Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:34])[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=2)[C:18]([O:29][CH2:30][CH2:31][OH:32])=[C:17]([Br:33])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C[N+]1([O-])CC[O:39]CC1.S(=O)(O)[O-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O.C(O)=O.CCOC(C)=O.O.CC#N>[Br:33][C:17]1[C:18]([O:29][CH2:30][C:31]([OH:39])=[O:32])=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=2)[CH:20]=[C:15]([C:14](=[O:34])[NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:16]=1
Reactant: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCO)c(-c2ccc(F)c(Cl)c2)c1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: Cl
Solvent: O
Solvent: O=CO
Solvent: CC#N
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCC(=O)O)c(-c2ccc(F)c(Cl)c2)c1
Reaction time: 8 h

Procedure:
To a solution of N-dodecyl-3-bromo-4-(2-hydroxyethoxy)-5-(3-chloro-4-fluorophenyl)benzamide (340 mg, 0.61 mmol) in 5 mL CH2Cl2 was added NMMOH2O (165 mg, 1.22 mmol) and TPAP (22 mg, 0.061 mmol). The reaction mixture was stirred overnight and 2 mL CH3CN and 50 mg, 0.14 mmol TPAP were added. The reaction was stirred for ca 7 hours then 90 mg, 0.665 mmol NMMO.H2O was added and the reaction was stirred overnight. The reaction was worked up by adding H2O and a mixture of sodium bisulfite/sodium dithionite and was stirred for 4 hours. The now grayish mixture was acidified with 2N HCl and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 followed by filtration and removal-of solvent in vacuo. There yielded a black semisolid that was subjected to column chromatography (40% EtOAc:60% Hexanes) on silica gel pretreated with HCOOH. Yield of the acid is 130 mg, 37% as a dark yellowish brown oil. 1H NMR (DMSO-d6) δ 0.84 (t, J=6.81 Hz, 3H); 1.22-1.27 (m, 18H); 1.50 (t, J=6.37 Hz, 2H); 3.23 (q, J=6.81 Hz, 2H); 4.19 (s, 2H); 7.51 (t, J=8.57 Hz, 1H); 7.57-7.61 (m, 1H); 7.81 (dd, J=7.25 Hz, 2.20 Hz, 1H); 7.85 (d, J=2.2 Hz, 1H); 8.10 (d, J=2.20 Hz, 1H); 8.56 (t, J=5.49 Hz, 1H); 12.75 (bs, 1H); IR 3370, 2930, 1730, 1635, 1400, 1225, 1150, and 700 cm−1; mass spectrum [(+)APCI], m/z 570 [M+H]+; Anal. Calcd. for C27H34BrClFNO4: C, 56.80; H, 6.00; N, 2.45, Found: C, 54.30; H, 5.73; N, 2.18.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[CH:15]([CH:24]=O)[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[CH2:33]([NH:35][NH2:36])[CH3:34]>CO>[C:18]1([CH2:17][CH2:16][C:15]2[CH:24]=[N:36][N:35]([CH2:33][CH3:34])[C:14]=2[CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=CC(CCc1ccccc1)C(=O)C1CCN(Cc2ccccc2)CC1
Reactant: CCNN
Agent: O=C(O)C(=O)O
Solvent: CO
Product: CCn1ncc(CCc2ccccc2)c1C1CCN(Cc2ccccc2)CC1
Yield: 55 %

Procedure:
di-TFA salt A solution of 1-(1-benzylpiperidin-4-yl)-2-formyl-4-phenyl-1-butanone from Step E (76.5 mg) and ethylhydrazine oxalate (45 mg) in methanol (4 mL) was heated at 45° C. for 15.5 h. The solvent was removed under reduced pressure. The residue was purified by preparative reverse-phase IHPLC using a 9.4×250 mm Semi-preparative Zorbax SB-C18 column with 30-50% acetonitrile gradient in water having 0.5% (v/v) TFA over 15 min at 7.1 mL per min to give the title compound (45 mg) as the faster-eluting, minor isomer.
Reaction SMILES: C(OC([N:11]1[CH2:24][CH2:23][C:14]2([C:18](=[O:19])[N:17]([O:20][CH3:21])[C:16](=[S:22])[CH2:15]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C(OCC)C.[BrH:30]>C(O)(=O)C>[BrH:30].[CH3:21][O:20][N:17]1[C:16](=[S:22])[CH2:15][C:14]2([CH2:23][CH2:24][NH:11][CH2:12][CH2:13]2)[C:18]1=[O:19]
Reactant: CON1C(=O)C2(CCN(C(=O)OCc3ccccc3)CC2)CC1=S
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CON1C(=O)C2(CCNCC2)CC1=S
Reaction time: 0.33 h

Procedure:
In an acetic acid solution (5 ml) of 25% hydrogen bromide was dissolved 8-benzyloxycarbonyl-2-methoxy-2,8-diazaspiro[4,5]decane-3-thion-1-one (0.5 g), and the solution was left standing at room temperature for 20 minutes. To the solution was added ethyl ether (100 ml), and resulting precipitates were collected by filtration, followed by recrystallization from ethanol to obtain 0.4 g of a pale yellow solid, m.p. 235° to 237° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28](O)=[O:29])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[CH3:32][N:33]1[CH2:37][CH2:36][C@H:35]([NH2:38])[CH2:34]1.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>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([NH:38][C@H:35]5[CH2:36][CH2:37][N:33]([CH3:32])[CH2:34]5)=[O:29])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)cc1Cl
Reactant: CN1CC[C@H](N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CC[C@H](NC(=O)c2ccc3c(n2)CCC2C3=NN(c3ccc(C#N)c(Cl)c3)C2C2CCCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.8 %

Procedure:
In a dried reaction flask, 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (0.421 g, 1.0 mmol), the crude (S)-1-methylpyrrolidine-3-amine hydrochloride (0.235 g), DIEA (0.26 mL, 1.5 mmol), and HATU (0.418 g, 1.1 mmol) were added to a mixed solvent of DMF (4 mL) and dichloromethane (8 mL). The mixture was stirred at room temperature for 2 hr and was concentrated under reduced pressure. Water was added to the residue. The mixture was filtered to produce a crude yellow solid, which was washed with methanol to produce a purified product (0.13 g) in 25.8% yield.
Reaction SMILES: CN(C)C=O.[CH3:6][C@@:7]1([CH2:10][N:11]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[N:13]=[C:12]2[S:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH2:9][O:8]1.[N:29]1([C:35]([O:37][CH2:38][CH:39]=[CH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)=[O:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.O>ClCCl.C(OCC)(=O)C>[N+:16]([C:14]1[N:13]=[C:12]([S:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[N:11]([CH2:10][C@:7]([OH:8])([CH3:6])[CH2:9][N:32]2[CH2:31][CH2:30][N:29]([C:35]([O:37][CH2:38][CH:39]=[CH:40][C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:49])([F:50])[F:48])=[CH:43][CH:42]=3)=[O:36])[CH2:34][CH2:33]2)[CH:15]=1)([O-:18])=[O:17]
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Sc2ccc([N+](=O)[O-])cc2)CO1
Reactant: O=C(OCC=Cc1ccc(C(F)(F)F)cc1)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C[C@](O)(CN1CCN(C(=O)OCC=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Sc1ccc([N+](=O)[O-])cc1
Yield: 89.4 %

Procedure:
N,N-Dimethylformamide (0.5 ml) solution of (R)-1-(2-methyl-2-oxiranylmethyl)-4-nitro-2-(4-nitrophenylthio)imidazole (100 mg) and 3-(4-trifluoromethylphenyl)-2-propenyl piperazine-1-carboxylate (103 mg) was stirred at 60° C. for 1 day. Water and ethyl acetate were added to the reaction mixture, and the organic layer was taken by separation. The ethyl acetate layer was washed with water and an aqueous solution being saturated with sodium chloride, then dried over anhydrous sodium sulfate. The residue obtained by removal of the solvent by distillation was purified by use of a silica gel column chromatography (eluent: dichloromethane/methanol=50/1 to 30/1) and a basic silica gel column chromatography (eluent: dichlormethane), there was obtained 3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-{3-[4-nitro-2-(4-nitrophenylthio)imidazol-1-yl]-2-hydroxy-2-methylpropyl]piperazin-1-carboxylate (173 mg, yield: 90%) as pale yellow amorphous product.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.[Br:25]Br>ClCCl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:25])[N:6]2[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=1
Reactant: COCCOc1nc(N)c2ncn(Cc3ccc(C#N)cc3)c2n1
Reactant: BrBr
Solvent: ClCCl
Product: COCCOc1nc(N)c2nc(Br)n(Cc3ccc(C#N)cc3)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of example 3 (700 mg) is dissolved in dichloromethane (400 mL) and bromine (7 mL) is added dropwise. The mixture is stirred overnight at room temperature and extracted with aqueous sodium thiosulfate (2 L of 0.1 M) solution and then with aqueous sodium bicarbonate (500 mL, saturated). The residue from the organic layer is chromatographed on silica gel using 3% methanol in dichloromethane) to yield 460 mg of bromo product. NMR, UV and MS are consistent with structure assignment.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[OH:9][C@@H:10]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@H:12]([C@@H:13]([OH:38])[CH2:14][C@@H:15]3[C@@H:32]2[CH2:31][CH2:30][C@@:29]2([CH3:37])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:28])[CH2:21][CH2:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH2:11]1.[BH4-].[Ca+2].[BH4-]>>[C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[OH:9][C@@H:10]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@H:12]([C@@H:13]([OH:38])[CH2:14][C@@H:15]3[C@@H:32]2[CH2:31][CH2:30][C@@:29]2([CH3:37])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:28])[CH2:21][CH2:22][CH:23]([OH:27])[CH:24]([CH3:26])[CH3:25])[CH2:11]1
Reactant: CC(C)C(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@H](O)[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CC(=O)O
Product: CC(C)C(O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@H](O)[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
3α,6α-Dihydroxy-5β-cholestan-24-one diacetate was treated with calcium borohydride to give 3α,6α,24-trihydroxy-5β-cholestane diacetate.
Reaction SMILES: C(OC1C=CC(C(Cl)=O)=CC=1)C.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1)[NH2:17].[CH2:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]([N:47]=[C:48]=[S:49])=[O:46])=[CH:41][CH:40]=1)[CH3:37]>C1(C)C=CC=CC=1.C(O)C>[CH2:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]([N:47]=[C:48]=[S:49])=[O:46])=[CH:41][CH:40]=1)[CH3:37].[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:48]([NH:47][C:45](=[O:46])[C:42]2[CH:43]=[CH:44][C:39]([O:38][CH2:36][CH3:37])=[CH:40][CH:41]=2)=[S:49])[CH:18]=[CH:19][C:20]=1[O:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: CCOc1ccc(C(=O)Cl)cc1
Agent: CCOc1ccc(C(=O)N=C=S)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
4-Ethoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-ethoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-ethoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (72 mg, yield 89%).
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:2]12.[Cl-].[Li+]>>[C:2]1(=[O:1])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C1CCCCCCCC2OC2CCCCCC1
Agent: [Cl-]
Agent: [Li+]
Product: O=C1CCCCCCCCCCCCCCC1
Yield: 98.5 %

Procedure:
10.5 g of epoxy-cyclohexadecane, 10 g of N,N-dimethyl ethylene urea and 0.5 g of lithium chloride were stirred at 200° C. for 6 hours. With a 100% conversion, a 98.5% yield of cyclohexadecanone was obtained.
Reaction SMILES: Cl.[F:2][C:3]([C:17]1[N:22]=[C:21]([O:23]C)[CH:20]=[C:19]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:18]=1)([CH3:16])[C:4]([N:6]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)=[O:5]>>[F:2][C:3]([C:17]1[NH:22][C:21](=[O:23])[CH:20]=[C:19]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:18]=1)([CH3:16])[C:4]([N:6]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: COc1cc(N2CCOCC2)nc(C(C)(F)C(=O)N2CCc3c(F)cccc32)n1
Agent: Cl
Product: CC(F)(C(=O)N1CCc2c(F)cccc21)c1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 71.9 %

Procedure:
17 ml of hydrochloric acid (4M in dioxane) are added to 340 mg of 2-fluoro-1-(4-fluoro-2,3-dihydro-1H-indol-1-yl)-2-[4-methoxy-6-(morpholin-4-yl)pyrimidin-2-yl]propan-1-one, obtained according to the previous step. The reaction medium is stirred at reflux for 5 hours, allowed to return to ambient temperature, and then concentrated under reduced pressure. The residue obtained is purified on a silica column, eluent: 98/02 dichloromethane/methanol, so as to give 236 mg of racemic 2-[2-fluoro-1-(4-fluoro-2,3-dihydro-1H-indol-1-yl)-1-oxopropan-2-yl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one in the form of a white solid which will be used as it is in the next step.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:7]1=O.[OH-].[Na+].Cl>O>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1
Reactant: CN(C)CCCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)CCCN1CCCc2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(3-(Dimethylamino)propyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (4.23 g, 15.25 mmol) was stirred in borane tetrahydrofuran complex, 1M (76 ml, 76 mmol) at 60° C. overnight. The reaction mixture was then cooled to 0° C. and quenched via addition of methanol. The resulting suspension was concentrated and then stirred in refluxing methanol (50 mL). To this solution was added sodium hydroxide (6.10 g, 153 mmol) as a solution in a minimal amount of water. The resulting mixture was refluxed at 90° C. After 1 h, no free product was observed, only product borane complex. The solution was then diluted with water and acidified with conc HCl and refluxed at 90° C. After 1 h, TLC analysis showed free product, and no borane complex. The mixture was then neutralized via addition of NaOH (3N) and extracted with dichloromethane (3×). 1H NMR (DMSO-d6) δ 7.87 (dd, J=9.3, 3 Hz, 1H), 7.77 (d, J=3 Hz, 1H), 6.68 (d, J=9.6 Hz, 1H), 3.43-3.38 (m, 4H), 2.74 (t, J=6 Hz, 2H), 2.23 (t, J=6.5 Hz, 2H), 2.13 (s, 6H), 1.85 (quint, J=6 Hz, 2H), 1.68 (quint, J=7 Hz, 2H). ESI-MS (m/z, %) 264 (MH+, 100).
Reaction SMILES: [P:1]([O:10][CH:11]([CH3:13])[CH3:12])([O:6][CH:7]([CH3:9])[CH3:8])[O:2]C(C)C.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1>>[N+:22]([C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][P:1](=[O:2])([O:6][CH:7]([CH3:8])[CH3:9])[O:10][CH:11]([CH3:12])[CH3:13])([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CC(C)OP(OC(C)C)OC(C)C
Product: CC(C)OP(=O)(Cc1cccc([N+](=O)[O-])c1)OC(C)C
Temperature: 100 °C

Procedure:
A mixture of triisopropyl phosphite (500 mg, 2.31 mmol) and 1-bromomethyl-3-nitrobenzene (506 mg, 2.43 mmol) was heated at 100° C. under nitrogen for 3 h. The crude dipropan-2-yl (3-nitrobenzyl)phosphonate thus formed was dissolved in MeOH (5 mL) and hydrogenated in the presence of 5% Pd/C (49 mg) for 2 h. The mixture was filtered and concentrated in vacuo and the dipropan-2-yl (3-aminobenzyl)phosphonate residue heated in a microwave reactor at 105° C. under nitrogen for 40 minutes with N-[3-({[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2-yl]-N-methylmethanesulfonamide XLIa (20 mg, 0.051 mmol), TFA (12 uL, 0.15 mmol) and 0.5 mL TFE. The mixture was evaporated to dryness and purified by preparative HPLC to afford 11 mg of dipropan-2-yl [3-({4-[({2-[methyl (methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate trifluoroacetate (Example 35, yield: 34%). 1H NMR (400 MHz, CD3OD) δ=1.19 (d, J=6.1 Hz, 6 H), 1.28 (d, J=6.1 Hz, 6 H), 3.06-3.12 (m, 4 H), 3.12-3.19 (m, 4 H), 4.51-4.63 (m, 2 H), 4.96 (s, 2 H), 7.14 (d, J=7.3 Hz, 1 H), 7.21-7.28 (m, 1 H), 7.29-7.33 (m, 1 H), 7.35-7.43 (m, 2 H), 7.76 (d, J=7.6 Hz, 1 H), 8.21 (s, 1 H), 8.45 (dd, J=4.8, 1.8 Hz, 1 H). MS (ES+): m/z 631.27 (100) [MH+]; HPLC: tR=1.03 min (UPLC, purity).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].S=[C:12]1[CH2:16][S:15][C:14](=[O:17])[NH:13]1>C(O)C>[O:10]=[C:6]1[CH2:7][CH2:8][CH2:9][N:5]1[CH2:4][CH2:3][CH2:2][NH:1][C:12]1[CH2:16][S:15][C:14](=[O:17])[N:13]=1
Reactant: O=C1NC(=S)CS1
Reactant: NCCCN1CCCC1=O
Solvent: CCO
Product: O=C1N=C(NCCCN2CCCC2=O)CS1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(3-aminopropyl)-2-pyrrolidone (1.12 mL) in ethanol (40 mL) was added 4-thioxo-1,3-thiazolidin-2-one (1.00 g), and the mixture was stirred at room temperature overnight. The precipitate was collected by filtration and washed with ethyl acetate to give the title compound (1.56 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][C:31]([OH:33])=O)[CH2:25]2)=[O:22])=[CH:17][CH:16]=1.[CH2:34]([NH2:36])[CH3:35]>O>[CH2:34]([NH:36][C:31]([CH2:30][N:26]1[CH2:27][CH2:28][CH2:29][CH:24]([NH:23][C:21](=[O:22])[C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:20][CH:19]=2)[CH2:25]1)=[O:33])[CH3:35]
Reactant: CCN
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCN(CC(=O)O)C2)cn1
Solvent: O
Product: CCNC(=O)CN1CCCC(NC(=O)c2ccc(OCc3c(-c4ccccc4)noc3C)nc2)C1
Yield: 63 %

Procedure:
As described for example 8b, (3-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-acetic acid (70 mg, 0.16 mmol) instead of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid was converted, using ethylamine (1 M in DMF) instead of methylamine, to the title compound (47 mg, 63%) which was obtained as an off white solid after trituration with water. MS: m/e=478.3 [M+H]+.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.[NH2:21][C:22]1[CH:33]=[CH:32][C:25]2[N:26]([CH3:31])[C:27](=[O:30])[CH2:28][O:29][C:24]=2[CH:23]=1>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:21][C:22]3[CH:33]=[CH:32][C:25]4[N:26]([CH3:31])[C:27](=[O:30])[CH2:28][O:29][C:24]=4[CH:23]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: CN1C(=O)COc2cc(N)ccc21
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc4c(c3)OCC(=O)N4C)nn12

Procedure:
The titled compound was prepared in analogous fashion as Example 113 using 2-methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine and 7-amino-4-methyl-4H-benzo[1,4]oxazin-3-one to give 7-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-4-methyl-4H-benzo[1,4]oxazin-3-one as a pale yellow foam. LCMS (E/I+) 402 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 7.75 (dd, 1H, J=1.5, 7.5 Hz), 7.64 (s, 1H), 7.41 (td, 1H, J=2, 8.2 Hz), 7.05 (m, 2H), 6.94 (d, 1H, J=4.6 Hz), 6.86 (m, 4H), 4.55 (s, 2H), 2.79 (s, 3H), 2.89 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5](=[O:8])[C:4]([O:9]CC2C=CC=CC=2)=[C:3]1[CH3:17]>Br>[CH3:1][N:2]1[CH:7]=[CH:6][C:5](=[O:8])[C:4]([OH:9])=[C:3]1[CH3:17]
Reactant: Cc1c(OCc2ccccc2)c(=O)ccn1C
Agent: Br
Product: Cc1c(O)c(=O)ccn1C
Yield: 82.4 %

Procedure:
1,2-Dimethyl-3-benzyloxypyrid-4-one (2 g) is added to concentrated hydrobromic acid (10 ml) and heated on a steam bath for 30 minutes. The resulting mixture is then recrystallised from water to yield 1,2-dimethyl-3-hydroxypyrid-4-one (1 g), m.p. 230° C. (with decomposition); νmax (nujol) 1,620, 3,150 cm-1 ; δ(d6DMSO) 2.3(s,3H), 3.8(s,3H) 6.9(d,1H), 7.8(d,1H); M+ 139.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:13]3[CH:12]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1>CCCCCC.C(O)C>[CH3:1][C:2]1[S:3][C:4]2[C:13]3[C@H:12]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CC(=O)NCCC1CCc2ccc3nc(C)sc3c21
Solvent: CCCCCC
Solvent: CCO
Product: CC(=O)NCC[C@@H]1CCc2ccc3nc(C)sc3c21
Yield: 50.4 %

Procedure:
Racemic N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]thiazol-8-yl)ethyl]acetamide (1.00 g) was fractionated by high performance liquid chromatography (instrument: Prep LC 2000 (manufactured by Nihon Waters K.K.), column: CHIRALPAK AD (50 mmID×500 mL, manufactured by Daicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol=90/10, flow rate: 80 mL/min, column temperature: 30° C., sample concentration: 10 mg/mL (hexane/ethanol=90/10), injection weight: 500 mg×2). A fraction containing an optically active compound having a shorter retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give the title compound (504 mg, 99.9% ee). Enantiomer excess (ee) was measured by high performance liquid chromatography (column: CHIRALPAK AD (4.6 mmID×250 mL, manufactured by Daicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol=90/10, flow rate: 1.0 mL/min, column temperature: 30° C., sample concentration: 0.25 mg/mL (hexane/ethanol=90/10), injection volume: 10 μL).
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:12]1[CH2:18][N:17]2[C:19]([CH2:22][CH:23]=[O:24])=[CH:20][N:21]=[C:16]2[C@H:15]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:14][CH2:13]1>O1CCCC1>[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:12]1[CH2:18][N:17]2[C:19]([CH2:22][CH:23]([OH:24])[CH3:1])=[CH:20][N:21]=[C:16]2[C@H:15]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:14][CH2:13]1
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC=O)cnc21
Solvent: C1CCOC1
Product: CC(O)Cc1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
Methylmagnesium bromide (3.0 M in ether; 0.70 mL, 2.10 mmol) was added to a solution of tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-(2-oxoethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (85 mg, 0.210 mmol) in tetrahydrofuran (5 mL). After 2 h, the reaction was quenched with saturated aqueous ammonium chloride. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol) gave the title compound (73 mg). MS 422.2 (M+1).