Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:24]2[C:12](=[C:13]([CH3:27])[C:14]3[N:15]([CH3:26])[C:16]4[CH:17]=[CH:18][C:19]([OH:25])=[CH:20][C:21]=4[C:22]=3[CH:23]=2)[CH:11]=[CH:10][N:9]=1)=[O:7].[C:29](O)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1.C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:24]2[C:12](=[C:13]([CH3:27])[C:14]3[N:15]([CH3:26])[C:16]4[CH:17]=[CH:18][C:19]([O:25][C:29]([C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)=[O:36])=[CH:20][C:21]=4[C:22]=3[CH:23]=2)[CH:11]=[CH:10][N:9]=1)=[O:7]
Reactant: Cc1c2ccnc(C(=O)NCCN(C)C)c2cc2c3cc(O)ccc3n(C)c12
Reactant: O=C(O)c1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: Cc1c2ccnc(C(=O)NCCN(C)C)c2cc2c3cc(OC(=O)c4cccnc4)ccc3n(C)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.2 %

Procedure:
A mixture containing 3 g of 1-[(2-dimethylaminoethyl)aminocarbonyl]-5,6-dimethyl-9-hydroxy-6H-pyrido[4,3-b]carbazole, 1.5 g of nicotinic acid, 3.7 g of dicyclohexylcarbodiimide and 1.5 g of dimethylaminopyridine dissolved in 100 ml of pyridine is stirred at room temperature for 16 hours. At the end of 16 hours, a further 2 g of dicyclohexylcarbodiimide and 0.75 g of nicotinic acid are added and the mixture is stirred for a further 24 hours and concentrated to dryness. The residue is taken up in dichloromethane and washed with sodium hydrogen carbonate, and the dichloromethane phase is concentrated to remove by filtration as much as possible of the dicyclohexylurea formed, and the filtrate is concentrated to dryness. The residue is chromatographed on silica using a mixture of toluene, ethanol and triethylamine (100:10:05) as eluant. 3.5 g of the desired product are obtained, m.p. (cap): 190-192° C.
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:35][C:36]1([C:39]#[N:40])[CH2:38][CH2:37]1.[CH2:41]1[C:45]2([CH2:50][CH2:49][N:48]([C:51]([NH:53][C@@H:54]([CH2:58][C:59]([F:68])([F:67])[CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[C:55](O)=[O:56])=[O:52])[CH2:47][CH2:46]2)[CH2:44][CH2:43][CH2:42]1>CN(C=O)C>[C:39]([C:36]1([NH:35][C:55]([C@@H:54]([NH:53][C:51]([N:48]2[CH2:47][CH2:46][C:45]3([CH2:44][CH2:43][CH2:42][CH2:41]3)[CH2:50][CH2:49]2)=[O:52])[CH2:58][C:59]([F:67])([F:68])[CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[O:56])[CH2:38][CH2:37]1)#[N:40]
Reactant: O=C(O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCC2(CCCC2)CC1
Reactant: N#CC1(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)[C@H](CC(F)(F)Cc2ccccc2)NC(=O)N2CCC3(CCCC3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DIPEA (331 μl, 252 mg, 1.95 mmol, 4 eq.), HATU (185 mg, 0.49 mmol, 1 eq.) and 1-aminocyclopropanecarbonitrile hydrochloride (58 mg, 0.49 mmol, 1 eq.) were added successively to a solution of the (S)-2-[(8-azaspiro[4.5]decane-8-carbonyl)amino]-4,4-difluoro-5-phenylpentanoic acid obtained as a crude product (192 mg, 0.49 mmol) in 10 ml of DMF. The reaction mixture was stirred at RT overnight and, the next day, concentrated under reduced pressure. The residue thus obtained was purified by preparative HPLC (gradient: acetonitrile/water and addition of 0.05% TFA). The title compound was obtained in the form of a colorless crystalline material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[N:12]=[C:11]([C:22]([F:25])([F:24])[F:23])[CH:10]=2)=[CH:5][CH:4]=1.[ClH:26]>C(O)C>[ClH:26].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:13]([C:14]3[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=3)[N:12]=[C:11]([C:22]([F:25])([F:23])[F:24])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(C#N)cc2)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(CN)cc2)cc1

Procedure:
A mixture of 4-[5-(4-methoxyphenyl)-3-(trifluoro-methyl)-1H-pyrazol-1-yl]benzonitrile obtained by Example 69 (400 mg) and 50% wet pd/C (400 mg) in ethanol (10 ml) and 1N hydrochloric acid (1.2 ml) was stirred under hydrogen atmosphere for 8 hrs.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.C[Si]([N:16]=[C:17]=[S:18])(C)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([C:17](=[S:18])[NH2:16])[C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)N=C=S
Reactant: Cc1ccnc2c1CCCC2
Solvent: Cc1ccccc1
Product: Cc1ccnc2c1CCCC2C(N)=S
Yield: 70.9 %

Procedure:
1.55M n-Butyl lithium in hexane (35.5 ml. 55mM) at 0° C. under argon was heated with a solution of N-benzylidine-tert-butylamine (8.85 g, 50mM) in toluene (40 ml) to form lithium N-t-butyl-N-(1-phenylpentyl) amide. After 2 hours a solution of 4-methyl-5,6,7,8-tetrahydroquinoline (7.35 g, 50mM) in toluene (10 ml) was added and after a further 0.5 hours the mixture was heated with a solution of trimethylsilyl isothio-cyanate (7.7 g, 55mM) in toluene (10 ml). After 0.5 hours the reaction was quenched with water, acidified (pH1) with sulphuric acid and the layers separated. The aqueous phase was mixed with an equal volume of cyclohexane and the pH adjusted to 10 with sodium hydroxide solution. The resultant precipitate was removed by filtration, washed with water and cyclohexane and dried in vacuo to give the title compound (7.3 g, 71%) identical with authentic material. (See Example 11 UK Patent Specification No. 1463666).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][C:8]([Si:11]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:12][C@@H:13](C)[CH2:14]C(O)=O)([CH3:10])[CH3:9].CN(C=O)C>C(Cl)Cl>[CH3:7][C:8]([Si:11]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[O:12][C@@H:13]([CH3:14])[CH2:1][C:2]([Cl:4])=[O:3])([CH3:9])[CH3:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@@H](CC(=O)O)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](CC(=O)Cl)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C

Procedure:
Oxalyl chloride (4.1 mL, 48 mmol; conc. 1.5 g/mL) was added dropwise to a stirred solution of intermediate D2 (11 g, 32 mmol) and DMF (1 mL) in DCM (300 mL) at r.t. for 90 min. The reaction mixture was evaporated under reduced pressure and co-evaporated with toluene (×3) to give the crude intermediate D3 as a yellow oil. This material was used in the next step of the reaction sequence without any further purification.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH:12]1[C:22]2[CH:21]=[CH:20][C:19]3[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=3[CH:17]([C:27]3[C:28](=[O:48])[NH:29][C:30](=[O:47])[N:31]([CH2:33][C:34]4[CH:35]=[C:36]([CH2:40][NH:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH:37]=[CH:38][CH:39]=4)[CH:32]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH:23]1[C:19]2[CH:20]=[CH:21][C:22]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[CH:17]([C:27]3[C:28](=[O:48])[NH:29][C:30](=[O:47])[N:31]([CH2:33][C:34]4[CH:35]=[C:36]([CH2:40][N:41]([C:2]([O:4][CH2:5][C:6]5[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=5)=[O:3])[CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH:37]=[CH:38][CH:39]=4)[CH:32]=3)[C:18]=2[CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)CNCc1cccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CN(Cc1cccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl chloroformate (0.145 ml) was added to a solution of the product of step (iv) (0.44 g) and triethylamine (0.17 ml) in dichloromethane (10 ml). The mixture was stirred at room temperature for 2 hours. Further aliquots of benzyl chloroformate (0.1 ml) and triethylamine (0.3 ml) were added after 2 and 4 hours. The mixture was stirred overnight and partitioned between ethyl acetate and water. The organic phase was dried (MgSO4), evaporated and purified by chromatography eluting with 60% ethyl acetate in isohexane.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH:15][CH:16]=O)=[N:12][NH:13][CH:14]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:14]=[N:13][NH:12][C:11]=1[NH:15][CH3:16]
Reactant: O=CNc1n[nH]cc1-c1nc2ccccc2s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1[nH]ncc1-c1nc2ccccc2s1
Reaction time: 1 h
Yield: 60.8 %

Procedure:
To the above prepared N-(4-benzothiazol-2-yl-1H-pyrazol-3-yl)-formamide (0.50 g, 2.0 mmol) in 50 mL of anhydrous THF at 0° C. was added 0.50 g of lithium aluminum hydride. The reaction was stirred for 1 hr and then was quenched by the addition of saturated ammonium chloride solution. The solids were removed by filtration. The solvent was then evaporated and the crude product was purified by recrystallization from acetone to yield 280 mg (61%) of the title compound. MS (m/z, ES+): 231.1 (M+1, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][C:9](=[O:12])[CH:8]([C:13]([O:15][CH3:16])=[O:14])[S:7][C:6]=2[CH:17]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22]>>[Cl:22][CH2:21][CH2:20][CH2:19][C:8]1([C:13]([O:15][CH3:16])=[O:14])[S:7][C:6]2[CH:17]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[O:11][CH2:10][C:9]1=[O:12]
Reactant: COC(=O)C1Sc2cc(C)ccc2OCC1=O
Reactant: ClCCCBr
Product: COC(=O)C1(CCCCl)Sc2cc(C)ccc2OCC1=O

Procedure:
Methyl 7-methyl-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate (4.1 g) is treated with 1-bromo-3-chloropropane in the same manner as described in Reference Example 25 to give methyl 4-(3-chloropropyl)-7-methyl-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate (2.0 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.[CH3:11][C:12]1(C)[C:16](C)(C)OB(/C=C/C)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](/[CH:11]=[CH:12]/[CH3:16])[CH:7]=1
Reactant: C/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: N#Cc1ncc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C/C=C/c1cnc(C#N)c(Cl)c1
Temperature: 25 °C

Procedure:
A solution of 3,5-dichloropicolinonitrile (1.0 eq.), (E)-4,4,5,5-tetramethyl-2-(prop-1-enyl)-1,3,2-dioxaborolane (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (3.4 eq.) in toluene/ethanol (2:1, 0.04 M) was stirred at 95° C. overnight. After cooling to ambient temperature, the reaction content was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give a white solid (E)-3-chloro-5-(prop-1-enyl)picolinonitrile.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:3]=12.[N+:23]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)([O-:25])=[O:24].ClC(Cl)C.ClCCl>N1C=CC=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:18]1([N:8]2[C:4]3=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]3[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([N+:23]([O-:25])=[O:24])[CH:31]=4)=[CH:15][CH:16]=3)=[N:9]2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1ncnc2c1c(-c1ccc(O)cc1)nn2C1CCCC1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: Nc1ncnc2c1c(-c1ccc(Oc3cccc([N+](=O)[O-])c3)cc1)nn2C1CCCC1
Temperature: 25 °C
Yield: 11.8 %

Procedure:
A mixture of 4-(4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenol (0.202 g, 0.684 mmol, 1 equiv), 3-nitrophenylboronic acid (0.571 g, 3.42 mmol, 5.0 equiv), copper (II) acetate (0.186 g, 1.02 mmol, 1.5 equiv), and 4 Å molecular sieves in pyridine (0.28 mL) and dichloroethane (6.8 mL) was heated at reflux for 24 h. The reaction mixture was allowed to cool to ambient temperature. Dichloromethane (25 mL) was added to the residue and the resulting solid was removed by filtration through a pad of Celite with the aid of MeOH (20 mL). The filtrate was concentrated to afford a brown liquid which was purified by column chromatography over silica gel (elution with 400 mL of heptane, 400 mL of 10% EtOAc/heptane, 400 mL of 20% EtOAc/heptane, and 800 mL of MeOH) to afford a red oil which was further purified by preparative RP-LC/MS (Gilson-Micromass C18, 5 μm, 130 Å, 21 cm, 0%-100% acetonitrile-0.1M ammonium acetate over 9 min, 25 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give 1-cyclopentyl-3-[4-(3-nitrophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a pale yellow solid (0.034 g, 0.081 mmol): 1H NMR (d6 DMSO, 400 MHz): δH 8.22 (1H, s), 7.28-7.74 (6H, m), 7.18 (2H, d, J=8.6 Hz), 7.7 (2H, bs), 5.13-5.26 (1H, m), 2.02-2.10 (4H, m), 1.89-1.91 (2H, m), 1.68-1.70 (2H, m); RP-HPLC (Hypercil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile-0.1M ammonium acetate over 15 min, 1 mL/min) Rt 19.98 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10]([CH2:11][O:12][CH2:13][CH2:14][O:15]C(=O)C)[CH:9]=[P:8][C:4]=2[N:5]=[CH:6][N:7]=1>N>[NH2:1][C:2]1[C:3]2[N:10]([CH2:11][O:12][CH2:13][CH2:14][OH:15])[CH:9]=[P:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(=O)OCCOCn1cpc2ncnc(N)c21
Agent: N
Product: Nc1ncnc2pcn(COCCO)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
A mixture of 7-amino-1-[(2-acetoxyethoxy)methyl]-1,3-azaphospholo[4,5-d]pyrimidine (compound 21, R=CH2OCH2CH2OAc, 0.45 g, 1.68 mmol) and methanolic ammonia (100 mL, saturated at 0° C.) was stirred at room temperature for 18 h. Methanolic ammonia was evaporated in vacuo and the residue was purified by silica gel column (2×8 cm) chromatography. The column was flash eluted with dichloromethane containing 0-12% methanol. The homogeneous fractions were pooled and evaporated to yield 0.35 g (92%) of the title compound, mp 165-166° C. Ir (KBr): ν705 (=P-C), 1210 (-P=CH), 2930, 3050, and 3270 (NH2, OH) cm-1. Uv (pH 1): λmax254 nm (ε24,200), 282 (15,200), and 312 (5000); (MeOH): λmax266 nm (ε28,900), and 340 (2300); (pH 11): 266 nm (ε34,700), and 340 (1900); 31 p nmr (DMSO-d6): δ 65.85; 1H nmr (DMSO-d6): δ 3.46 (m, 4 H, 2CH2), 4.70 (br s, 1 H, OH), 5.70 (s, 2 H, CH2), 8.52 and 8.69 (2s, 2 H, NH2), 8.65 (d, 1 H, C5H), and 8.96 (d, 1 H, J=54 Hz, C2H ). Anal. Calcd. for C8H11N4O2P.0.35 CH2Cl2 : C, 37.54; H, 4.61; N, 21.89. Found: C, 37.43; H, 4.13; N, 21.53.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[O:16]=[C:17]1[C:25]2([C:29]3=[CH:30][C:31]4[O:32][CH2:33][CH2:34][O:35][C:36]=4[CH:37]=[C:28]3[O:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]1[CH2:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1>ClCCl>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:43](=[O:44])[C:42]1[CH:41]=[CH:40][C:39]([CH2:38][N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]3([C:29]4[C:28](=[CH:37][C:36]5[O:35][CH2:34][CH2:33][O:32][C:31]=5[CH:30]=4)[O:27][CH2:26]3)[C:17]2=[O:16])=[CH:47][CH:46]=1
Reactant: Nc1ccccc1F
Reactant: O=C(Cl)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1F)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 42 h
Yield: 50.1 %

Procedure:
To a stirred solution of 4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoic acid (0.400 g, 0.93 mmol) in anhydrous chloroform (20 mL) was added thionyl chloride (0.27 mL, 3.7 mmol). The solution was heated at reflux for 2 h and concentrated in vacuo to afford 4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoyl chloride (0.45 g) as a pale yellow solid. To a solution of 2-fluoroaniline (0.1 mL, 1.0 mmol) and triethylamine (0.43 mL, 3.1 mmol) in anhydrous dichloromethane (10 mL) at 0° C. under nitrogen was added 4-((2′-oxo-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indoline]-1′-yl)methyl)benzoyl chloride (0.46 g, 1.0 mmol). The reaction mixture was stirred at ambient temperature for 42 h and was washed with 10% w/v hydrochloric acid (10 mL), water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with hexanes/ethyl acetate (1/1) to afford N-(2-fluorophenyl)-4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzamide (0.262 g, 49%) as a colorless solid: mp 245-251° C.; 1H NMR (300 MHz, CDCl3) δ 8.48-8.43 (m, 1H), 8.11-8.04 (m, 1H), 7.88 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 7.24-7.02 (m, 6H), 6.75 (d, J=7.8 Hz, 1H), 6.52 (s, 1H), 6.24 (s, 1H), 5.16 (d, J=15.9 Hz, 1H), 4.95 (d, J=8.7 Hz, 1H), 4.89 (d, J=15.9 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.21-4.10 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.6, 164.9, 155.3, 152.7 (d, J=241.4 Hz), 144.7, 141.7, 140.0, 138.3, 134.1, 132.2, 128.8, 127.8 (d, J=4.1 Hz), 126.4 (d, J=9.8 Hz), 124.7-124.6 (m), 124.1, 123.7, 121.8, 120.8, 114.8 (d, J=19.1 Hz), 111.4, 109.1, 99.5, 80.1, 64.5, 63.9, 58.0, 43.8; MS (ES+) m/z 523.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C@@H:7]([NH:12][C:13](=[O:31])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])=[C:16]([N+:28]([O-])=O)[CH:15]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl.O>C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:32])[C@@H:7]([NH:12][C:13](=[O:31])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])=[C:16]([NH2:28])[CH:15]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C[C@H](NC(=O)c1ccc(Nc2ccccc2Cl)c([N+](=O)[O-])c1)C(=O)OC(C)(C)C
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)C[C@H](NC(=O)c1ccc(Nc2ccccc2Cl)c(N)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.7 %

Procedure:
140 mg of (S)-2-[4-(2-Chloro-phenylamino)-3-nitro-benzoylamino]-4-methyl-pentanoic acid tert-butyl ester were dissolved in 5 ml ethyl acetate, 342 mg of tin(II)chloride-dihydrate were added and the mixture was stirred at rt for 4 h. Water was added to the reaction. The mixture was filtrated over celite. The pH of the filtrate was adjusted to 7, the layers were separated and the organic layer was extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulphate and concentrated to yield 103 mg (79%) of (S)-2-[3-Amino-4-(2-chloro-phenylamino)-benzoylamino]-4-methyl-pentanoic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28]C)[C:23]4=[O:30])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[C:23]4=[O:30])=[CH:20][CH:21]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: COc1cccn(-c2ccc(-n3cc(CNC(=O)c4ccc(Cl)s4)nn3)cc2)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(NCc1cn(-c2ccc(-n3cccc(O)c3=O)cc2)nn1)c1ccc(Cl)s1
Reaction time: 2 h

Procedure:
5-Chloro-N-((1-(4-(3-methoxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (306 mg, 0.69 mmol, prepared using a similar procedure as described in Example 4) was stirred in 40 mL DCM as a slurry. BBr3 (200 μL, 2.1 mmol) was added. The mixture was stirred for 2 hrs and concentrated in vacuo. The residue was dissolved in 1 mL and 5 mL DMSO and subjected to prep HPLC to isolate the title compound as a white powder. MS found for C19H14ClN5O3S (M+H)+ 428.1, 430.1 (Cl pattern).
Reaction SMILES: C1(C2NN=C(N[C:10]3[C:15]([F:16])=C[C:13]([CH2:17]N4CCOCC4)=[C:12]([NH:24][C@H:25](C4C=CC(F)=CC=4)C)[N:11]=3)C=2)CC1.[BH4-].[Na+].C[OH:37]>>[F:16][C:15]1[CH:25]=[N:24][C:12]([CH:13]([OH:37])[CH3:17])=[N:11][CH:10]=1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN1CCOCC1)c1ccc(F)cc1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)c1ncc(F)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
1-(5-Fluoropyrimidin-2-yl)ethanone (Method 75, 0.77 g) was dissolved in MeOH (15 ml), and the solution was cooled to 0° C. NaBH4 (0.210 g, 5.55 mmol) was added. The mixture was stirred at room temperature for 1 hour and then partitioned between EtOAc and H2O. The organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated to give the title compound as a yellowish oil (0.79 g, 99%). 1H NMR (CDCl3) δ 8.65 (s, 2H), 5.20 (m, 1H), 4.00 (br s, 1H), 1.80 (d, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@H:14]([CH2:15][S:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([CH3:24])[CH:18]=2)[C@H:13]([OH:25])[C@@H:12]2[C@H:10]1[C@H:11]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:40][S:41](Cl)(=[O:43])=[O:42]>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@:9]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@H:14]([CH2:15][S:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([CH3:24])[CH:18]=2)[C@H:13]([O:25][S:41]([CH3:40])(=[O:43])=[O:42])[C@@H:12]2[C@H:10]1[C@H:11]2[C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(SC[C@@H]2[C@H](O)[C@H]3[C@H](C(=O)OC(C)(C)C)[C@H]3[C@]2(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1F
Solvent: c1ccncc1
Product: Cc1cc(SC[C@@H]2[C@H](OS(C)(=O)=O)[C@H]3[C@H](C(=O)OC(C)(C)C)[C@H]3[C@]2(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1F
Temperature: 40 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
Di-tert-butyl (1S,2R,3S,4R,5R,6R)-2-(tert-butoxycarbonylamino)-3-[(4-fluoro-3-methyl-phenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate (4.6 g, 8.10 mmol) in pyridine (60 mL) is cooled to 0° C. To this mixture is added methanesulfonyl chloride (1.88 ml, 24.31 mmol). The mixture is warmed to 40° C. and stirred for 1 hour, and cooled to ambient temperature and allowed to stir for 18 hours. The mixture is concentrated under reduced pressure to give a residue. The residue is partitioned between ethyl acetate and 1N aqueous HCl (2×50 mL). The organic layer is separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (5.2 g, 8.05 mmol, 99.4% yield): MS (m/z): 643.6 (M−H).