O:35])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH3:34])=[CH:22][CH:21]=3)=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CC=[N+]=CC
Reactant: C1CCOC1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccccc1C(=O)N(CN(C)C)c1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reaction time: 1 h

Procedure:
To a suspension of 14 mg of 60% sodium hydride in oil, in 2 ml of tetrahydrofuran is added 0.13 g of N-[4-[(6,11-dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]phenyl]-2-methylbenzamide. The reactants are stirred for 1 hour and 62 mg of N,N-dimethylmethylene ammonium iodide added followed by stirring for 2 hours. The mixture is diluted with 10 ml of ether and filtered. The filtrate is evaporated in vacuo to a residue which is stirred with hexanes to give 0.13 g of the desired product as a white solid, m.p. 131°-133° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.N1C2C(=CC=CC=2)C=C1.[CH3:29][O:30]C1NC2C(C=1)=CC=CC=2>>[O:4]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:30][CH3:29])[CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCC2(C1)OCCO2
Reactant: COc1cc2ccccc2[nH]1
Agent: c1ccc2[nH]ccc2c1
Product: COc1ccc2[nH]cc(C3=CCC4(CC3)OCCO4)c2c1
Yield: 82 %

Procedure:
This compound was prepared in the manner described above for intermediate 1a by replacing indole with 5 methoxy indole (5 g, 34 mmol) in 82% yield (7.95 g) as a white solid: mp 161-162° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[N:6].C(N(CC)C(C)C)(C)C.[F:16][C:17]([F:38])([F:37])[C:18]([N:20]([CH:28]1[CH2:30][CH:29]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:19]>C(#N)C>[C:5]([CH2:4][CH2:3][CH2:2][N:25]1[CH2:24][CH2:23][CH:22]([CH2:21][N:20]([CH:28]2[CH2:30][CH:29]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:18](=[O:19])[C:17]([F:16])([F:37])[F:38])[CH2:27][CH2:26]1)#[N:6]
Reactant: O=C(N(CC1CCNCC1)C1CC1c1ccccc1)C(F)(F)F
Reactant: N#CCCCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#CCCCN1CCC(CN(C(=O)C(F)(F)F)C2CC2c2ccccc2)CC1

Procedure:
Added 4-bromobutanenitrile (100 mg, 0.674 mmol) to a solution of N,N-diisopropylethylamine (0.353 mL, 2.022 mmol), 2,2,2-trifluoro-N-(2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (220 mg, 0.674 mmol) in acetonitrile (25 mL) and heated to reflux for 16 hours. Concentrated on rotovap and the residue was purified via Biotage (0% to 100% EtOAc:Hex; then 0% to 20% MeOH:DCM to get off more product: 10 g-HP—silica gel column).
Reaction SMILES: [CH:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=O)[NH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:20])=O>ClC(Cl)C>[Cl:20][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:8][N:9]=1
Reactant: O=c1[nH]nc(C2CCCCC2)c2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: Clc1nnc(C2CCCCC2)c2ccccc12
Temperature: 100 °C
Reaction time: 4 h

Procedure:
1.0 g of 4-cyclohexyl-1-phthalazinone and 5 ml of phosphorus oxychloride were dissolved in 10 ml of dichloroethane, and the solution was stirred at 100° C. for 4 hours. The reaction solution was distilled off, and a 1-N aqueous NaOH solution was added thereto under cooling with ice. The solution was extracted with chloroform and dried over magnesium sulfide. The solvent was then distilled off, thereby obtaining 1.1 g of 1-chloro-4-cyclo-hexylphthalazine.
Reaction SMILES: Cl[C:2]1=[C:3]([C:24]([O:26][CH3:27])=[O:25])[NH:4][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[CH2:6]/[C:7]/1=[N:8]\OS(C)(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH3:34][S-].[Na+].[CH3:37][S:38](C)=O>>[NH2:8][C:7]1[CH:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[N:4]=[C:3]([C:24]([O:26][CH2:27][CH3:34])=[O:25])[C:2]=1[S:38][CH3:37]
Reactant: CS(C)=O
Reactant: COC(=O)C1=C(Cl)/C(=N/OS(C)(=O)=O)CC(c2ccc(Cl)c(OC)c2F)N1
Reactant: C[S-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: CCOC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(N)c1SC
Yield: 34 %

Procedure:
To a solution of (E)-methyl 3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-(((methylsulfonyl)oxy)imino)-1,4,5,6-tetrahydropyridine-2-carboxylate (200 mg, 0.44 mmol) in DMSO (1.4 mL) was added K2CO3 (181 mg, 1.3 mmol) followed by sodium thiomethoxide (93 mg, 1.3 mmol). After 10 min the reaction was quenched with 1 M HCl solution and then extracted with diethyl ether. The organics were washed with brine, dried with Na2SO4, filtered and purified by silica gel chromatography eluting with 30% Et2O in pentane to yielded to afford a brown solid (56 mg, 34%): mp 93-94° C.; 1H NMR (300 MHz, CDCl3) δ 7.67 (dd, J=8.6, 7.7 Hz, 1H), 7.22 (m, 1H), 7.11 (d, J=1.9 Hz, 1H), 5.16 (s, 2H), 4.47 (q, J=7.1 Hz, 2H), 3.96 (d, J=0.9 Hz, 3H), 2.30 (d, J=1.7 Hz, 3H), 1.43 (t, J=7.1 Hz, 3H); ESIMS m/z 369 ([M−H]−).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)=[CH:19][CH:18]=2)[S:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S[CH2:41]CC(OC)=O>C(Cl)Cl.[Zn+2].[I-].[I-]>[CH3:41][O:15][C:14](=[O:16])[CH2:13][CH2:12][S:11][CH:10]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34](=[O:39])[C:35]([F:36])([F:37])[F:38])=[CH:30][CH:29]=2)=[CH:19][CH:18]=1)[CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCS
Reactant: O=C(O)CCSC(CCCc1ccccc1)c1ccc(OCCCOc2ccc(C(=O)C(F)(F)F)cc2)cc1
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: COC(=O)CCSC(CCCc1ccccc1)c1ccc(OCCCOc2ccc(C(=O)C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirring solution of the product of Step 4 (270 mg) and methyl 3-mercaptopropionate (250 mL) in 20 mL of CH2Cl2 was added ZnI2 (700 mg) at 0° C. The mixture was stirred for 20 min. at r.t. and then quenched with 20 mL of 25% NH4OAc, extracted with 100 mL of 2:1 Hexane/EtOAc. The organic extract was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography eluted with 5:1 Hexane/EtOAc to give 320 mg of the title compound.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:24]=[C:23]([CH2:25][CH3:26])[S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[CH:24]=[C:23]([CH2:25][CH3:26])[S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: NCCc1ccccc1
Reactant: CCc1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: CCc1cc2c(NCCc3ccccc3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(isoxazol-5-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-phenethylamino-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:14]2[C:9](=[C:10]([NH2:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].[Cl:16][C:17]1[C:22]([C:23](O)=[O:24])=[C:21]([F:26])[C:20]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:19][CH:18]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:16][C:17]1[C:22]([C:23]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:9]=2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][CH:1]([CH3:3])[CH3:2])=[O:24])=[C:21]([F:26])[C:20]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:19][CH:18]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: CC(C)Nc1ncnc2c(N)cccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1ncnc2c(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)cccc12
Yield: 12.3 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-isopropylquinazoline-4,8-diamine (Intermediate-57, 140 mg, 0.69 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 223 mg, 0.78 mmol), oxalyl chloride (147 mg, 1.17 mmol), DMF (1 drop) and DIPEA (267 mg, 2.07 mmol) in CH2Cl2 (5 mL) to afford 40 mg of the title product. 1H NMR (400 MHz, DMSO-d6): δ 10.38 (s, 1H), 8.69 (d, J=7.0 Hz, 1H), 8.48 (s, 1H), 8.16-8.14 (t, J=5.8 Hz, 1H), 8.10-8.07 (m, 2H), 7.55-7.51 (t, J=8.0 Hz, 1H), 7.42-7.40 (d, J=8.4 Hz, 1H), 7.36-7.33 (t, J=8.0 Hz, 1H), 4.56-4.51 (m, 1H), 4.31 (d, J=5.8 Hz, 2H), 1.28 (s, 3H), 1.25 (s, 3H), 1.14 (s, 9H); MS (m/z): 472.40 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:17])=[C:4](C2C=CC=C3C=2C=CN3)[CH:5]=CC=1.[Br-].[Br-].[Br-].[NH+:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH+]1C=C[CH:30]=[CH:29][CH:28]=1.[NH+]1C=CC=CC=1.[C:39]([OH:42])(=O)[CH3:40]>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:22]=[C:23]([C:24]2[CH:30]=[CH:29][CH:28]=[C:26]3[C:25]=2[CH2:40][C:39](=[O:42])[NH:21]3)[CH:5]=[CH:4][C:3]=1[F:17]
Reactant: Fc1c(Cl)cccc1-c1cccc2[nH]ccc12
Reactant: c1cc[nH+]cc1
Reactant: CC(=O)O
Agent: [Br-]
Agent: [Zn]
Solvent: CC(C)(C)O
Solvent: CCO
Product: O=C1Cc2c(cccc2-c2ccc(F)c(Cl)c2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To the suspension of 4-(3-chloro-fluoro-phenyl)-1H-indole (2.03 g, 8.26 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (99 mL) was added pyridinium tribromide (7.93 g, 24.79 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (40 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was dissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO3 and brine, and dried over Na2SO4. After filtration and evaporation, the crude product was triturated with diethyl ether to provide product 4-(3-chloro-4-fluoro-phenyl)-1,3-dihydro-indol-2-one (1.39 g, 64%) as a tan solid.
Reaction SMILES: [NH2:1][C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH3:22])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[NH:4][C:3]1=[O:13].Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>N1C=CC=CC=1>[C:27]1([O:26][C:24](=[O:25])[NH:1][C:2]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH3:22])[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=3)[NH:4][C:3]2=[O:13])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOc1ccccc1C1(N)C(=O)Nc2ccc(OC)cc21
Solvent: c1ccncc1
Product: CCOc1ccccc1C1(NC(=O)Oc2ccccc2)C(=O)Nc2ccc(OC)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.8 g (6 mmol) of the intermediate from Step C were dissolved in 20 ml pyridine. At 0° C. 0.99 g (6.3 mmol) phenyl chloroformate were added and afterwards the reaction mixture was stirred for 1 h at 0° C. This mixture was poured into an ice/water mixture. The pH of the aqueous phase was adjusted to 5 and the resulting mixture was extracted with ethyl acetate. The organic phase was separated, dried over magnesium sulfate and the solvent was removed in vacuo. The resulting solid (2 g) was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+].O>C(O)C>[CH2:20]([NH:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCCN)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCC1CCN(CCCCNCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
A solution of 4-(3-tert-butoxycarbonylaminomethylpyrrolidin-1-yl)-butylamine (2.0 g) and benzaldehyde (0.86 g) in ethanol (50 ml) was stirred at 70° C. for 3 hr. After cooling, sodium borohydride was added, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 1.74 g of N-benzyl-4-(3-tert-butoxycarbonylaminomethylpyrrolidin-1-yl)butylamine.
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])=[O:13].N1C=CC=CC=1.[C:27](Cl)([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].O>C(Cl)Cl>[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:17][CH2:16]1)(=[O:14])=[O:13]
Reactant: O=S(=O)(c1ccc2ccccc2c1)N1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.8 %

Procedure:
In a two neck round bottom flask, 1-(naphthalene-2-ylsulfonyl)piperazine hydrochloride (compound 4, 0.72 mmoles, 0.200 g) and pyridine (7.22 mmoles, 2 mL) were charged in DCM (20 mL) at 0° C. CBZCl (1.08 mmoles, 0.30 g) was added slowly at the same temperature and then allowed the reaction mixture to stir for 3 h at room temperature. After completion of the reaction, water (10 mL) was added and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (1×20 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by Column Chromatography (Silica gel 60-120, MeOH/DCM) to obtain the title compound (0.150 g, 50.6%) as an off-white solid.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:14])[N:6]([CH3:13])[N:7]=[CH:8][C:9]=1[N:10](C)C)(=O)[CH3:2].[NH2:15]N>C(O)C>[CH3:2][C:1]1[C:4]2[C:5](=[O:14])[N:6]([CH3:13])[N:7]=[CH:8][C:9]=2[NH:10][N:15]=1
Reactant: NN
Reactant: CC(=O)c1c(N(C)C)cnn(C)c1=O
Solvent: CCO
Product: Cc1n[nH]c2cnn(C)c(=O)c12
Reaction time: 6 h

Procedure:
4-Acetyl-5-dimethylamino-2-methyl-3(2H)-pyridazinone (137 mg) was added to hydrazine (224 mg)/ethanol (5 ml) and the mixture was refluxed with stirring for 6 hours. After the ethanol-hydrazine was distilled off, the residue was washed with diethyl ether and dried. White powder, 114 g. 1H-NMR (CDCl3) 8: 2.57(3H,s), 3.64(3H,s), 8.30(1H,s).