Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1.[CH2:26](Br)[CH2:27][CH2:28][CH3:29]>>[CH2:26]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1)[CH2:27][CH2:28][CH3:29]
Reactant: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Reactant: CCCCBr
Product: CCCCn1cc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)c2ccccc21

Procedure:
Substantially the same procedure as in Example 3 was repeated using Compound 1 (1.69 g) obtained in Example 1 and butyl bromide (0.81 ml) to give Compound 4 (1.48 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][S:4]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])=[O:5].[CH:14]([NH2:17])([CH3:16])[CH3:15].Cl.CCOCC>CO>[ClH:1].[C:8]1([CH2:7][S:4]([CH2:3][CH2:2][NH:17][CH:14]([CH3:16])[CH3:15])(=[O:6])=[O:5])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)(CCCl)Cc1ccccc1
Reactant: CC(C)N
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC(C)NCCS(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.8 %

Procedure:
A mixture of 51.49 g (0.236 mole) of benzyl 2-chloroethyl sulfone and 600 ml of isopropylamine was stirred at room temperature for 72 hr. The solvent was removed in vacuo, and the residue was partitioned between ether and dilute sodium hydroxide. The ether solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give an oil. This was dissolved in methanol, and excess ethereal hydrogen chloride was added. Ether was added, and a white solid precipitated to give 43.11 g (65.8%) of a white crystalline solid, m.p. 180.5°-181.5° C.
Reaction SMILES: I[C:2]1([C:27](OC(C)(C)C)=O)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]([S:19]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)(=[O:21])=[O:20])C(OC(C)(C)C)=O)[CH:9]=2)[N:4]=[N:3]1.N[C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[NH:40]N=[C:38]2I.S1C=CC=C1S(Cl)(=O)=O.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>>[NH:40]1[C:41]2[C:37](=[CH:36][CH:35]=[CH:43][CH:42]=2)[CH:38]=[C:27]1[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:19]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)(=[O:20])=[O:21])[CH:9]=2)[NH:4][N:3]=1
Reactant: Nc1ccc2[nH]nc(I)c2c1
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)C(I)(C(=O)OC(C)(C)C)N=N2)S(=O)(=O)c1cccs1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=S(=O)(Cl)c1cccs1
Product: O=S(=O)(Nc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1)c1cccs1

Procedure:
tert-Butyl 3-iodo-5-(N-tert-butoxycarbonyl-2-thiophenesulfonylamino)-indazolecarboxylate can be prepared as described in Example 85 using 2 g of 5-amino-3-iodo-1H-indazole and 1.61 g of thiophene-2-sulfonyl chloride. The intermediate crude is purified by flash chromatography (98/2 by volume dichloromethane/methanol), resulting in 2.30 g of an orangey solid, which is then treated with 3.71 g of di-tert-butyl dicarbonate according to the procedure. After purification by flash chromatography (eluent: dichloromethane), 3.15 g of tert-butyl 3-iodo-5-(N-tert-butoxycarbonyl-2-thiophenesulfonylamino)indazolecarboxylate are obtained in the form of a white solid melting at 163° C. (LC/MS analysis: Tr=4.34 minutes; [M+H]+=605.93; [M+H]+-tert-butyl=549.90).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[C:11](OC(=O)C)(=[O:13])[CH3:12].O>N1C=CC=CC=1>[C:11]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)CCC2
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
To a solution of 5-aminoindane (2.0 g, 15.0 mmol) in 5 mL of anhydrous pyridine at 0° C. was added acetic anhydride (2.1 mL, 22.5 mmol) and the solution was stirred at rt for 3 h. The solution was then added to 50 mL of water and the resulting solid filtered and washed with water, then dried under vacuum to yield the title compound (2.23 g, 78%). 1H NMR (CDCl3): 7.44 (s, 1H), 7.2 (bs, 1H), 7.12 (s, 2H), 2.88 (q, 4H), 2.18 (s, 3H), 2.09 (p, 2H).
Reaction SMILES: BrC1C=C(C=CC=1)C(NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C)=O.[NH2:32][CH:33]([C:35]1[N:40]=[N:39][C:38]([NH:41][C:42]2[CH:47]=[C:46]([O:48][CH3:49])[C:45]([O:50][CH3:51])=[C:44]([O:52][CH3:53])[CH:43]=2)=[N:37][CH:36]=1)[CH3:34].[CH3:54][N:55]1[C:63]2[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:57]([C:64](O)=[O:65])=[CH:56]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:54][N:55]1[C:63]2[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:57]([C:64]([NH:32][CH:33]([C:35]2[N:40]=[N:39][C:38]([NH:41][C:42]3[CH:43]=[C:44]([O:52][CH3:53])[C:45]([O:50][CH3:51])=[C:46]([O:48][CH3:49])[CH:47]=3)=[N:37][CH:36]=2)[CH3:34])=[O:65])=[CH:56]1
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Reactant: Cn1cc(C(=O)O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3cn(C)c4ccccc34)nn2)cc(OC)c1OC
Yield: 70.2 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (200 mg, 0.65 mmol), 1-methyl-1H-indole-3-carboxylic acid (150 mg, 0.85 mmol), diisopropylethylamine (0.34 mL, 1.95 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (350 mg, 0.92 mmol) in dimethylformamide (5 mL) gave 1-methyl-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)-1H-indole-3-carboxamide (211 mg, 70%) as a yellow solid. MS m/z 462 (M+1).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]1[CH:17]=[CH:18][C:19]([N+:31]([O-:33])=[O:32])=[C:20]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:21]=1.[H-].[Na+]>CN(C)C=O>[CH3:30][N:22]([C:20]1[CH:21]=[C:16]([O:14][C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:19]=1[N+:31]([O-:33])=[O:32])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(Oc3ccccc3)cc2)ccc1[N+](=O)[O-]
Yield: 97.4 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 4-phenoxyphenol (4.0 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (5.8 g), sodium hydride (55 wt. %, 1.1 g) and anhydrous N,N-dimethylformamide (35 ml) and the reaction mixture was purified to give the title compound (8.6 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:26]
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1ccccc1F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccccc1F
Yield: 83.5 %

Procedure:
0.5 g (0.0026 mol) of 1-benzyl-4-hydroxypiperidine and 0.64 ml (0.0046.mol). of triethylamine were dissolved in 20 ml of toluene and treated with 0.32 ml (0.0027 mol) of 2-fluoro-benzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:1). 0.68 g (83%) of 1-benzyl-piperidin-4-yl 2-fluoro-benzoate was obtained as a colorless oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([N:17]=[O:18])[C:5](=O)[O:6]C1C=CC=CC=1[N+]([O-])=O.[NH2:19][C@@H:20]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:25]([OH:26])[C@H:23]([OH:24])[C@H:21]1[OH:22]>CN(C)C=O.C(O)C>[C@@H:20]1([NH:19][C:5](=[O:6])[N:4]([CH2:3][CH2:2][Cl:1])[N:17]=[O:18])[O:28][C@H:27]([CH2:29][OH:30])[C@@H:25]([OH:26])[C@H:23]([OH:24])[C@H:21]1[OH:22]
Reactant: O=NN(CCCl)C(=O)Oc1ccccc1[N+](=O)[O-]
Reactant: N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Solvent: CN(C)C=O
Solvent: CCO
Product: O=NN(CCCl)C(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
3.28 g (12 mmol) of o-nitrophenyl N-(2-chloroethyl)-N-nitrosocarbamate is dissolved in a mixture of 10 ml anhydrous dimethylformamide and 10 ml anhydrous ethanol, and to this solution is added little by little 1.79 g (10 mmol) of 1-amino-1-deoxy-β-D-glucopyranose powder, while stirring, at 5°-10° C. over 10 minutes. The resultant mixture is, after adding 5 ml of anhydrous dimethylformamide thereto, stirred further at 10° C. for 5 hours, and the thus reacted solution is concentrated at 40° C. and below, under reduced pressure. The crystalline residue obtained is washed with anhydrous ethyl ether and then with acetone, dried under reduced pressure, and recrystallized from anhydrous ethanol-ethyl ether (1:5) to give 2.47 g of 3-(β-D-glucopyranosyl)-1-(2-chloroethyl)-1-nitrosourea. Yield 78.7%. mp 77°-78° C. (decomp.). [α]D25 -10.3° (C 1.0, water). Analysis for C9H16N3O7Cl (MW 313.69):
Reaction SMILES: [ClH:1].[CH:2]1([CH2:8][N:9]2[CH2:14][CH2:13][C:12](=O)[CH:11]([C:16]([O:18]CC)=O)[CH2:10]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[ClH:1].[CH:2]1([CH2:8][N:9]2[CH2:14][CH2:13][C:12]3[S:28][C:25]4[CH:26]=[CH:27][C:22]([F:21])=[CH:23][C:24]=4[C:16](=[O:18])[C:11]=3[CH2:10]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Fc1ccc(S)cc1
Reactant: CCOC(=O)C1CN(CC2CCCCC2)CCC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=c1c2c(sc3ccc(F)cc13)CCN(CC1CCCCC1)C2
Reaction time: 2 h
Yield: 37.9 %

Procedure:
A mixture of 6.68 g of the product of Step B and 2.51 g of p-fluoro-thiophenol were added in two portions with stirring over 20 minutes to 80 g of polyphosphoric acid heated to 100° to 120° C. and the mixture was held at 110° C. for two hours to form a yellow solution which was poured into 500 ml of water. The resulting suspension was adjusted to a pH of 8 by addition of sodium carbonate and the yellow precipitate formed was recovered by filtration. The product was washed with water and dissolved in 250 ml of dichloromethane. The solution was washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was dissolved in a mixture of ethyl acetate and ethanol and 10 ml of a solution of 10% hydrogen chloride in ethanol were added thereto. The mixture was filtered and the pale cream colored product was washed with a little ethanol and dried under reduced pressure to obtain 2.73 g (39 % yield) of 2-cyclohexylmethyl-8-fluoro-1,2,3,4-tetrahydro-10H-(1)-benzothiopyrano[3,2-c]pyridin-10-one hydrochloride melting at 243° C. (decomp.).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][N:35]([CH2:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1)[CH3:36]>>[CH3:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][N:35]([CH2:37][C:38]1[CH:39]=[CH:40][C:41]([NH:42]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:43][CH:44]=1)[CH3:36]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: COCCOCCN(C)Cc1ccc(N)cc1
Product: COCCOCCN(C)Cc1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-((N-(2-(2-methoxy-ethoxy)-ethyl)-N-methyl-amino)-methyl)-aniline Rf value: 0.4 (silica gel, methylene chloride/methanol=9:1) C30H33N3O5
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[C:10]([O:13][C@@H:14]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@@H:15]1Br)(=[O:12])[CH3:11]>[O-2].[Zn+2]>[C:10]([O:13][C@@H:14]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:15]1[S:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: N#Cc1cccc(S)c1
Agent: [O-2]
Agent: [Zn+2]
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2cccc(C#N)c2)SC[C@H]1OC(C)=O
Yield: 30.8 %

Procedure:
If the procedure described in Preparation IV is followed starting from 10.3 g (74.1.10-3 mol) of 3-mercaptobenzonitrile, 28.94 g (81.5.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 6.05 g (74.3.10-3 mol) of zinc oxide (ZnO), 9.6 g (yield: 31%) of the expected product are obtained.
Reaction SMILES: O[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([O:14]C)=O.[CH3:16][NH:17][C:18]([NH2:20])=[NH:19].NC(N)=N>>[CH3:16][NH:17][C:18]1[NH:20][C:12](=[O:14])[C:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[CH2:10][CH2:11][C:2]=2[N:19]=1
Reactant: CNC(=N)N
Reactant: COC(=O)C1=C(O)CCc2ccccc21
Agent: N=C(N)N
Product: CNc1nc2c(c(=O)[nH]1)-c1ccccc1CC2

Procedure:
Methyl 3,4-dihydro-2-hydroxy-1-naphthoate was reacted with methylguanidine in the same manner as for the analogous reaction using guanidine (example 1) to obtain 5,6-dihydro-3-(methylamino)benzo[f]quinazolin-1(2H)-one. 1H NMR(DMSO-d6, 200 MHz) δ: 2.52-2.64(m, 2H, CH2), 2.68-2.82(m, 2H, CH2), 2.81(d, J=5 Hz, 3H, NCH3), 6.54(br s, 1H, C3NH), 7.02 (ddd, J=8, 8, 2 Hz, 1H, Ar), 7.07-7.18(m, 2H, Ar), 8.42(dd, J=8,2 Hz, 1H, Ar), 10.98(br s, 1H, N2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClC(Cl)(Cl)Cl>[Br:12][CH2:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(F)c(CBr)c1
Reaction time: 16 h

Procedure:
186 g (1.2 mol) of 2-fluoro-5-nitrotoluene are dissolved in 1.2 l of tetrachloromethane and admixed with 214 g (1.20 mol) of N-bromosuccinimide. 19.7 g (120 mmol) of azodiisobutyronitrile are added and the mixture is heated under reflux. After 16 h, the mixture is allowed to cool, filtered and concentrated to dryness under reduced pressure. The residue is dissolved in 300 ml of dichloromethane and admixed with 300 g of Seesand. Then the mixture is concentrated to dryness under reduced pressure again, and the residue is applied to a 1 kg silica gel column. It is chromatographed with a 20:1 mixture of cyclohexane and ethyl acetate, and the product fractions are concentrated to dryness under reduced pressure. The residue is crystallized with cyclohexane and dried under reduced pressure. This affords 92 g (32% of theory) of the desired product.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][CH2:9][CH3:10])[C:5](Cl)=[O:6])[CH2:2][CH3:3].[CH3:11][S:12]([C:15]1[N:19]=[CH:18][NH:17][N:16]=1)(=[O:14])=[O:13].C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:4]([CH2:8][CH2:9][CH3:10])[C:5]([N:17]1[CH:18]=[N:19][C:15]([S:12]([CH3:11])(=[O:14])=[O:13])=[N:16]1)=[O:6])[CH2:2][CH3:3]
Reactant: CS(=O)(=O)c1nc[nH]n1
Reactant: CCCN(CCC)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)n1cnc(S(C)(=O)=O)n1

Procedure:
Dipropylcarbamoyl chloride (5.5 g.) was added to a solution of 4.4 g. 3-methylsulphonyl-1,2,4-triazole and 6 ml. dry triethylamine in 25 ml. dry tetrahydrofuran and the resulting mixture refluxed for 2.5 hours under anhydrous conditions. The cooled reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate poured with stirring into 150 ml. ice-cold 0.1N aqueous sodium hydroxide. The precipitated product was collected by filtration, washed with ice-cold water, dried, and crystallized twice from toluene to give 1-dipropylcarbamoyl-3-methylsulphonyl-1,2,4-triazole, m.p. 94° C. Elemental analysis satisfactory.
Reaction SMILES: ClC1C=CC=C(C(OO)=O)C=1.[OH2:12].[Mn]([O-])(=O)(=O)=O.[Na+].[CH3:19][C@H:20]1[CH2:25][O:24][CH2:23][CH2:22][N:21]1[C:26]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:48])[NH:40][CH2:41][C:42]3[CH:43]=[N:44][N:45]([CH3:47])[CH:46]=3)=[CH:34][CH:33]=2)[N:29]=[C:28]([CH2:49][S:50][CH2:51][CH2:52][NH:53][C:54](=[O:56])[CH3:55])[CH:27]=1.[OH2:57]>O1CCOCC1>[CH3:19][C@H:20]1[CH2:25][O:24][CH2:23][CH2:22][N:21]1[C:26]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:48])[NH:40][CH2:41][C:42]3[CH:43]=[N:44][N:45]([CH3:47])[CH:46]=3)=[CH:34][CH:33]=2)[N:29]=[C:28]([CH2:49][S:50]([CH2:51][CH2:52][NH:53][C:54](=[O:56])[CH3:55])(=[O:57])=[O:12])[CH:27]=1
Reactant: O
Reactant: CC(=O)NCCSCc1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)NCc3cnn(C)c3)cc2)n1
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)NCCS(=O)(=O)Cc1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)NCc3cnn(C)c3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
meta-Chloroperbenzoic acid (156 mg, 0.90 mmol) dissolved in Dioxane (2 mL), and sodium permanganate monohydrate (192 mg, 1.20 mmol) dissolved in water (1 mL) were added dropwise to N-[2-[[6-[(3S)-3-methylmorpholin-4-yl]-2-[4-[(1-methylpyrazol-4-yl)methylcarbamoylamino]phenyl]pyrimidin-4-yl]methylsulfanyl]ethyl]acetamide (162 mg, 0.30 mmol) in dioxane (6 mL) and water (2 mL) at RT under nitrogen. The resulting solution was stirred at RT for 1 hour. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M ammonia in methanol and pure fractions were evaporated to dryness. The crude product was purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents, to give the desired material as a white solid (61 mg).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.Cl[C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[N:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([F:1])=[CH:3][C:4]=1[O:12][C:14]1[CH:19]=[N:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(F)cc1Oc1ccc([N+](=O)[O-])nc1
Temperature: 110 °C

Procedure:
Methyl 4-fluoro-2-hydroxybenzoate (3.00 g), 5-chloro-2-nitropyridine (3.08 g), and potassium carbonate (4.87 g) were added to dimethyl sulfoxide (50 mL), heated to 110° C. for one hour, cooled, added to water, and extracted with ethyl ether. The ether was washed with brine and dried on anhydrous sodium sulfate. The solution was filtered and concentrated and purified by flash column chromatography on silica gel using 10% ethyl acetate in hexanes increasing to 20% ethyl acetate in hexanes and increasing again to 30% ethyl acetate in hexanes.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@H:13]([CH3:21])[CH2:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].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.[OH:55][C@H:56]1[CH2:60][NH:59][C@H:58]([C:61]([O:63][CH3:64])=[O:62])[CH2:57]1>ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]([C@H:13]([CH3:21])[CH2:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])[C:10]([N:59]1[CH2:60][C@H:56]([OH:55])[CH2:57][C@H:58]1[C:61]([O:63][CH3:64])=[O:62])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoic acid (2 g, 6.6 mmole), synthesized using Scheme 1, in dichloromethane (20 mL) was added DIPEA (11.5 mL, 33.0 mmole), HATU (2.7 g, 7.2 mmole) followed by (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate (1.3 g, 7.2 mmole) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mass was diluted with DCM and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get crude (2S,4R)-methyl 1-((3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate. The crude product was taken to the next step without further purification (2.2 g, 80%). MS: MS m/z 427.2 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](I)=[N:9]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:18]([O:20]CC)=[CH2:19])CCC.Cl>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:18](=[O:20])[CH3:19])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2ccc(I)nc2c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)c1ccc2ccc(Br)cc2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a stirred slurry of 7-bromo-2-chloro-quinoline (obtained from AstaTech, Inc.), (8.10 g, 33.4 mmol) and sodium iodide (50.0 g, 334 mmol) in acetonitrile (27 mL) was slowly added acetyl chloride (3.56 mL, 50.0 mmol). The flask was stoppered and sealed and heated at 80° C. for 3 h before being allowed to cool. The mixture was treated sequentially with 10% w/w aqueous potassium carbonate solution (80 mL), 5% w/w aqueous sodium sulfite solution (80 mL) and saturated aqueous sodium thiosulfate solution (80 mL) and the mixture extracted with dichloromethane (2×). The combined organic extracts were dried over sodium sulfate, filtered and evaporated to give a crude 7-bromo-2-iodo-quinoline. To the quinoline was added tributyl(1-ethoxyvinyl)tin (13.6 mL, 40.1 mmol), 1,4-dioxane (67 mL) and bis(triphenylphosphine)palladium(II) dichloride (2.37 g, 3.34 mmol) and the reaction mixture heated at 100° C. for 5 h before being allowed to cool. 2 M aqueous hydrochloric acid (67 mL) was added and the reaction stirred for 1 h. The mixture was filtered and the solids washed with ethyl acetate and the filtrate evaporated to remove organics. The residue was extracted with ethyl acetate (3×) and the combined organic extracts were dried over sodium sulfate, filtered and evaporated. The product was purified on silica gel doped with 10% w/w potassium carbonate eluting with a gradient of 0% to 6% ethyl acetate in iso-hexanes to afford the title compound (5.5 g, 66%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.86 (s, 3H), 7.72-7.80 (m, 2H), 8.21 (ABq, ΔδAB=0.11, JAB=8.5 Hz, 2H), 8.42 (s, 1H). LCMS (m/z) 250.1/252.1 [M+H], Tr=2.90 min.