Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[CH3:30][N:31]([CH:33]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[CH:43]=1)[CH:34]1[CH2:39][CH2:38][CH:37]([CH:40]=O)[CH2:36][CH2:35]1)[CH3:32].Cl>C1COCC1.O>[CH3:30][N:31]([CH:33]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[CH:43]=1)[CH:34]1[CH2:39][CH2:38][CH:37]([CH2:40][CH:2]=[O:3])[CH2:36][CH2:35]1)[CH3:32]
Reactant: CN(C)C(c1cccc(F)c1)C1CCC(C=O)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(c1cccc(F)c1)C1CCC(CC=O)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(Methoxymethyl)triphenylphosphonium chloride (26.73 g, 78 mmole) was suspended in absolute THF (90 ml) under argon, potassium tert-butylate (8.75 g, 78 mmole), dissolved in absolute THF (90 ml), was added dropwise at 0° C., and the mixture was then stirred for 15 minutes at 0° C. The aldehyde 9b (13.69 g, 52 mmole), dissolved in absolute THF (90 ml), was then added dropwise at RT and the mixture was stirred overnight at RT. The mixture was hydrolysed by dropwise addition of water (50 ml) and 6N HCl (150 ml), while cooling with iced water. After stirring for one hour at RT the mixture was extracted 10 times with ether (each time 50 ml). The aqueous phase was adjusted to pH 11 with 5N NaOH, shaken three times with ethyl acetate (each time 100 ml), dried over Na2 SO4 and concentrated by evaporation in vacuo. The crude product was purified by flash chromatography with ethyl acetate/cyclohexane (1:1).
Reaction SMILES: [CH2:1]1[C:7]2=[CH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4][NH:3][CH2:2]1.C=O.[C:17]([BH3-])#N.[Na+]>CO>[CH3:17][N:3]1[CH2:2][CH2:1][C:7]2=[CH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4]1
Reactant: c1ccc2c(c1)cc1n2CCNCC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCc2cc3ccccc3n2CC1
Reaction time: 0.67 h
Yield: 58.4 %

Procedure:
A solution of 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole (372 mg, 2.0 mmol) in methanol (25 mL) is treated with a solution of 37% aqueous formaldehyde (24 mmol, 2.0 mL). The resulting clear solution is treated with a single portion of sodium cyanoborohydride (251 mg, 4.0 mmol) turning slightly a lighter yellow color. After 40 min, the reaction is quenched with 1M hydrochloric acid (15 mL), stirred over 10 min, basified to pH 13, volatiles removed under reduced pressure, and extracted twice with ethyl acetate (25 mL). The combined organics are washed with brine (20 mL), dried over MgSO4, filtered, and concentrated to give a crude oil. This material is purified by LC (230-400 silica gel) eluting with 70% acetone/heptane to afford 234 mg (58%) of 3-methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole as a white solid, mp 59-60° C. IR (drift) 2924, 2781, 2758, 2741, 1458, 1413, 1377, 1339, 1326, 1315, 1290, 1133, 1003, 799, 737 cm−1. MS (EI) m/z 200 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:20]([C:21]#[N:22])=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=4)[C:18]([C:33]#[N:34])=[CH:17][N:16]=3)[N:12]=2)=[CH:4][CH:3]=1.[CH:35]([NH2:38])([CH3:37])[CH3:36].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:20]([C:21]#[N:22])=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=4)[C:18]([C:33]#[N:34])=[C:17]([NH:38][CH:35]([CH3:37])[CH3:36])[N:16]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)N
Reactant: N#Cc1cnc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Nc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At RT, 60 mg (0.11 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-ylmethyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 0.011 ml (0.13 mmol) of isopropylamine were stirred in 1.5 ml of THF for 60 min. Another 11 μl (0.13 mmol) of isopropylamine were then added, and the mixture was stirred at RT for another 60 min. About 10 ml of water were added to the reaction mixture, and the precipitate formed was filtered off, washed with water and dried under high vacuum. This gave 35 mg (56% of theory) of the desired target compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:19][N:20]=[C:21]([C:23]1[O:27][C:26]([N:28]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:25][CH:24]=1)[CH3:22]>CN(C=O)C>[F:10][C:9]([F:12])([F:11])[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][O:19][N:20]=[C:21]([C:23]2[O:27][C:26]([N:28]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:25][CH:24]=2)[CH3:22])=[CH:4][CH:5]=1
Reactant: CCOC(=O)CN(CC(=O)OCC)c1ncc(C(C)=NO)o1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CC(=O)OCC)c1ncc(C(C)=NOCc2ccc(C(F)(F)F)cc2)o1
Reaction time: 18 h
Yield: 74.5 %

Procedure:
To a solution of 1-(bromomethyl)-4-(trifluoromethyl)benzene (200 mg, 0.84 mmoles) in DMF (2 mL), cesium carbonate (408 mg, 1.26 mmoles) was added followed by addition of diethyl 2,2′-((5-(1-(hydroxyimino)ethyl)oxazol-2-yl)azanediyl)diacetate (262 mg, 0.84 mmoles) at 25° C. under nitrogen atmosphere and the reaction mixture was stirred at the same temperature for 18 h. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evaporated under reduced pressure. The crude product was purified by column chromatography (Eluent: 15% ethyl acetate in hexane) to yield 295 mg (75%) product as thick liquid.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][C:3]=1[C:4]#[N:5].C1C(=O)N(Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[NH:49]1[CH2:54][CH2:53][CH:52]([N:55]2[C:59]3=[N:60][CH:61]=[N:62][C:63]([NH2:64])=[C:58]3[CH:57]=[N:56]2)[CH2:51][CH2:50]1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[NH2:64][C:63]1[N:62]=[CH:61][N:60]=[C:59]2[N:55]([CH:52]3[CH2:53][CH2:54][N:49]([CH2:16][C:13]4[CH:14]=[CH:15][C:10]([C:8]5[C:7]([C:17]6[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=6)=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[N:9]=5)=[CH:11][CH:12]=4)[CH2:50][CH2:51]3)[N:56]=[CH:57][C:58]=12
Reactant: Nc1ncnc2c1cnn2C1CCNCC1
Reactant: Cc1ccc(-c2nc(Cl)c(C#N)cc2-c2ccccc2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(n4ncc5c(N)ncnc54)CC3)cc2)nc1Cl
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-6-(4-methylphenyl)-5-phenylnicotinonitrile (4-4) (0.204 g, 0.67 mmol), NBS (0.125 g, 0.70 mmol) and benzoylperoxide (0.032 g, 0.13 mmol) in chloroform (5 mL) was heated to reflux for 24 h. Concentrated in vacuo and the residue was dissolved in MeOH (15 mL) and THF (15 mL). To this solution was added 1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.146 g, 0.67 mmol) and diisopropylethylamine (0.433 g, 3.35 mmol). The mixture was stirred overnight and concentrated. The residue was treated with Na2CO3 (20 mL, 2M) and extracted with CH2Cl2. The combined organic layers was dried, filtered and concentrated in vacuo. The solid was purified by silicon gel chromatography (2-4% MeOH in CH2Cl2) to give the title compound. LRMS m/z (M+H) Calcd: 522.03, found: 521.27.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:6]=[CH:7][C:8]2[C:14](=[O:15])[CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:9]=2[N:10]=1)([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[OH:15][CH:14]1[C:8]2[CH:7]=[N:6][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:10][C:9]=2[CH2:11][N:12]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:13]1
Reactant: CC(C)Nc1ncc2c(n1)CN(C(=O)OC(C)(C)C)CC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)Nc1ncc2c(n1)CN(C(=O)OC(C)(C)C)CC2O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To a solution of 126 (400 mg, 1.31 mmol) in MeOH (1 mL) cooled to 0° C. was added slowly NaBH4 (49.4 mg, 1.31 mmol) and the reaction was stirred at RT for 15 min. The reaction was quenched with water and the mixture was extracted with DCM. The organic layer was dried, filtered and concentrated to afford 400 mg (99%) of tert-butyl 5-hydroxy-2-(isopropylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (128) which was used with out additional purification.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].C(Cl)Cl.C(N(CC)CC)C.[CH3:16][C@H:17]1[O:22][C@@H:21]([CH3:23])[CH2:20][NH:19][CH2:18]1.O>>[CH3:23][C@H:21]1[O:22][C@@H:17]([CH3:16])[CH2:18][N:19]([S:1]([Cl:5])(=[O:3])=[O:2])[CH2:20]1
Reactant: O=S(=O)(Cl)Cl
Reactant: C[C@@H]1CNC[C@H](C)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1CN(S(=O)(=O)Cl)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of sulfuryl chloride (0.773 mL, 0.00955 mol) in methylene chloride (2.39 mL, 0.0372 mol) at 0° C. was added a mixture of triethylamine (0.666 mL, 0.00478 mol) and cis-2,6-dimethylmorpholine (0.55 g, 0.0048 mol) at such a rate as to keep the temperature below 20° C. The reaction mixture was stirred at room temperature for 2 h, then poured into iced water (5 g, 0.3 mol) and extracted with dichloromethane. The combined organic layers were washed with 10% HCl, cold water, brine, dried over calcium chloride, evaporated to dryness. The crude sulfamoyl chloride was used directly in next step.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:17](=[O:18])[O:16][C:14](=[O:15])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[CH3:25][O:26][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH2:29].O>C(O)(=O)C>[CH3:25][O:26][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH:29][C:17](=[O:18])[C@H:12]([CH2:13][C:14](=[O:15])[OH:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C1C[C@H](NC(=O)OCc2ccccc2)C(=O)O1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 68.9 %

Procedure:
In 75.3 g of acetic acid, 25.1 g (0.1 mole) of N-benzyloxycarbonyl-L-aspartic anhydride was suspended and 9.2 g (0.11 mole) of sodium acetate was added at 20°-25° C. with stirring. After cooling to 15°-20° C., 64.8 g of an acetic acid solution containing 21.6 g (0.1 mole) of L-phenylalanine methyl ester hydrochloride was added at the same temperature. The reaction was carried out for 2 hours with stirring at the same temperature. Thereafter 110.1 g of water was added at the same temperature and cooled to 0°-5° C. Precipitated crystals were filtered, washed and dried. Crystals of N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl ester were obtained. The yield was 29.5 g (68.9% yield on L-phenylalanine methyl ester hydrochloride).
Reaction SMILES: [CH:1]([C:3]1[C:7](=[O:8])[O:6][CH2:5][C:4]=1[N:9]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:10]1=[O:26])=[O:2].CO.[BH4-].[Na+]>C1COCC1>[OH:2][CH2:1][C:3]1[C:7](=[O:8])[O:6][CH2:5][C:4]=1[N:9]1[CH2:13][CH2:12][C:11]2([CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:17][CH2:18]2)[C:10]1=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=C(C=O)C(=O)OC1)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=C(CO)C(=O)OC1)C2=O
Reaction time: 0.25 h

Procedure:
tert-butyl 2-(4-formyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (1.18 g, 3.24 mmol) was dissolved in THF (13 mL) and MeOH (13 mL) and the mixture was cooled to −78° C. and stirred for 15 min. Sodium borohydride (0.147 g, 3.89 mmol) was added in two equal portions and the resulting mixture was stirred for ˜15 min. at −78° C. LC-MS after 15 minutes stirring at −78° C. showed complete consumption of starting material. The reaction mixture was diluted with ethyl acetate and quenched with aqueous ammonium chloride solution at −78° C. The aqueous layer was extracted with EtOAc (2×), combined organic layers were washed with water, brine, then dried (MgSO4) and filtered, and the solvent was evaporated under reduced pressure to obtain the product, which was taken to the next step without purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[C:9]([S:22][C:23]2[CH:33]=[CH:32][C:26]([C:27](OCC)=[O:28])=[CH:25][CH:24]=2)=[CH:10][C:11]2[C:12]([CH3:21])([CH3:20])[CH2:13][CH2:14][C:15]([CH3:19])([CH3:18])[C:16]=2[CH:17]=1>C1COCC1>[CH3:7][C:8]1[C:9]([S:22][C:23]2[CH:33]=[CH:32][C:26]([CH2:27][OH:28])=[CH:25][CH:24]=2)=[CH:10][C:11]2[C:12]([CH3:21])([CH3:20])[CH2:13][CH2:14][C:15]([CH3:18])([CH3:19])[C:16]=2[CH:17]=1
Reactant: CCOC(=O)c1ccc(Sc2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc2c(cc1Sc1ccc(CO)cc1)C(C)(C)CCC2(C)C

Procedure:
144 mg (3.8 mmol) of lithium aluminum hydride and 50 ml of THF were introduced into a three-necked flask and under a nitrogen stream. Next, a solution of 1.4 g (3.8 mmol) of ethyl 4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoate in 25 ml of THF was introduced dropwise and the mixture was heated at reflux for 8 hours. The excess hydride was destroyed with a potassium sodium tartrate solution and the reaction medium was extracted with ethyl acetate. The organic phase was decanted off, dried over magnesium sulfate and evaporated.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[Se:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:18][CH2:19][C:20]([OH:22])=[O:21]>>[CH2:1]([NH:8][C:12]([C:11]1[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=1[Se:9][S:18][CH2:19][C:20]([OH:22])=[O:21])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CS
Reactant: O=c1c2ccccc2[se]n1Cc1ccccc1
Product: O=C(O)CS[Se]c1ccccc1C(=O)NCc1ccccc1

Procedure:
Prepared similar to example 1 from 2,88 g (10,0 mmol) of 2-benzyl-1,2-benzisoselenazole-3(2H)-one and 0,95 g (10,3 mmol) mercaptoactic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10](=[O:19])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)=[C:4]([N+:20]([O-:22])=O)[CH:3]=1.[K+].[Br-]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[NH:9][C:10](=[O:19])[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1)=[N+:20]2[O-:22]
Reactant: Cc1cccc(CC(=O)Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])c1
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Product: Cc1cccc(-c2c(=O)[nH]c3cc(Cl)c(Cl)cc3[n+]2[O-])c1
Yield: 97 %

Procedure:
The title compound was prepared according to the general procedure described in Example 6 by instituting 8 mmol of 133 for 125. Yield: 97%; mp 260°-262° C. (from EtOH); IR (KBr) 3454, 3044, 2923, 2801, 1653, 1617, 1380, 1364, 1311 and 1245 cm-1 ; 1H NMR (in DMSO-d6) δ2.31 (s, 3H), 7.23 (m, 1H,), 7.33 (m, 1H), 7.43 (m, 1H), 7.44 (s, 1H, 7.51 (s, 1H), 8.27 (s, 1H), 12.59 (br.s, 1H, N--H); HPLC: 97%; HRMS Calcd for C15H10N2O2Cl2 : 320.0119.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]2[S:12][C:13]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=4)=[O:22])=[CH:16][C:14]=3[CH:15]=2)=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.[CH3:31][S@:32]([CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])(=[NH:34])=[O:33].C(N(C(C)C)CC)(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>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:34]=[S:32]([CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])([CH3:31])=[O:33])=[O:7])=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=3)=[O:22])=[CH:16][C:14]=2[CH:15]=1
Reactant: Cc1cccc(NC(=O)Nc2ccc3sc(-c4cc(C(=O)O)cnc4N)cc3c2)c1
Reactant: COC(=O)CCCC[S@@](C)(=N)=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(-c2cc3cc(NC(=O)Nc4cccc(C)c4)ccc3s2)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To 6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinic acid (418 mg, 1 mmol, 1 equiv.) and (S)-methyl 5-(S-methylsulfonimidoyl)pentanoate (232 mg, 1.2 equiv.) in anhydrous DMF (6 mL) under nitrogen atmosphere was added diisopropylethylamine (0.348 mL, 2.0 equiv.) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (486.5 mg, 1.1 equiv.). The reaction mixture was heated to 60° C. and stirred for 2 hours. After the reaction was cooled to room temperature, it was diluted with EtOAc and washed sequentially with saturated aqueous NaHCO3, brine, aqueous NH4Cl, and brine. After the organic layer was dried (anhydrous Na2SO4), it was decanted, concentrated, and the brown oily residue was subject to a column chromatography (EtOAc-Hex 1:4 to 6:1). methyl 5-[N-({6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]pentanoate was obtained as a yellow foam in amount of 394 mg (66%).
Reaction SMILES: C(O[C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:5])C.[CH3:20][S:21]([NH:24][C:25]1[CH:40]=[CH:39][C:28]2[NH:29][C:30]([CH2:35][C:36](O)=[O:37])=[CH:31][S:32](=[O:34])(=[O:33])[C:27]=2[CH:26]=1)(=[O:23])=[O:22].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.[H-].[Na+]>CN(C)C=O.Cl>[F:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:11]2[C@@H:7]3[C@@H:6]([CH2:10][CH2:9][CH2:8]3)[C:4]([OH:5])=[C:35]([C:30]3[NH:29][C:28]4[CH:39]=[CH:40][C:25]([NH:24][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:26][C:27]=4[S:32](=[O:33])(=[O:34])[CH:31]=3)[C:36]2=[O:37])=[CH:18][CH:17]=1
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)cc1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)C=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)C=C(C1=C(O)[C@@H]3CCC[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
A solution of cis-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (prepared as described in Example 11, 154 mg, 0.580 mmol), (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid (175 mg, 0.527 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (117 mg, 0.609 mmol) in anhydrous N,N-dimethylformamide (6 mL) was treated with N-methylmorpholine (123 mg, 134 μL, 1.22 mmol). The reaction was stirred for 1 h at 25° C., diluted with 1.0 M aqueous hydrochloric acid solution (20 mL), and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was taken up in ethanol (6 mL) and treated with a 60% oil dispersion of sodium hydride (93 mg, 3.87 mmol). The reaction was heated at 70° C. for 1 h, allowed to cool to 25° C., and quenched with 1.0 M aqueous hydrochloric acid solution (50 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL), and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude oil was purified by prep-HPLC [Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 45-70% acetonitrile in water; 30 mL/min flow rate for 4 min run] to afford the desired product, cis-N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-7-yl}-methanesulfonamide (60 mg, 0.112 mmol, 21%), as a light yellow solid. 1H NMR (400 MHz, CDCl3) 1H NMR (400 MHz, Acetone-d6) δ: 1.34-1.47 (m, 1H), 1.50-1.91 (m, 4H), 2.32-2.42 (m, 1H), 2.96-3.03 (m, 1H), 3.11 (s, 3H), 3.83-3.94 (m, 1H), 4.54-4.67 (m, 1H), 4.97-5.07 (m, 1H), 5.37-5.78 (m, 2H), 7.07-7.14 (m, 2H), 7.36-7.54 (m, 3H), 7.66-7.71 (m, 1H), 7.81-7.83 (m, 1H), 8.95 (bs, 1H). LC-MS calcd for C24H24FN3O6S2 533.6, found 534.3 [M+H+].
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][O:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:13]=1[CH2:14][NH2:15].[Cl:22][C:23]1[CH:28]=[C:27](Cl)[N:26]=[CH:25][N:24]=1>C(O)CCC>[Cl:22][C:23]1[N:24]=[CH:25][N:26]=[C:27]([NH:15][CH2:14][C:13]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:12]=2[O:11][CH3:10])[CH:28]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2cc(Cl)ncn2)c(OC)c1
Temperature: 100 °C
Yield: 85.2 %

Procedure:
N,N-Diisopropylethylamine (8.10 mL, 46.50 mmol) and 2,4-dimethoxybenzylamine (2.52 mL, 16.78 mmol) were added to a solution of 4,6-dichloropyrimidine (2.50 g, 16.78 mmol) in butanol (80 mL) and reaction mixture was heated at 100° C. for 2 hours. The reaction mixture was cooled to room temperature and washed with water (30 mL). The aqueous layer was extracted with ethyl acetate (30 mL) and the combined organic layers were dried over anhydrous MgSO4, filtered and evaporated. The residue was triturated in heptane to give the title compound (4.00 g, 85%) as a solid.
Reaction SMILES: [F-].[K+].[Br:3][C:4]1[N:8]2[N:9]=[C:10](Cl)[CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:21]2[C@@H:25]([O:26][Si](C(C)C)(C(C)C)C(C)C)[CH2:24][CH2:23][NH:22]2)[CH:18]=[CH:19][CH:20]=1>CS(C)=O.CO>[Br:3][C:4]1[N:8]2[N:9]=[C:10]([N:22]3[CH2:23][CH2:24][C@H:25]([OH:26])[CH:21]3[C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[CH:16]=3)[CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1
Reactant: CC(C)[Si](O[C@H]1CCNC1c1cccc(F)c1)(C(C)C)C(C)C
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [F-]
Agent: [K+]
Solvent: CO
Solvent: CS(C)=O
Product: O[C@H]1CCN(c2ccc3ncc(Br)n3n2)C1c1cccc(F)c1
Temperature: 110 °C

Procedure:
In step 3-4, KF (100 mg, 1.72 mmol) and 3-bromo-6-chloroimidazo[1,2-b]pyridazine (12-1) (700 mg, 3.0 mmol) were added to a solution of (3S)-2-(3-fluorophenyl)-3-(triisopropylsilyloxy)pyrrolidine (4-3) (700 g, 2.0 mmol) in 3 mL of DMSO. The resulting slurry was heated to 110° C. for 6 hours and then cooled, diluted with 8 mL of MeOH and purified using reverse phase C-18 chromatography (water/acetonitrile 90:10 to 10:90 gradient) to furnish (3S)-1-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-2-(3-fluorophenyl)pyrrolidin-3-ol (3-4) as a solid (as a mixture of diastereomers). 1H NMR (400 MHz, D6 acetone) δ ppm 8.20 (app t, J=6.5 Hz, 1H), 7.85-6.70 (m, 6H), 5.05 (app d, J=5.5 Hz, 1H), 4.68 (app q, J=7.5 Hz, 1H), 4.30 (br s, 1H), 4.01-3.92 (m, 1H), 3.82-3.70 (m, 1H), 2.35-1.87 (m, 2H). LCMS observed m/z 377.1, 379.1 major ion.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[NH:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:3].C(N(CC)CC)C.[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>ClCCl>[CH3:22][C:21]([CH3:24])([CH3:23])[C:20]([N:12]=[C:5]([O:4][CH2:2][CH3:3])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:25]
Reactant: CCOC(=N)CC(=O)OCC
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(=NC(=O)C(C)(C)C)OCC
Temperature: -15 °C
Reaction time: 18 h
Yield: 70.6 %

Procedure:
Ethyl 3-Ethoxy-3-iminopropanoate Hydrochloride (Preparation 118, 50 g, 0.256 mol) was suspended in dichloromethane (600 mL). The suspension was cooled to −15° C. and triethylamine (7.8 mL, 0.56 mol) followed by pivaloyl chloride (31.5 mL, 0.256 mol) were added. The reaction mixture was left for 18 hours at room temperature, then washed with water, dried over MgSO4, and evaporated. The residue was triturated with hexane. The resulting precipitate was filtered and dried to afford the title compound (44 g, 70%). Taken directly on to the next step.