Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:13])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8]Br.C1N2CN3CN(C2)CN1C3.C(O)(=[O:26])C>O>[Cl:1][C:2]([Cl:13])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:26]
Reactant: ClC(Cl)=COc1cccc(CBr)c1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: O=Cc1cccc(OC=C(Cl)Cl)c1

Procedure:
To a solution of 8.5 g of 3-(2,2-dichlorovinyloxy)-benzyl bromide in 12.6 ml of acetic acid and 12.6 ml of water are added 8.4 g of hexamethylene tetramine. The resultant solution is refluxed for two hours. Subsequently 10 ml of HC1 are added and the reaction mixture is stirred for half an hour at 100°-110° C. The solution is washed with 100 ml of water and extracted cold (3 times) with 100 ml of ethyl acetate. The extract is washed with sodium carbonate solution and evaporated, to yield 5.8 g of 3-(2,2-dichlorovinyloxy)-benzaldehyde as a yellowish-brown oil, which can be used without further purification.
Reaction SMILES: C(O)(C(F)(F)F)=O.[OH:8][C:9]([C:35]1[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=1)([C:11]1[CH:12]=[N:13][N:14](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:15]=1)[CH3:10].C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:8][C:9]([C:35]1[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=1)([C:11]1[CH:12]=[N:13][NH:14][CH:15]=1)[CH3:10]
Reactant: COC(=O)c1ccc(C(C)(O)c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(C(C)(O)c2cn[nH]c2)cc1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
TFA (0.1 mL) in DCM (2 mL) were added dropwise to a mixture of methyl 4-[1-hydroxy-1-(1-trityl-1H-pyrazol-4-yl)ethyl]benzoate (0.2 g, 0.8 mmol), triethylsilane (0.2 mL) in DCM (5 mL) cooled to −40° C. Then the mixture was stirred at −40° C. for 2 hours. The mixture was adjusted to pH 7 by adding aqueous sodium bicarbonate solution at −40° C. After the reaction warmed to room temperature, the mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was purified by preparative thin layer chromatography to afford methyl 4-[1-hydroxy-1-(1H-pyrazol-4-yl)ethyl]benzoate. MS ESI calc'd. for C13H15N2O3 [M+H]+ 247. found 247. 1H NMR (400 MHz, CD3OD): δ 7.98 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 7.50 (s, 2H), 3.90 (s, 3H), 1.89 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH2:8][N:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[O:11][C:10]2=[O:24])[CH:7]=1.[H-].[Na+].[CH3:28][S:29][CH2:30]Cl>CN(P(N(C)C)(N(C)C)=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:28][S:29][CH3:30])=[C:6]([CH2:8][N:9]2[N:13]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=3)[O:11][C:10]2=[O:24])[CH:7]=1
Reactant: O=c1oc(-c2ccc(C(F)(F)F)cc2)nn1Cc1cc(Cl)ccc1O
Reactant: CSCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CSCOc1ccc(Cl)cc1Cn1nc(-c2ccc(C(F)(F)F)cc2)oc1=O
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A solution of 3-[(5-chloro-2-hydroxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one (6.0 g, 16.2 mmol) in dry HMPA (50 mL) was added dropwise under nitrogen to a stirred suspension of sodium hydride (0.77 g of 60% dispersion in mineral oil, 19.4 mmol) in HMPA (15 mL). The resultant yellow solution was stirred for 30 min and then neat chloromethyl methyl sulfide (1.49 mL, 17.8 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight and the product was extracted with ethyl acetate (500 mL). The EtOAc layer was washed with satd. NaHCO3, water, brine and then dried (MgSO4). Rotary evaporation of EtOAc gave a yellow semi-solid which was recrystallized from ethyl acetate/hexanes to afford the title compound as white crystals (4.4 g, 70%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C[O:17][C:18](=[O:35])[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br>>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:1][C:2]2[CH:12]=[CH:11][C:5]3[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=3[C:3]=2[CH2:13][CH2:14][CH3:15])=[C:21]([CH2:20][CH2:19][C:18]([OH:35])=[O:17])[CH:26]=1
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: COC(=O)CCc1cc(Cl)ccc1OCCCCCBr
Product: CCCc1c(OCCCCCOc2ccc(Cl)cc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 70.9 %

Procedure:
Using the procedure of example 4,5-chloro-2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid methyl ester, a pale-yellow oil, was prepared in quantitative yield starting from 0.62 g (3 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 1.21 g (3.33 mmol) of 2-[(5-bromopentyl)oxy]-5-chlorobenzenepropanoic acid methyl ester. Saponification using the procedure of example 4 afforded 1.01 g (71%) of 5-chloro-2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid as a colorless solid, mp 101°-103° C.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[Br:21][CH2:22][CH2:23][CH2:24]Br>C(#N)C>[CH3:14][N:2]([CH3:1])[C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:24][CH2:23][CH2:22][Br:21])=[C:6]([O:11][CH3:12])[CH:5]=1
Reactant: BrCCCBr
Reactant: COc1cc(C(=O)N(C)C)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(=O)N(C)C)ccc1OCCCBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.7 %

Procedure:
To N,N-dimethyl-4-hydroxy-3-methoxybenzamide (5.64 g, 28.7 mmol) in acetonitrile (450 ml) was added potassium carbonate (7.9 g) followed by 1,3-dibromopropane (11.6 g). The resulting reaction mixture was refluxed for 3 hours and stirred at room temperature for 12 hours. The mixture was filtered and concentrated to an oil. Following purification by column chromatography, N,N-dimethyl-4-bromopropoxy-3-methoxybenzamide as a colorless oil (7.6 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:21][C@H:20]([CH2:22][O:23][C:24](=[O:27])[CH2:25][CH3:26])[C@@H:14]([O:15][C:16](=[O:19])[CH2:17][CH3:18])[C@H:8]2[O:9][C:10](=[O:13])[CH2:11][CH3:12])[CH:5]=[N:4][C:3]=1[C:28]([NH2:30])=O.C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O.O>ClCCl>[NH2:1][C:2]1[N:6]([C@@H:7]2[O:21][C@H:20]([CH2:22][O:23][C:24](=[O:27])[CH2:25][CH3:26])[C@@H:14]([O:15][C:16](=[O:19])[CH2:17][CH3:18])[C@H:8]2[O:9][C:10](=[O:13])[CH2:11][CH3:12])[CH:5]=[N:4][C:3]=1[C:28]#[N:30]
Reactant: CCC(=O)OC[C@H]1O[C@@H](n2cnc(C(N)=O)c2N)[C@H](OC(=O)CC)[C@@H]1OC(=O)CC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(=O)OC[C@H]1O[C@@H](n2cnc(C#N)c2N)[C@H](OC(=O)CC)[C@@H]1OC(=O)CC
Reaction time: 1.5 h

Procedure:
A solution of 840 g of 5-amino-1-(2,3,5-tri-O-propionyl-β-D-ribofuranosyl)imidazole-4-carboxamide, 5.4 l of dichloromethane and 1.38 l of triethylamine was cooled to 0° C. or less, and a solution of 196 ml of phosphorus oxychloride in dichloromethane (1.8 l) was added dropwise thereto while maintaining the temperature below 0° C. After stirring for 1.5 hours, 2 l of water was added to the mixture below 0° C. and the dichloromethane layer was separated. The dichloromethane layer was washed successively with 2 l each of water, twice with 2 l of 1 N hydrochloric acid, and twice with 2 l each of a saturated aqueous sodium chloride solution, and then concentrated to dryness under reduced pressure to obtain 5-amino-1-(2,3,5-tri-O-propionyl-β-D-ribofuranosyl)imidazole-4-carbonitrile as a yellow brown viscous syrup.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].F[C:16](F)(F)[C:17](O)=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][C@@H:47]1[CH2:52][CH2:51][CH2:50][NH:49][CH2:48]1.C(Cl)(=O)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:17]([N:49]1[CH2:50][CH2:51][CH2:52][C@@H:47]([CH2:46][C:45]([NH:44][C:36]2[CH:37]=[CH:38][C:39]3[NH:40][C:41]4[N:42]=[C:26]([NH:27][C:28]5[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=5)[CH2:33][CH2:34][C:35]=2[CH:43]=3)[N:25]=[CH:24][C:23]=4[Cl:22])=[O:53])[CH2:48]1)(=[O:18])[CH3:16]
Reactant: O=C(C[C@@H]1CCCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCC[C@@H](CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)C1
Yield: 77 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-piperidin-3-yl]acetamide tris(trifluoroacetate) and acetyl chloride as the starting materials in 77% yield. LCMS for C26H29ClN7O2 (M+H)+: m/z=506.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:57][NH:58][CH2:59][C:60]1[CH:73]=[CH:72][C:63]([CH2:64][N:65]2[CH2:70][CH2:69][CH:68]([OH:71])[CH2:67][CH2:66]2)=[CH:62][CH:61]=1>C(Cl)Cl.O>[OH:71][CH:68]1[CH2:69][CH2:70][N:65]([CH2:64][C:63]2[CH:72]=[CH:73][C:60]([CH2:59][N:58]([CH3:57])[C:21]([C:18]3[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH3:24])(=[O:11])=[O:12])[CH3:14])[O:20][CH:19]=3)=[O:22])=[CH:61][CH:62]=2)[CH2:66][CH2:67]1
Reactant: CNCc1ccc(CN2CCC(O)CC2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(O)CC4)cc3)co2)c(C)c1
Reaction time: 0.08 h

Procedure:
5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (30 mg, 0.085 mmol) was dissolved in DCM (10 mL) and EDCI (27 mg, 0.11 mmol), HOBt (17 mg, 0.127 mmol) and DIPEA (0.03 mL, 0.17 mmol) were added. The resulting solution was stirred for 5 min prior to the addition of 1-{4-[(methylamino)methyl]benzyl}piperidin-4-ol dihydrochloride (28 mg, 0.102 mmol) and stirred at ambient temperature for 16 h. The reaction was diluted with water (5 mL) and extracted with EtOAc (2×15 mL). The combined organic extracts were washed with water (2×5 mL) and brine (5 mL), dried over Na2SO4, and concentrated in vacuo. The resulting residue was purified by FCC eluting with 5% MeOH in DCM to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:36])[NH:10][CH2:11][C:12]([N:14]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]([C:25]([O:27]C)=[O:26])[CH2:16][CH:15]2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:13])=[CH:4][CH:3]=1.O.CO>[OH-].[K+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:36])[NH:10][CH2:11][C:12]([N:14]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]([C:25]([OH:27])=[O:26])[CH2:16][CH:15]2[C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])=[O:13])=[CH:6][CH:7]=1
Reactant: COC(=O)C1CC(C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc2ccc(Cl)cc2)C1c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)C1CC(C(=O)O)C(c2ccccc2)N1C(=O)CNC(=O)Nc1ccc(Cl)cc1
Yield: 68.5 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 2.1 g of 2-tert-butyl 4-methyl (2RS,4RS,5SR)-1-{2-[3-(4-chlorophenyl)ureido]acetyl}-5-phenylpyrrolidine-2,4-dicarboxylate in a mixture of 4 cm3 of a normal aqueous potassium hydroxide solution, 20 cm3 of distilled water and 60 cm3 of methanol. After treatment, there are obtained 1.4 g of 2-tert-butyl hydrogen (2RS,4SR,5SR)-1-{2-[3-(4-chlorophenyl)ureido]acetyl}-5-phenylpyrrolidine-2,4-dicarboxylate, melting at 248° C.
Reaction SMILES: [CH3:1][N:2]([S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:19])=[O:18])[C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]=1[C:13]([O:15]C)=[O:14].[Li+].[I-]>N1C=CC=CC=1>[CH3:1][N:2]([S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][CH2:27][CH:28]1[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]1)(=[O:18])=[O:19])[C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]=1[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1c(N(C)S(=O)(=O)c2ccccc2NCC2CCNCC2)ccc2c1CCCC2
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CN(c1ccc2c(c1C(=O)O)CCCC2)S(=O)(=O)c1ccccc1NCC1CCNCC1
Temperature: 150 °C
Yield: 22.3 %

Procedure:
A mixture of Example 487A (0.064 g, 0.14 mmol) in 1.4 mL pyridine was treated with LiI (0.068 g, 0.5 mmol), heated to 150° C. for 25 minutes in a microwave reactor, and concentrated. The concentrate was purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product (14.3 mg). MS (ESI(+)) m/e 458 (M+H)+; (ESI(−)) m/e 456 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 7.58 (dd, 1H), 7.37 (dt, 1H), 7.19 (d, 1H), 6.85 (d, 1H), 6.82 (d, 1H), 6.57 (t, 1H), 6.43 (m, 1H), 3.19 (m, 4H), 2.90 (s, 3H), 2.72, (m, 2H), 2.68 (m, 4H), 1.83 (m, 3H), 1.68 (m, 6H).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[C:8]([CH3:13])=[CH:7][C:5]=2[N:6]=1.[C:14](ON=O)([CH3:17])(C)[CH3:15].[Br-].COC1C(C)=CC2N=C(N)SC=2C=1>C(#N)C>[CH:17]1([C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][CH3:12])[C:8]([CH3:13])=[CH:7][C:5]=3[N:6]=2)[CH2:14][CH2:15]1
Reactant: COc1cc2sc(Br)nc2cc1C
Reactant: CC(C)(C)ON=O
Agent: COc1cc2sc(N)nc2cc1C
Agent: [Br-]
Solvent: CC#N
Product: COc1cc2sc(C3CC3)nc2cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Preparation of (2-bromo-6-methoxy-5-methylbenzo[d]thiazole (6A): To a solution of t-butylnitrite (5.17 ml, 43.5 mmol) in acetonitrile (50 ml) was added coppeer (II) bromide (7.2 g, 32.2 mmol) slowly. The reaction mixture was stirred at room temperature for half hour. Then the reaction mixture was put to a 60° C. oil bath and 6-methoxy-5-methylbenzo[d]thiazol-2-amine (5A) (4.2 g, 21.76 mmol) was added slowly. The reaction mixture was stirred at 60° C. for 1 h. The reaction was cooled to room temperature; washed with water and extracted with EtOAc. The organic phase was combined, dried over MgSO4, filtered, concentrated and purified by silica gel column, eluting by 0-50% EtOAc in hexanes. LCMS-ESI+: calc'd for C9H8BrNOS: 257.9 (M+H+). Found: 258.0 (M+H+).
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[NH2:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:21][NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl>[Cl:32][C:31]1[CH:30]=[CH:29][C:20]([CH2:21][NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:19][C:18]=1[N:17]=[C:1]=[S:2]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N)c1
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1,1′-Thiocarbonyldi-2-pyridone (2.12 g, 9.1 mmol) was added to a mixture of N-(3-amino-4-chlorobenzyl)-2,2-dimethyl-propionamide (2.00 g, 8.3 mmol) and DCM (60 mL) and stirred at rt for 1.5 h. The mixture was filtered over silica gel. The organic layer was concentrated to give the sub-title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH3:24])[C:19]2[CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][CH2:28][C:18]3=2)[C:11](=[O:36])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:37]>CO.CCOCC>[ClH:37].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH3:24])[C:19]2[CH2:25][NH:26][CH2:27][CH2:28][C:18]3=2)[C:11](=[O:36])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c2c(c3cc(-n4ccc(OCc5ccccc5)cc4=O)ccc31)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cn1c2c(c3cc(-n4ccc(OCc5ccccc5)cc4=O)ccc31)CCNC2
Reaction time: 1 h
Yield: 98 %

Procedure:
tert-Butyl 6-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (0.340 g, 0.70 mmol) was dissolved in MeOH (5 mL) and 2 N HCl in ether (15 mL) was added. After stirring for 1 h, the liquid was decanted off and the resultant solid was filtered and washed with ether (3×). This provided the title compound (267 mg, 98%) as a light yellow solid: mp 290-300° C.; 1H NMR (500 MHz, CD3OD) δ 7.66 (d, J=7.5 Hz, 1H), 7.57-7.52 (m, 2H), 7.46 (d, J=7.7 Hz, 2H), 7.41 (overlapping dd, J=7.3 Hz, 2H), 7.36 (d, J=7.5 Hz, 1H), 7.19 (dd, J=8.6, 2.0 Hz, 1H), 6.42 (dd, J=7.5, 2.7 Hz, 1H), 6.22 (d, J=2.6 Hz, 1H), 5.22 (s, 2H), 4.55 (s, 2H), 3.75 (s, 3H), 3.58 (t, J=6.0 Hz, 2H), 3.10 (t, J=6.0 Hz, 2H); ESI MS m/z 386 [M+H]+; HPLC (Method B) 98.8% (AUC), tR=12.8 min.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]([O:13]C)=[O:12])[O:8][N:7]=1.[OH-].[Na+]>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[O:8][N:7]=1
Reactant: COC(=O)c1cc(OCCCBr)no1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(OCCCBr)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
A solution of methyl 3-(3-bromopropoxy)isoxazole-5-carboxylate (250 mg, 0.93 mmol) in tetrahydrofuran (1.5 mL) was treated with 1 N aqueous sodium hydroxide (2.0 mL) and the mixture was stirred at room temperature for 30 min. The mixture was concentrated in vacuo and was neutralized with 1N aqueous hydrochloric acid. The resulting precipitate was filtered and washed with water andried in vacuo to yield the pure product (230 mg, 99%). MF=C7H9BrNO4; LCMS calculated for C7H9BrNO4 (M+H)+: m/z=250.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.C1(C2[O:21]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>ClCCl.CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([S:11]([CH3:12])=[O:21])[N:3]=1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CSc1nc(N)nc(Cl)c1C#N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)c1nc(N)nc(Cl)c1C#N
Reaction time: 16 h
Yield: 69.4 %

Procedure:
To a stirred suspension of 2.00 g (9.97 mmol) 2-amino-4-chloro-6-methylsulfanyl-pyrimidine-5-carbonitrile in 6 ml dichloromethane and 20 ml DMF was added 5.21 g (19.9 mmol) 3-phenyl-2-(phenylsulfonyl)oxaziridine and stirring continued for 16 hours at room temperature. The reaction mixture was then concentrated in vacuo and the residue recrystallised from ether/dichloromethane to afford 1.50 g (69%) 2-amino-4-chloro-6-methanesulfinyl-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 239 (M+Na+, 45), 234 (M+NH4+, 55), 217 (M+H+, 100).
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:24]([F:27])([F:26])[F:25])=[N:5][N:6]([CH2:8][C:9]([NH:11][C:12]2[S:16][C:15]3[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[C:13]=2[C:21]([NH2:23])=[O:22])=[O:10])[CH:7]=1)=[O:2].[CH3:28][Mg]Br.C(OCC)C>C1COCC1>[OH:2][CH:1]([C:3]1[C:4]([C:24]([F:27])([F:25])[F:26])=[N:5][N:6]([CH2:8][C:9]([NH:11][C:12]2[S:16][C:15]3[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[C:13]=2[C:21]([NH2:23])=[O:22])=[O:10])[CH:7]=1)[CH3:28]
Reactant: C[Mg]Br
Reactant: NC(=O)c1c(NC(=O)Cn2cc(C=O)c(C(F)(F)F)n2)sc2c1CCCC2
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Temperature: -50 °C
Reaction time: 1.5 h
Yield: 48 %

Procedure:
To 2-(2-(4-formyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (1.6 g, 4.00 mmol) in THF (10 mL) at −50° C. under an argon atmosphere was added 3M methylmagnesium bromide in diethyl ether (1.249 mL, 3.75 mmol) in a dropwise manner over 10 min. The reaction was stirred at −50° C. for 1.5 h. The reaction was quenched with saturated aqueous NH4Cl before partitioning between EtOAc/water (×2), and washing with EtOAc (×1) and brine (×1). The organics were dried over MgSO4 before removing the solvent in vacuo. The residue was purified by silica gel flash chromatography (1:2 heptane/EtOAc) and the solvent removed in vacuo to give the title compound as a yellow solid (0.8 g, 1.921 mmol, 48%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:27][CH3:28])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:11][C:12]=2[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[N:6]1.[OH:29]O>CO>[CH3:1][O:2][CH:3]([O:27][CH3:28])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:29])=[CH:11][C:12]=2[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[N:6]1
Reactant: OO
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cc2cnn(CC(OC)OC)c12
Solvent: CO
Product: COC(=O)c1cc(O)cc2cnn(CC(OC)OC)c12
Reaction time: 3 h

Procedure:
At room temperature, to a solution of methyl 1-(2,2-dimethoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-7-carboxylate (287 mg, 0.7 mmol) from Step E above in methanol (12 ml) was added 30% hydrogen peroxide (20.0 eq). The reaction mixture was stirred for 3 h, and then quenched with aqueous sodium sulfite. The mixture was extracted with ethyl acetate and washed with water. The organic extract was concentrated in vacuo to give methyl 1-(2,2-dimethoxyethyl)-5-hydroxy-1H-indazole-7-carboxylate as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.96 (s, 1H), 7.50 (d, J=2.5 Hz, 1H), 7.24 (d, J=2.5 Hz, 1H), 4.90 (d, J=5.5 Hz, 2H), 4.86 (s, 1H), 4.52 (t, J=5.5 Hz, 1H), 3.97 (s, 3H), 3.27 (s, 6H); MS (ESI+) m/z 249 (M+H).
Reaction SMILES: [H-].[Na+].[CH2:3]1COCC1.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][N:25]3[C:34](=[O:35])[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[CH:26]3)[CH2:21][CH:22]=2)=[CH:9]1.IC>O>[CH3:3][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][N:25]3[C:34](=[O:35])[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[CH:26]3)[CH2:21][CH:22]=2)=[CH:9]1
Reactant: C1CCOC1
Reactant: O=c1c2ccccc2ncn1CCN1CC=C(c2c[nH]c3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cn1cc(C2=CCN(CCn3cnc4ccccc4c3=O)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
A dried flask under nitrogen was loaded with sodium hydride (0.015 g, 0.37 mmol) and THF (10 mL). At 0° C. 3-[2-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H) -pyridinyl)ethyl]-4(3H)-quinazolinone (0.80 g, 2.16 mmol), was added and the mixture stirred for 15 minutes. Keeping the reaction temperature at 0° C., the iodomethane was added dropwise (0.14 mL, 2.16 mmol). This was allowed to warm to room temperature and stir overnight. Water was slowly added to the mixture to quench and the organics were extracted in chloroform, washed with water and dried over Na2SO4, filtered and concentrated. The residue was chromatograhed using silica (2% methanol:chloroform system); 0.52 g of 3-[2-(4-(1-methyl-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-4(3H)-quinazolinone was isolated as an orange solid. Yield 63%; MS: 384.9 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 2.79 (m, 2H), 3.17 (m, 4H), 3.20 (m, 2H), 3.61 (m, 2H), 3.76 (s, 3H), 4.44 (t, 2H), 6.12 (t, 1H), 7.00 (t, 1H), 7.37 (m, 1H), 7.53 (m, 1H), 7.45 (m, 2H), 7.81 (m, 1H), 8.17 (d, 1H), 8.35 (s, 1H).