Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][N:7]([C:9]3[C:10]4[CH:17]=[CH:16][NH:15][C:11]=4[N:12]=[CH:13][N:14]=3)[CH2:6][CH2:5][NH:4]2)[CH2:2]1.[CH3:18][NH:19][S:20](Cl)(=[O:22])=[O:21].O>N1C=CC=CC=1.CCOCC>[CH3:18][NH:19][S:20]([N:4]1[CH2:5][CH2:6][N:7]([C:9]2[C:10]3[CH:17]=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH2:8][C:3]21[CH2:1][CH2:2]2)(=[O:22])=[O:21]
Reactant: c1nc(N2CCNC3(CC3)C2)c2cc[nH]c2n1
Reactant: CNS(=O)(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: CNS(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 4-(4,7-Diaza-spiro[2.5]oct-7-yl)-7H-pyrrolo[2,3-d]pyrimidine (2 g, 8.7 mmol) (intermediate 21) in dry pyridine (100 mL) was cooled to 0° C. and dropwise added a solution of commercial available methylsulfamoyl chloride (419 mg, 8.7 mmol) in dry Et2O (5 mL). After complete addition, the reaction mixture was allowed to warm up to rt and was afterwards stirred at rt for 1 h. An additional equivalent of methylsulfamoyl chloride (419 mg, 8.7 mmol) in dry Et2O (5 mL) was added and after additional 1 h at rt a third equivalent of methylsulfamoyl chloride (419 mg, 8.7 mmol) in dry Et2O (5 mL) was added. The crude mixture was treated with water (150 mL) and extracted with EtOAc (3×100 mL). The combined organic phases were washed with H2O (2×50 mL), brine (2×50 mL), dried over Na2SO4, filtered and concentrated in vacuo. Recrystallised in EtOH:CH2Cl2 affording the title compound as white crystals.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][O:9][CH:10]1[CH2:13][NH:12][CH2:11]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[O:45]=[C:46]1[NH:55][C:54]2[N:53]=[CH:52][C:51](/[CH:56]=[CH:57]/[C:58](O)=[O:59])=[CH:50][C:49]=2[CH2:48][CH2:47]1>CN(C)C=O>[CH3:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][O:9][CH:10]1[CH2:11][N:12]([C:58](=[O:59])/[CH:57]=[CH:56]/[C:51]2[CH:50]=[C:49]3[C:54](=[N:53][CH:52]=2)[NH:55][C:46](=[O:45])[CH2:47][CH2:48]3)[CH2:13]1
Reactant: Cc1ccsc1COC1CNC1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccsc1COC1CN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)C1
Reaction time: 8 h
Yield: 43 %

Procedure:
3-((3-methylthiophen-2-yl)methoxy)azetidine hydrochloride (129.0 mg, 0.6 mmol), EDCI (112.0 mg, 0.6 mmol), HOBt (82.0 mg, 0.6 mmol) and diisopropylethylamine (170 μL, 1.0 mmol) were successively added to a solution of (E)-3-(7-Oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acid hydrochloride (100.0 mg, 0.4 mmol) in dimethylformamide (10 mL) at room temperature. The reaction mixture was stirred overnight and then partitioned between ethyl acetate (30 mL) and water (30 mL). The aqueous layer was separated and extracted with ethyl acetate (2×20 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×30 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel, using dichloromethane/methanol (100:0 to 95:5) as eluent. The residue was triturated in acetone to give a white solid (66.0 mg, 44%).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:19][CH2:20][CH:21]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH2:21][CH2:20][CH2:19][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:32][CH2:31]2)=[CH:28][CH:29]=1
Reactant: Cc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(c4ccc(Cl)cc4)CC3)nn2-c2ccccc2)cc1

Procedure:
73 mg (52%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (80 mg, 0.276 mmol), 1-(4-chlorophenyl)piperazine (74 mg, 0.276 mmol), DIPEA (0.072 mL, 0.414 mmol) and NaBH(OAc)3 (175 mg, 0.828 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][CH:7]=[CH:6]2.P(Cl)(Cl)([Cl:16])=O.C([O-])(O)=O.[Na+]>>[Cl:16][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: COc1ccc2c(=O)[nH]ccc2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc2c(Cl)nccc2c1
Temperature: 90 °C
Yield: 86.4 %

Procedure:
A slurry of 6-methoxyisoquinolone (116 g, 662 mmol) in phosphorous oxychloride (200 mL, 2.14 mol) was charged to a rotavap flask. The resulting thick paste was heated on the rotovap to 90° C. for ˜30 min. The reaction thinned to a thick black solution with gas evolution then became pasty again, and was heated continuously at 90° C. for an additional 30 min and checked by TLC. An additional quantity of phosphorous oxychloride (100 mL, 1.07 mol) was added and the reaction was heated continuously for another 2 h. The reaction was complete (checked by TLC; complete consumption of starting material with some production of a polar impurity) so the excess POCl3 was removed under high vacuum to leave a solid mass of crude product. This solid mass was triturated with ethyl acetate (500 mL) at 0° C. for 3.5 h. The solid product was filtered and washed with cold ethyl acetate (250 mL). Mother liquors contained essentially no product and were discarded. The weight of this crude solid salt was ˜208 grams. This salt was dissolved in a mixture of cold ethyl acetate (1000 mL) and water (1000 mL) and neutralized to pH=6.75 with NaHCO3 (209 g, 2.49 mol, 3.75 eq based on starting material). The phases were split, and the aqueous phase was back extracted with ethyl acetate (500 mL) and combined with the first product containing the ethyl acetate phase. The ethyl acetate was removed under reduced pressure to yield 110.8 g crude residue. In order to remove the polar impurity, this residue was dissolved in a mixture of ethyl acetate 200 mL and heptanes 100 mL and passed through a silica gel plug (500 g) and eluted with a mixture of ethyl acetate/heptanes 1:1. The product containing fractions was concentrated to a residue to provide pinkish-yellow solids. These solids were recrystallized from hot (˜75° C.) heptanes (1000 mL) and cooled to rt then to 0° C. Filtration and washing with cold heptanes (250 mL) followed by drying under vacuum provided purified 1J as a off-white crystalline solid. (98.02 g, 506 mmol, 76.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:38](=[O:44])OC(Cl)(Cl)Cl)Cl.[Br:46][C:47]1[CH:48]=[C:49]([C@H:53]([NH2:55])[CH3:54])[CH:50]=[CH:51][CH:52]=1>C(Cl)(Cl)Cl>[Br:46][C:47]1[CH:48]=[C:49]([C@H:53]([NH:55][C:38]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][C:18]=2[C:23]([F:25])([F:26])[F:24])=[O:44])[CH3:54])[CH:50]=[CH:51][CH:52]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C(F)(F)F)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@@H](N)c1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@H](C)c4cccc(Br)c4)c(C(F)(F)F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-(trifluoromethyl)aniline (82 mg) was dissolved in chloroform (2 ml) and triethylamine (0.2 ml) to prepare a solution. A solution of triphosgene (70 mg) in chloroform (0.4 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1R)-1-(3-bromophenyl)ethylamine (70 mg) in chloroform (0.4 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (39 mg, yield 29%).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][C:5]([CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([NH:31][S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[C:27]([Cl:30])=[N:28][CH:29]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:23][C:24]3[CH:25]=[C:26]([NH:31][S:32]([N:35]([CH3:37])[CH3:36])(=[O:33])=[O:34])[C:27]([Cl:30])=[N:28][CH:29]=3)=[N:3][CH:4]=[C:5]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:6]=2)[N:9]=1
Reactant: Cc1nc(N)nc(-c2cc(CN3CCOCC3)cnc2F)n1
Reactant: CN(C)S(=O)(=O)Nc1cc(N)cnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(-c2cc(CN3CCOCC3)cnc2Nc2cnc(Cl)c(NS(=O)(=O)N(C)C)c2)n1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 41 %

Procedure:
To a stirred solution of 4-(2-fluoro-5-(morpholinomethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (Example 384, Step 2, 0.0614 g, 0.202 mmol) and N′-(5-amino-2-chloro-3-pyridinyl)-N,N-dimethylsulfamide (KY, 0.050 g, 0.199 mmol) in DMF (1 mL) in 5 mL microwave vial, NaHMDS (Aldrich, 1 M in THF, 0.80 mL, 0.80 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 45 min. The reaction mixture was partitioned between saturated aqueous ammonium chloride (30 mL) and 25% isopropanol in chloroform (20 mL). The aqueous phase was acidified to a pH of about 3 to 4 then extracted with 25% isopropanol in chloroform (2×30 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (25 g, eluent: iPrOH in CHCl3 0%-25%) to afford N′-(5-((3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-(4-morpholinylmethyl)-2-pyridinyl)amino)-2-chloro-3-pyridinyl)-N,N-dimethylsulfamide (0.0437 g, 44% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.28 (s, 1H) 9.57 (s, 1H) 8.82 (s, 1H) 8.76 (d, J=2.35 Hz, 1H) 8.53 (d, J=2.35 Hz, 1H) 8.29 (d, J=2.35 Hz, 1H) 7.74-7.98 (m, 2H) 3.57 (t, J=4.21 Hz, 4H) 3.48 (s, 2H) 2.79 (s, 6H) 2.46 (s, 3H) 2.35-2.43 (m, 4H). m/z (ESI, positive ion): 535.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH:25]3[C:30](O)=[O:31])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:33][N:34]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.NO.[CH:57](O)=[O:58]>CN(C=O)C>[OH:33][NH:34][C:30]([C@@H:25]1[C@H:24]([NH:23][S:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH2:29][CH2:28][N:27]([CH:57]=[O:58])[CH2:26]1)=[O:31]
Reactant: On1nnc2ccccc21
Reactant: Cc1cc(COc2ccc(S(=O)(=O)NC3CCNCC3C(=O)O)cc2)c2ccccc2n1
Reactant: O=CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCN(C=O)C[C@@H]3C(=O)NO)cc2)c2ccccc2n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 10.9 %

Procedure:
To a solution of 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-3-carboxylic acid (0.210 g, 0.459 mmol) and 1-hydroxybenzotriazole (HOBT, 0.186 g, 1.38 mmol) in DMF (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.264 g, 1.38 mmol) at 0° C. The reaction mixture stirred at 0° C. for 10 min, then warmed to 25° C. over 1.0 h. After re-cooling the reaction to 0° C., hydroxylamine (50% by wt in water solution, 0.5 mL, 4.6 mmol) was added. The reaction was allowed to warm to 25° C. over 19 h and then formic acid (0.151 g, 3.2 mmol) added. The reaction was stirred for 10 min at 25° C. and 40° C. for 30 min and then allowed to warm to 25° C. over 19 h. The DMF was removed in vacuo and the resulting oil was diluted in ethyl acetate (100 mL) and then washed with saturated aqueous sodium bicarbonate (3×30 mL) and brine (30 mL). The organic layer was dried over MgSO4, filtered and concentrated to obtain a crude solid (0.195 g). The crude product was purified by reverse phase HPLC (Gilson) on a Phenomex C-18 semi-prep column eluting with an acetonitrile:water gradient, to afford (3S,4R)-1 -formyl-4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl amino]-piperidine-3-carboxylic acid hydroxyamide as an amorphous white solid (0.025 g, 11.6%). MS: 499 (M+H)+
Reaction SMILES: [C:1](Cl)(=O)[O:2]C1C=CC([N+]([O-])=O)=CC=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([OH:45])([C:41]([F:44])([F:43])[F:42])[C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)[CH2:25][CH2:24]2)=[O:22])=[CH:17][CH:16]=1.[NH2:46][CH2:47][C:48]([CH3:51])([OH:50])[CH3:49]>ClCCl>[F:42][C:41]([F:44])([F:43])[C:36]([C:33]1[CH:32]=[CH:31][C:30]([CH2:29][N:26]2[CH2:27][CH2:28][N:23]([C:21]([C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:1]([NH:46][CH2:47][C:48]([OH:50])([CH3:51])[CH3:49])=[O:2])=[CH:20][CH:19]=3)=[O:22])[CH2:24][CH2:25]2)=[CH:35][CH:34]=1)([OH:45])[C:37]([F:38])([F:39])[F:40]
Reactant: CC(C)(O)CN
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Solvent: ClCCl
Product: CC(C)(O)CNC(=O)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Reaction time: 1 h
Yield: 24 %

Procedure:
4-Nitrophenyl carbonochloridate (0.217 mmol, 43.7 mg) was added to a stirred solution of (4-aminophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)-piperazin-1-yl)methanone (0.217 mmol, 100 mg) in dichloromethane (1 mL). After 1 hour, 1-amino-2-methylpropan-2-ol (0.650 mmol, 58.0 mg) was added and stirring continued for 1 hour. The reaction mixture was purified by silica column chromatography (eluant dichloromethane/methanol 0% to 10%) to yield the title compound (30 mg).
Reaction SMILES: C(O[CH:4](OCC)[C:5](=[NH:8])OC)C.[CH3:12][C:13]1[CH:14]=[C:15]([CH2:20][NH2:21])[CH:16]=[CH:17][C:18]=1[CH3:19]>CO>[CH3:19][C:18]1[CH:17]=[C:16]2[C:4](=[CH:12][C:13]=1[CH3:14])[CH:5]=[N:8][C:20]([NH2:21])=[CH:15]2.[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[C:4]2[C:14]=1[CH:15]=[C:20]([NH2:21])[N:8]=[CH:5]2
Reactant: CCOC(OCC)C(=N)OC
Reactant: Cc1ccc(CN)cc1C
Solvent: CO
Product: Cc1cc2cnc(N)cc2cc1C
Product: Cc1ccc2cnc(N)cc2c1C
Temperature: 70 °C
Reaction time: 16 h
Yield: 219.6 %

Procedure:
To a solution of methyl 2,2-diethoxyacetimidate (1.50 g, 9.32 mmol) in methanol (4.9 mL) was added (3,4-dimethylphenyl)methanamine (1.20 g, 8.88 mmol) dropwise at ambient temperature. The reaction flask was then placed into a preheated oil-bath and stirred at 70° C. for 16 h; after which time, the flask was removed from the oil-bath and allowed to cool to ambient temperature. The volatiles were removed under reduced pressure and the crude material was added dropwise to sulfuric acid (19.7 mL) at ambient temperature. The reaction mixture was stirred for 72 h, then the flask was placed into an ice-water bath, diluted with water (50 mL), and slowly neutralized to pH=10 with sodium hydroxide (10 N). As the reaction mixture became basic, an orange precipitate formed. This precipitate was filtered, washed with water, and dried to afford a mixture (2:1) of 6,7-dimethylisoquinolin-3-amine and 5,6-dimethylisoquinolin-3-amine (1.68 g, 9.75 mmol, >100%). MS (LC/MS) R.T.=0.32; [M+H]+=173.13.
Reaction SMILES: [Na].[C:2]([O:5][CH2:6][CH2:7][C:8]12[CH2:20][CH2:19][C:18](=[O:21])[CH:17]=[C:16]1[C:15]1[C:10](=[CH:11][C:12]([O:24][CH2:25][C:26]#[N:27])=[C:13]([Cl:23])[C:14]=1[Cl:22])[CH2:9]2)(=[O:4])[CH3:3].[Cl-].[NH4+:29]>CO>[ClH:22].[C:2]([O:5][CH2:6][CH2:7][C:8]12[CH2:20][CH2:19][C:18](=[O:21])[CH:17]=[C:16]1[C:15]1[C:10](=[CH:11][C:12]([O:24][CH2:25][C:26](=[NH:29])[NH2:27])=[C:13]([Cl:23])[C:14]=1[Cl:22])[CH2:9]2)(=[O:4])[CH3:3]
Reactant: CC(=O)OCCC12CCC(=O)C=C1c1c(cc(OCC#N)c(Cl)c1Cl)C2
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na]
Solvent: CO
Product: CC(=O)OCCC12CCC(=O)C=C1c1c(cc(OCC(=N)N)c(Cl)c1Cl)C2
Product: Cl
Reaction time: 4 h

Procedure:
To a solution of sodium metal (0.116 g) in methanol (180 ml) was added {[9a-(2-acetoxyethyl)-5,6-dichloro-3-oxo-2,3,9,9a-tetrahydro-1H-fluoren-7-yl)oxy]acetonitrile (7.2 g, 18.3 mMole). The reaction mixture was stirred for 11/4 hours in a nitrogen atmosphere then treated with ammonium chloride (2.0 g, 37 mMole) and stirring was continued for 21/2 hours. The methanol was evaporated in vacuo, the residue dissolved in water, treated with 10N NaOH (10 ml), extracted with diethyl ether (100 ml) and then CH2Cl2 (3×50 ml), washed with water, dried over potassium carbonate and evaporated in vacuo. The residue was dissolved in diethyl ether, treated with a slight excess of ethanolic HCl, filtered under nitrogen, and washed with diethyl ether to give the {[9a-(2-acetoxyethyl)-5,6-dichloro-3-oxo-2,3,9,9a-tetrahydro-1H-fluoren-7-yl]oxy}ethanimidamide hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][N:5]2[C:11]=1[I:12].[Cl:13]C1N=C2C=C(Cl)C(Cl)=CN2C=1.C1C(=O)N(I)C(=O)C1>>[I:12][C:11]1[N:5]2[CH:6]=[C:7]([Cl:10])[C:8]([Cl:13])=[CH:9][C:4]2=[N:3][C:2]=1[Cl:1]
Reactant: Clc1ccc2nc(Cl)c(I)n2c1
Reactant: Clc1cn2cc(Cl)c(Cl)cc2n1
Agent: O=C1CCC(=O)N1I
Product: Clc1cc2nc(Cl)c(I)n2cc1Cl
Yield: 82 %

Procedure:
Following the preparation of compound 19, compound 16 (1.7 g, 7.7 mmol) was treated with NIS to give 2.2 g (82%) of compound 25 as a white crystalline solid.
Reaction SMILES: [OH-].[K+].[CH2:3]([C:10]([CH2:21][S:22][CH3:23])([C:16]([O:18]CC)=[O:17])[C:11]([O:13]CC)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO.Cl>O>[CH2:3]([C:10]([CH2:21][S:22][CH3:23])([C:11]([OH:13])=[O:12])[C:16]([OH:18])=[O:17])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(CSC)(Cc1ccccc1)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSCC(Cc1ccccc1)(C(=O)O)C(=O)O
Temperature: 100 °C
Reaction time: 4 h
Yield: 71.7 %

Procedure:
Powdered potassium hydroxide (4.8 g, 86 mmol, 5.0 equiv) was added to a stirred solution of diethyl 2-benzyl-2-(methylthiomethyl)malonate (5.3 g, 17 mmol, 1.0 equiv) in 3:1 methanol:water (28 mL) at 23° C. The resulting pale yellow suspension was heated to 100° C. and stirred for 4 h. The cooled reaction mixture was acidified to pH≈9 with concentrated hydrochloric acid and washed with diethyl ether (4×50 mL). The aqueous layer was acidified to pH≈1 with concentrated hydrochloric acid and extracted with dichloromethane (4×60 mL). The combined organic layers were dried (Na2SO4), gravity-filtered, and concentrated by rotary evaporation to afford the title compound as a white powder (3.1 g, 72%): 1H NMR (300 MHz, DMSO-d6) δ 7.13-7.34 (m, 5H), 3.15 (s, 2H), 2.73 (s, 2H), 2.08 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH2:9][N:8]([S:12]([CH3:15])(=[O:14])=[O:13])[C:7]=2[CH:16]=1.[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)C(C)C)(C)C>CC(O)C>[CH3:15][S:12]([N:8]1[C:7]2[CH:16]=[C:3]([CH2:2][N:20]3[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]3)[CH:4]=[CH:5][C:6]=2[O:11][CH2:10][CH2:9]1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)N1CCOc2ccc(CBr)cc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc3c(c2)N(S(C)(=O)=O)CCO3)CC1
Yield: 71.5 %

Procedure:
6-Bromomethyl-4-methanesulfonyl-3,4-dihydro-2H-benzo[1,4]oxazine (2.6 g, 8.5 mmol) and tert-butyl piperazine-1-carboxylate (1.58 g, 8.5 mmol) were treated with propan-2-ol (100 mL) followed by N,N-diisopropylethylamine (10.96 g, 85 mmol) and the resulting mixture heated at reflux for 72 h then evaporated to dryness under reduced pressure. The residue was partitioned between ethyl acetate and saturated NaHCO3 aq. and the phases separated. The organic phase was washed with water, saturated brine, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography on SiO2, eluting with ethyl acetate in 60°–80° petroleum ether, gave the title compound (2.5 g, 71%) as a brown foam.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([NH:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=4)[C:8]=23)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:25]([O:29][C:30]([NH:32][C@H:33]([CH:37]([CH3:39])[CH3:38])[C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:38][CH:37]([CH3:39])[C@@H:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:28])([CH3:27])[CH3:26])[C:34]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([NH:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=4)[C:8]=23)[CH2:6][CH2:5]1)=[O:35]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(Nc1c[nH]c2nccc(N3CCNCC3)c12)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(c2ccnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Reaction time: 2 h
Yield: 29.7 %

Procedure:
N-(4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (0.025 g, 0.058 mmol, see Example 50), (R)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (0.0138 g, 0.0637 mmol), HOBT-H2O (0.0124 g, 0.0811 mmol) and EDCI (0.0144 g, 0.0752 mmol) were placed in DCM (3 mL). DIEA (d 0.742; 0.0504 mL, 0.290 mmol) was then added, and the reaction was stirred for 2 hours. The reaction was quenched with saturated Na2CO3. The mixture was then extracted with DCM. The organic fractions were dried, filtered, and concentrated to give a crude oil that was purified by column chromatography (500:20-500:28) to give (R)-tert-butyl 3-methyl-1-(4-(3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-1-oxobutan-2-ylcarbamate (0.009 g, 29.7% yield).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]2[CH:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:12][CH2:13][N:6]2[C:5](=[O:21])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl.CCOC(C)=O>[O:21]=[C:5]1[CH2:4][CH2:3][C@H:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])[C:8](=[O:9])[N:7]2[C@H:10]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:11][CH2:12][CH2:13][N:6]12
Reactant: CC(C)(C)OC(=O)C1CCCN2C(=O)CCC(N)C(=O)N12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](NS(C)(=O)=O)C(=O)N12
Reaction time: 1 h
Yield: 76.9 %

Procedure:
A solution of t-butyl 9-amino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate (GB 2,128,984; 831 mg, 2.79 mmol) and diisopropylethylamine (1.22 ml, 6.99 mmol, 2.5 equiv) in CH2Cl2 (10 ml) under dry nitrogen was treated with methanesulphonyl chloride (237 μl, 3.07 mmol 1.1 equiv). The mixture was stirred for 1 h, diluted with EtOAc (75 ml) and washed with saturated NaHCO3 (50 ml) and saturated aqueous sodium chloride (30 ml), dried (MgSO4) and concentrated. Flash chromatography (10-35% EtOAc in CH2Cl2) afforded (211b) (806 mg, 77%) as a colourless solid: mp 68-70° C.; [α]D23 -109 (c 1.09, CH2Cl2); IR (KBr) 3270, 2980, 2939, 1735, 1677, 1458, 1447, 1418, 1396, 1370, 1328, 1272, 1252, 1232, 1222, 1156, 1131, 991; 1H NMR (CDCl3) δ 6.15 (1H, d), 5.31 (1H, m), 4.65-4.11 (2H, m), 3.47 (1H, m) 2.99 (3H, s), 2.89 (1H, m), 2.72-2.51 (2H, m), 2.34 (1H, m), 2.26 (1H, m), 2.05-1.62 (4H, m), 1.47 (9H, s); Anal. Calcd for C15H23N3O6S: C, 47.97; H, 6.71; N, 11.19; S, 8.54. Found: C, 48.28; H, 6.68; N, 10.86; S, 8.28. MS (+FAB) 376 (M+ +1, 66%), 320 (100).