Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[S:3][CH:4]=[C:5]([CH3:7])[CH:6]=1.[C:8]([C:12]1[CH:16]=[C:15]([NH2:17])[NH:14][N:13]=1)([CH3:11])([CH3:10])[CH3:9].CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[K+].[K+].N#N>C1(C)C=CC=CC=1.[Cu]I>[C:8]([C:12]1[CH:16]=[C:15]([NH2:17])[N:14]([C:2]2[S:3][CH:4]=[C:5]([CH3:7])[CH:6]=2)[N:13]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: Cc1csc(I)c1
Reactant: CC(C)(C)c1cc(N)[nH]n1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: N#N
Solvent: Cc1ccccc1
Product: Cc1csc(-n2nc(C(C)(C)C)cc2N)c1

Procedure:
To a solution of 2-iodo-4-methylthiophene (WO 2008/121666) (1.00 g, 4.50 mmol) in anhydrous toluene (15.0 mL) was added 3-tert-butyl-1H-pyrazol-5-amine (683 mg, 4.91 mmol) followed by (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (140 μL, 0.89 mmol) and potassium carbonate (1.30 g, 9.37 mmol). The mixture was purged with N2, copper(I) iodide (42 mg, 0.22 mmol) was added and the reaction mixture was heated at reflux under N2 for 16 hr during which time most of the solvent was lost. The resulting mixture was partitioned between ethyl acetate (150 mL) and water (150 mL) and the organic layer was separated and extracted with aq. citric acid solution (10% w/v, 150 mL) followed by brine (50 mL), and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 120 g, DCM, isocratic elution) to afford the title compound, Intermediate A20, as a brown solid (340 mg, 32%); Rt 1.94 min (Method 2); m/z 236 (M+H)+ (ES+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[C:30]([F:36])[CH:29]=1>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:32][C:31]2[CH:34]=[CH:35][C:28]([Cl:27])=[CH:29][C:30]=2[F:36])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1cccc(Cc2cc(Cl)ccc2O)n1
Reactant: Fc1cc(Cl)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1
Temperature: 50 °C

Procedure:
A mixture of ethyl 6-[(5-chloro-2-hydroxyphenyl)methyl]-2-pyridinecarboxylate (92 mg, 0.31 mmol), potassium carbonate (109 mg, 2.5 equivalents) and 4-chloro-2-fluorobenzyl bromide (78 mg, 1.1 equivalents) in acetone (˜6 ml) was heated at 50° C. for 3-4 hours until there was no more SM (starting material). Cooled down, filtered off and washed with acetone. LC/MS okay, Rt4.05. Purified by SPE, product came off with ˜20% ethyl acetate in iso-hexane. 108 mg of a white solid. Rt=4.05 [MH+] 434, 437.
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[O:17]1[C:21]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=O)[O:30]C3C=CC([N+]([O-])=O)=CC=3)[CH:25]=[CH:26][CH:27]=2)=[N:20][CH:19]=[N:18]1>C(#N)C.CN(C)C=O>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([NH:1][C:29]([NH:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([C:21]4[O:17][N:18]=[CH:19][N:20]=4)[CH:23]=3)=[O:30])[C:7]=2[CH:8]=1)#[N:13]
Reactant: O=C(Nc1cccc(-c2ncno2)c1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)Nc2cccc(-c3ncno3)c2)[C@@H]1O
Temperature: 80 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A mixture of (3S-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.65 g, 0.0030 mol, from example 1, part B) and [3-(1,2,4-oxadiazol-5-yl)]phenylcarbamic acid, 4-nitrophenyl ester (1.08 g, 0.0033 mol) in acetonitrile (25 mL) and dimethylformamide (20 mL) was stirred at 80° C. for one hour. The reaction mixture was concentrated in vacuo and the residue, diluted with ethyl acetate, was washed with 10% citric acid and water. The organic layer was dried over MgSO4 and concentrated in vacuo. The product was purified by flash chromatography (Sorbisol C 60 flash silica gel, 400 mL) and eluted with Hexane/EtOAc (2:1) and Hexane/EtOAc (1:1). The solvent was removed in vacuo, to give a solid that was triturated with anhydrous ether and dried in vacuo to yield 1.08 g of the title compound, m.p. 168°-170° C. TLC, silica gel, EtOAc/Hexane(2:l), Rf =0.42. 1H-NMR (DMSO-d6) δ9.1 (s, 1H), 9.0 (s, 1H), 8.5 (s, 1H), 7.5 (m, 4H), 7.0 (d, J=8.8 Hz 1H), 6.8 (d, J=8.8 Hz, 1H), 5.7 (d, J=5.9 Hz, 1H), 4.7 (t, J=8.8 Hz, 1H), 3.7 (dd, J=5.9 & 3.5 Hz, 1H), 3.4 (s, 1H), 1.5 (s, 3H), 1.2 (s, 3H); 13C-NMR (DMSO-d6) δ174.8, 158.6, 156.3, 155.7, 141.4, 132.6, 132.5, 130.0, 125.9, 123.7, 122.3, 120.6, 119.1, 117.9, 116.7, 102.7,l 80.4, 71.3, 49.5, 26.6, 18.9; IR (KBr) 2228, 1667, 1574, 1551, 1489 cm-1.M.S. (M+H)+ at 406, M.W. 405; [α]D =-55.20° (c=0.86 DMSO).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH:18]=[CH2:19])[C@@H:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[NH2:10])[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[CH:29](/[S:37](Cl)(=[O:39])=[O:38])=[CH:30]\[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH:18]=[CH2:19])[C@H:9]([NH:10][S:37](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:39])=[O:38])[C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=C[C@H](c1cccc(Cl)c1)[C@H](N)c1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C=C[C@H](c1cccc(Cl)c1)[C@H](NS(=O)(=O)/C=C/c1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 5.33 g (18.24 mmol) of (1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-en-1-amine (Example 115, Step E) in DCM (45.0 mL) was added N,N-diisopropylethylamine (4.8 mL, 27.5 mmol), followed by trans-beta-styrenesulfonyl chloride (4.17 g, 20.58 mmol). The resulting solution was stirred at ambient temperature under an N2 atmosphere. After being stirred for 3.25 hours, the reaction was diluted with water and extracted with DCM. The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated. Purification by flash chromatography on silica gel (0 to 40% EtOAc in hexanes gradient) provided the title compound as a yellow solid.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[F:20][C:21]1[C:34]([NH:35][C:36]([CH:38]2[NH:43][CH2:42][CH:41]3[CH:39]2[CH2:40]3)=[O:37])=[CH:33][C:24]2[N:25]([CH2:30][C:31]#[CH:32])[C:26](=[O:29])[CH2:27][O:28][C:23]=2[CH:22]=1.O>C(Cl)Cl>[F:20][C:21]1[C:34]([N:35]2[C:36](=[O:37])[CH:38]3[CH:39]4[CH2:40][CH:41]4[CH2:42][N:43]3[C:2]2=[O:4])=[CH:33][C:24]2[N:25]([CH2:30][C:31]#[CH:32])[C:26](=[O:29])[CH2:27][O:28][C:23]=2[CH:22]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C#CCN1C(=O)COc2cc(F)c(NC(=O)C3NCC4CC43)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C#CCN1C(=O)COc2cc(F)c(N3C(=O)C4C5CC5CN4C3=O)cc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of triphosgene (57 mg) in CH2Cl2 (1 mL) was added dropwise to a stirred solution of triethylamine (0.2 mL) and the compound of Step G, Example 3, (190 mg) in CH2Cl2 (50 mL) under N2 at room temperature. The solution was stirred at room temperature for 20 minutes. 30 mL of water was added. The organic layer was separated, dried (MgSO4) and evaporated to dryness. Flash chromatography yielded the title compound of Step H, a compound of the invention, as a white solid (127 mg), 62%; m.p. 217°-219° C.; IR (nujol, cm-1): 3253.6 and 2129.3 (C≡C), 1625 and 1715 (C=O).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:16][OH:17])=[C:13]([OH:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.CO.O=[Mn]=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:16]=[O:17])=[C:13]([OH:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(OCc2ccccc2)cc1O
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CO
Product: O=Cc1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-benzyloxy-2-hydroxymethylphenol (2.39 g, 10.4 mmol) in CH2Cl2 (52 mL) and MeOH (5 mL) is added MnO2 (9.05 g, 104 mmol). The suspension is stirred at ambient temperature overnight. The mixture is filtered and the solvent removed under reduced pressure. The crude material is purified by flash chromatography using CH2Cl2 to afford 4-benzyloxy-2-hydroxybenzaldehyde as a pale yellow solid: 1H NMR (CDCl3) δ 11.45 (s, 1H), 9.70 (s, 1H), 7.43-7.39 (m, 6H), 6.59 (dd, J=2.28 Hz), 6.50 (d, J=2.27 Hz, 1H), 5.10 (s, 2H); (M+H)+=229.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1>>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:13][CH:12]=1
Reactant: CN1CCC(=O)CC1
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNC2CCN(C)CC2)cc1

Procedure:
Starting materials: 1-Methyl-4-piperidone (1.13 g, 10.0 mmol, 1.0 eq.), 4-methoxybenzylamine (1.37 g, 1.0 eq.).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([C:16]2[C:17](=[O:32])[NH:18][C:19](=[O:31])[C:20]=2[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:29]=2[N:28]([CH3:30])[CH:27]=[CH:26]3)=[CH:6]1.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:58]>CCOC(C)=O.O>[Br:58][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([C:16]2[C:17](=[O:32])[NH:18][C:19](=[O:31])[C:20]=2[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:29]=2[N:28]([CH3:30])[CH:27]=[CH:26]3)=[CH:6]1
Reactant: COc1ccc2c(C3=C(c4cccc5ccn(C)c45)C(=O)NC3=O)cn(CCCO)c2c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2c(C3=C(c4cccc5ccn(C)c45)C(=O)NC3=O)cn(CCCBr)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
To a solution of 3-[1-(3-hydroxypropyl)-6-methoxy-1H-indol-3-yl]-4-(1-methyl-1H-indol-7-yl)-pyrrole-2,5-dione (3.0 g, 7.0 mmol) in solution of DMF (300 mL) was added PPh3 (2.6 g, 10.5 mmol) and CBr4 (3.3 g, 10.5 mmol). The reaction mixture was stirred at room temperature and under nitrogen for 1 h. The reaction was monitored by TLC and was completed after 2 h. The reaction mixture was diluted with EtOAc (300 mL) and water (800 mL). The aqueous phase was extracted with EtOAc (3×300 ml). The combined organic phases were washed with saturated aq NaHCO3 (300 mL), brine (500 mL) dried (MgSO4), filtered and concentrated. Flash chromatography (SiO2, 30% EtOAc/hexanes) gave the title compound (2.4 g, 71%) as a red solid. 1H NMR (300 MHz, DMSO-d6) 11.04 (s, 1H), 7.88 (s, 1H), 7.62 (d, J=6.1 Hz, 1H), 7.19 (d, J=2.6 Hz, 1H), 7.00–6.91 (m, 2H), 6.84 (d, J=6.0 Hz, 1H), 6.48 (d, J=2.5 Hz, 1H), 6.10 (m, 2H), 4.27 (t, J=5.8 Hz, 2H), 3.71 (s, 3H), 3.62 (s, 3H), 3.32 (t, J=5.8 Hz, 2H), 2.11 (m, 2H). MS (electrospray, m/z) 492.1/494.1 (M++1), 490.2/492.2 (M−−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=[O:10])[CH3:9])[CH:3]=1.[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2([CH3:9])[O:13][CH2:12][CH2:11][O:10]2)[CH:3]=1
Reactant: OCCO
Reactant: CC(=O)c1cc(Cl)ccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(c2cc(Cl)ccn2)OCCO1
Yield: 91.9 %

Procedure:
1-(4-Chloro-2-pyridyl)ethanone (440 mg, 2.83 mmol) and ethyleneglycol (480 mg, 3 mmol) were mixed with toluene (10 ml), a catalytic amount of p-toluenesulfonic acid was added and the mixture was heated at reflux overnight. The mixture was evaporated to dryness to yield 523 mg of a solid (2.6 mmol, 93%). MS (APCI) m/z=200.0 [M+H]+.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:21]([O:22]C(=O)C)[C@H:20]([O:26]C(=O)C)[CH2:19][S:18][C@H:6]1[S:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:9]=1[C:16]#[N:17])(=O)C>C(Cl)Cl.CO>[S:7]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:9]=1[C:16]#[N:17])[C@@H:6]1[S:18][CH2:19][C@@H:20]([OH:26])[C@H:21]([OH:22])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccc(C#N)cc2C#N)SC[C@H]1OC(C)=O
Solvent: ClCCl
Solvent: CO
Product: N#Cc1ccc(S[C@@H]2SC[C@@H](O)[C@H](O)[C@H]2O)c(C#N)c1
Yield: 67 %

Procedure:
If the procedure described in Preparation V is followed, except that the reaction is carried out at 0° C., starting from 1.5 g (34.10-3 mol) of 2,4-dicyanophenyl 2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 16a), 0.71 g (yield: 67%) of the expected product is obtained after chromatography on silica using a CH2Cl2 /CH3OH mixture (8/1 v/v) as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][N:13](C(=O)[C@H](OC)C3C=CC=CC=3)[CH2:12][CH2:11][O:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Li+].[B-](CC)(CC)CC.Cl>C1COCC1>[Cl:8][C:6]1[CH:5]=[C:4]([C@@H:9]2[O:10][CH2:11][CH2:12][NH:13][CH2:14]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CO[C@@H](C(=O)N1CCO[C@@H](c2cc(Cl)cc(Cl)c2)C1)c1ccccc1
Agent: CC[B-](CC)CC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1cc(Cl)cc([C@H]2CNCCO2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Synthesized according to General Procedure 35. To a stirring solution of (R)-1-((S)-2-(3,5-dichlorophenyl)-morpholino)-2-methoxy-2-phenylethanone (24 mg, 0.06 mmol) and THF (2.2 mL), under N2, at 0° C., was added a solution of Super-hydride in THF (1.0 M, 0.4 mL, 0.4 mmol) dropwise over 10 minutes. The solution was stirred at 0° C. for 30 minutes. The solution was poured into 2M aqueous HCl solution (3 mL) and washed with diethyl ether (3×3 mL). The aqueous phase was concentrated and purified by preparative HPLC. The ee was determined to be >98%. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=232.1; tR=1.04 min. SFC (Chiralpak IA, (0.46×25 cm), 35% methanol (0.1% DEA)/CO2, 3 mL/min): tR (S)=2.0 min, tR (R)=3.39 min.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:13][CH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)cc1[N+](=O)[O-]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc(CBr)c([N+](=O)[O-])c1
Yield: 44.9 %

Procedure:
A solution of 4-methyl-3-nitro-benzonitrile (3.0 g, 18.5 mmol), N-bromosuccinimide (4.12 g), and benzoyl peroxide (0.224 g) in carbon tetrachloride was refluxed overnight. The reaction mixture was diluted with dichloromethane and washed with sodium bicarbonate solution and brine, dried, and concentrated. The residue was purified by silica gel chromatography in 10% ethyl acetate hexanes to give compound 65a (2.0 g, 45%).
Reaction SMILES: Cl.[NH2:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[C:8]([NH2:10])=[O:9].C(N(CC)CC)C.C(O)(=O)C.[C:22]([NH:29][CH2:30][CH:31]=O)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO>[C:8]([C:4]1[NH:5][CH:6]=[N:7][C:3]=1[NH:2][CH2:31][CH2:30][NH:29][C:22](=[O:23])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:9])[NH2:10]
Reactant: NC(=O)c1nc[nH]c1N
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCNc1nc[nH]c1C(N)=O
Reaction time: 0.25 h
Yield: 55.1 %

Procedure:
The reaction mixture of 5-amino-imidazole-4-carboxamide hydrochloride (10 g, 62 mmol) and triethylamine (8.7 mL, 63 mmol) in anhydrous methanol (100 mL) was stirred for 15 min. Acetic acid (0.9 mL, 16 mmol) and N-boc-2-aminoacetaldehyde (11 g, 67 mmol) were added. The reaction mixture was stirred for 3 h, then sodium cyanoborohydride (5 g, 80 mmol) was added and the mixture was stirred o.n. A solution of saturated sodium bicarbonate was added and most of the methanol was removed in vacuo. The mixture was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated. Purification by silica gel column chromatography, (dichloromethane/ammonia (7N in methanol), 0-6%) gave 9.2 g (55% yield) of the title compound.
Reaction SMILES: Br[C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:21])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:23])[CH2:4][CH2:5][C:6](=[O:22])[CH:7]=1.C(O)(=O)CS.O>CN(C=O)C>[OH:20][C@H:19]1[CH2:18][C@@:16]2([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]2=[O:21])[C@H:11]2[C@H:2]1[C@:3]1([CH3:23])[C:8]([CH2:9][CH2:10]2)=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]1
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)C[C@H](O)[C@@]12Br
Agent: O=C(O)CS
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)C(=O)CC[C@@H]12
Yield: 85.3 %

Procedure:
A solution of 9α-bromo-11β-hydroxyandrost-4-ene-3,17-dione (III, 3.00 g) thioglycolic acid (3.0 ml) in DMF (17 ml) is stirred under nitrogen in a 45°-50° water bath. A chromous sulfate solution (1.4 M, 7.0 ml) is added dropwise over about 5 minutes. The mixture is allowed to cool, and the resulting slurry is diluted by slow addition of water (50 ml). The mixture is cooled to about 5° and filtered. The filter cake is washed with water and air dried to give the title compound (2.03 g, 85.3% chemical yield) which is identical with an authentic sample. The filtrate is extracted to give additional material (0.34 g, 14.3%).
Reaction SMILES: O=[C:2]1[N:8]([C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH2:7][C:6](=[O:17])[C:3]21[CH2:5][CH2:4]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[OH:17][CH:6]1[C:3]2([CH2:5][CH2:4]2)[CH2:2][N:8]([C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH2:7]1
Reactant: C[C@H](c1ccccc1)N1CC(=O)C2(CC2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](c1ccccc1)N1CC(O)C2(CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
A suspension of 1.5 g of compound 12 and 500 mg of lithium aluminum hydride in 30 ml of tetrahydrofuran was refluxed for 16 hours. 0.5 ml of water, 0.5 ml of 15% aqueous sodium hydroxide and 1.5 ml of water were added to the mixture in the mentioned order, and the mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration and the filtrate was concentrated to dryness to yield 1.4 g of 7-hydroxy-5-[1-(R)-phenylethyl]-5-azaspiro[2.4]heptane as a pale yellow oil. 5 ml of acetic anhydride and 5 ml of pyridine were added to 1.4 g of 7-hydroxy-5-[1-(R)-phenylethyl]-5-azaspiro[2.4]heptane which was cooled on an ice-bath. The mixture was stirred at room temperature for 3 hours. Ethyl acetate was added thereto and the solution was washed with saturated aqueous sodium bicarbonate and water, then, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to yield 1.6 g of 7-acetoxy-5-[1-(R)-phenylethyl]-5-azaspiro[2.4]heptane as a yellow oil. A mixture of 1.6 g of 7-acetoxy-5-[1-(R)-phenylethyl]-5-azaspiro[2.4]heptane and 1.2 g of palladium-on-carbon (50% water wet) in 20 ml of ethanol was shaken under 3.8 atm of pressured hydrogen atmosphere for 5 hours. During the reduction reaction, the reaction vessel was warmed by a tungsten lamp. The catalyst was removed by filtration and the solvent was removed under reduced pressure to give 880 mg of title compound 69 as an oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([C:15]([CH:17]([C:23]([O:25]CC)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>OS(O)(=O)=O>[F:8][C:7]1[C:2]([F:1])=[C:3]2[C:4]([CH:23]([OH:25])[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:15](=[O:16])[C:9]32[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2cccc(F)c2F)CCOCC1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1C(=O)C2(CCOCC2)c2c(ccc(F)c2F)C1O
Temperature: 0 °C
Yield: 7.9 %

Procedure:
To 10 mL concentrated H2SO4 stirred at 0° C. was added diethyl 2-(4-(2,3-difluorophenyl)-tetrahydro-2H-pyran-4-carbonyl)malonate (3.3 g, 8.6 mmol) dropwise. The mixture was stirred at 0° C. and allowed to warm to room temperature over 2 hours. The mixture was poured into 100 g crushed ice and extracted with EtOAc (3×100 mL). The combined organic layers were washed with saturated NaCl (20 mL), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by column chromatography (20% EtOAc/hexane) to give the title compound 0.23 g as a pale yellow solid. MS m/e: (M+H)+ 339.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:19]1([C:22]([NH2:24])=[O:23])[CH2:21][CH2:20]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([NH:24][C:22]([CH:19]3[CH2:21][CH2:20]3)=[O:23])=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: NC(=O)C1CC1
Reactant: Fc1cccc(Cl)c1-c1nc2ccnc(Br)c2s1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1nccc2nc(-c3c(F)cccc3Cl)sc12)C1CC1
Temperature: 25 °C
Yield: 39.2 %

Procedure:
To a microwave tube was added 4-bromo-2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridine (0.050 g, 1.5 mmol), cyclopropanecarboxamide (0.019 g, 0.22 mmol), Pd2(dba)3 (0.013 g, 0.017 mmol), XantPhos (0.017 g, 0.034 mmol) and Cs2CO3 (0.11 g, 0.34 mmol) in dioxane (2.0 mL). The mixture was degassed with N2 for 10 minutes and then irradiated in a microwave reactor at 160° C. for 2 hours. After cooling to room temperature, the solid was removed via filtration and the filtrate was concentrated under reduced pressure. The residue was purified with reverse phase column chromatography, eluting with a 0-60% gradient of CH3CN in 0.5% NH4HCO3 to give the desired product as a white solid (0.030 g, 59% yield). 1H NMR (500 MHz, DMSO-d6): δ 11.43 (s, 1H), 8.46 (d, J=6.0 Hz, 1H), 7.92 (d, J=6.0 Hz, 1H), 7.72-7.68 (m, 1H), 7.67-7.59 (m, 1H), 7.52-7.49 (m, 1H), 2.09-2.06 (m, 1H), 0.92-0.86 (m, 4H). LCMS (Method A): RT=6.30 min, m/z: 348.0 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[CH3:26][NH:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29].C(=O)([O-])[O-].[Na+].[Na+].ClCCl>O1CCOCC1.O.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10]([C:33]3[CH:34]=[CH:35][C:30]([C:28]([NH:27][CH3:26])=[O:29])=[CH:31][CH:32]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CCCC3)nc(Cl)nc21
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CCCC4)c23)cc1
Temperature: 90 °C
Yield: 62.5 %

Procedure:
2-Chloro-4-(cyclopentyloxy)-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv) and (4-(methylcarbamoyl)phenyl)boronic acid (1.3 equiv) were combined in 1,4-dioxane (0.3 M). Sodium carbonate (3 equiv), dissolved in water (3.6 M), was added to the reaction mixture, followed by addition of [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (0.1 equiv). Nitrogen gas was bubbled through the reaction mixture for 2 min then reaction was heated at 90° C. for 3 h. The solvent was removed under reduced pressure and the product was purified by silica gel chromatography (Biotage, 0-80% ethyl acetate in hexane over 2.2 L). The fractions containing the desired product were combined and evaporated under reduced pressure to give the title compound (62.5% yield) as an orange solid. MS (ESI) m/z 501.4 [M+1]+.