Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][CH2:4][CH:5]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:6][C:7]([O:9]CC)=[O:8].[OH-].[Na+]>C1COCC1.CCO>[F:1][C:2]([F:21])([F:22])[CH2:3][CH2:4][CH:5]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)CC(CCC(F)(F)F)Cc1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cccc(CC(CCC(F)(F)F)CC(=O)O)c1
Yield: 97.7 %

Procedure:
Ethyl ester (119) (1.75 g, 5.50 mmol) was saponified with 1 N NaOH in THF and EtOH to give 1.56 g (98%) of the title compound (120) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 1.60-1.70 (m, 2H), 2.05-2.40 (m, 5H), 2.55-2.70 (m, 2H), 3.80 (s, 3H), 6.70-6.74 (m, 1H), 6.74-6.80 (m, 2H), 7.21 (t, J=7.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([CH:17]4[CH2:19][CH2:18]4)[C:11]=3[C:10](=[O:20])[NH:9]2)=[CH:4][CH:3]=1.Cl[C:22]1[CH:23]=[C:24]([N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:25]2[N:26]([C:28]([CH3:31])=[N:29][N:30]=2)[N:27]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([CH:17]4[CH2:19][CH2:18]4)[C:11]=3[C:10](=[O:20])[N:9]2[C:22]2[CH:23]=[C:24]([N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:38])[CH3:37])[C:25]3[N:26]([C:28]([CH3:31])=[N:29][N:30]=3)[N:27]=2)=[CH:4][CH:3]=1
Reactant: Cc1nnc2c(N(C)C(=O)OC(C)(C)C)cc(Cl)nn12
Reactant: Cc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)NC2=O
Solvent: CO
Solvent: ClCCl
Product: Cc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(N(C)C(=O)OC(C)(C)C)c3nnc(C)n3n1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 110 using 4-(4-chlorophenyl)-1-cyclopropyl-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 85.6) and tert-butyl (6-chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl)(methyl)carbamate (Step 112.5). tR: 5.60 min (HPLC 1); tR: 1.29 min (LC-MS 2); ESI-MS: 549 [M+H]+ (LC-MS 2); Rf=0.56 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.09 (m, 2H) 1.19-1.25 (m, 2H) 1.43 (s, 9H) 1.90 (s, 3H) 2.52 (s, 3H) 3.44 (s, 3H) 3.79-3.88 (m, 1H) 6.45 (s, 1H) 7.33-7.38 (m, 2H) 7.43-7.48 (m, 2H) 8.30 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:9](=[C:10]([OH:22])[C:11]4[N:12]=[CH:13][CH:14]=[N:15][C:16]=4[C:17]=3[OH:21])[C:8]2=[O:23])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C=O)C>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:8](=[O:23])[C:9]3[C:18](=[C:17]([OH:21])[C:16]4[N:15]=[CH:14][CH:13]=[N:12][C:11]=4[C:10]=3[O:22][C:33](=[O:34])[O:35][CH2:36][CH3:37])[C:19]2=[O:20])=[CH:4][CH:3]=1
Reactant: O=C1c2c(c(O)c3nccnc3c2O)C(=O)N1Cc1ccc(F)cc1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)Oc1c2c(c(O)c3nccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Reaction time: 16 h
Yield: 98 %

Procedure:
7-(4-Fluoro-benzyl)-5,9-dihydroxy-pyrrolo [3,4-g]quinoxaline-6,8-dione 242 (1 g, 2.95 mmol, 1 equiv.) was dissolved in DMF (30 ml, 0.1 M) and pyridine (477 μL, 5.89 mmol, 2 equiv.) before ethyl chloroformate was added (237 μL, 2.95 mmol, 1 equiv.). The reaction was stirred for 16 hours before being quenched with HCl (30 ml, 1 N) and extracted with ethyl acetate (2×30 mL). The organic layer washed several times with water (4×30 mL), saturated NaHCO3 (50 mL), brine solution (50 mL). It was dried over Na2SO4, filtered and concentrated in vacuo. Recrystallization was carried out in ethyl acetate and Hexanes to yield carbonic acid ethyl ester 7-(4-fluoro-benzyl)-9-hydroxy-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoxalin-5-yl ester 243 as a light brown solid (98%, 1.20 g, 2.89 mmol). 1H NMR (300 MHz) CDCl3 δ 9.09 (d, J=6 Hz, 1 H), 8.97 (d, J=6 Hz, 1 H), 8.65 (bs, 1 H), 7.46 (d, J=4.8 Hz, 2 H), 7.03 (d, J=4.8 Hz, 2 H), 4.85 (s, 2 H), 4.04 (q, J=2.8 Hz, 2 H), 1.43 (q, J=2.8 Hz, 3 H). MS: 412.6 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10](O)[C:9]2=[O:19])=[CH:4][CH:3]=1.O.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:10]1[C:9](=[O:19])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:17]2[C:12]([N:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1c(O)nc2ccccc2n1-c1ccc(Cl)cc1
Solvent: O
Product: O=c1c(Cl)nc2ccccc2n1-c1ccc(Cl)cc1

Procedure:
A solution of 1-(4-chlorophenyl)-1,2-dihydro-3-hydroxyquinoxalin-2-one (20 g) in phosphorus oxychloride (64 ml) was refluxed for 4 hours and then poured slowly into iced water. The resulting solid was filtered off, triturated with pentane and dried giving the title compound (19.4 g) mp>300° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.[Li]CCCC.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[O:29][C:28]([CH3:30])=[N:27][C:26]=3[CH3:31])=[O:24])[CH:21]=2)[N:16]=[C:15]([O:32][CH3:33])[C:14]=1[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=1>C1COCC1>[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[O:29][C:28]([CH3:30])=[N:27][C:26]=3[CH3:31])([C:6]3[N:2]([CH3:1])[N:3]=[N:4][CH:5]=3)[OH:24])[CH:21]=2)[N:16]=[C:15]([O:32][CH3:33])[C:14]=1[CH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=1
Reactant: COc1nc2ccc(C(=O)c3oc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: Cn1ccnn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3oc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -40 °C
Reaction time: 0.58 h

Procedure:
To a flask containing 1-methyl-1H-1,2,3-triazole (200 mg, 2.41 mmol, prepared according to PCT Int. Appl., 2008098104) was added THF (20 mL) and the colorless solution was cooled to −40° C. Then, n-BuLi (2.5 M in hexanes, 1.0 mL, 2.5 mmol) was added drop wise which afforded a dark reddish-brown viscous solution. The mixture was stirred at −30° C. for 35 minutes, then a homogeneous THF solution of (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,4-dimethyloxazol-5-yl)methanone (500 mg, 1.05 mmol, in 4 mL THF, Intermediate 87: step b) was introduced at −20° C. The reaction mixture became a dark brown color and was then placed in an ice-water bath and allowed to warm gradually to room temperature. After 45 minutes, the mixture was quenched with aqueous NH4Cl solution and extracted with EtOAc:THF (10:2), 4×50 mL. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to provide a brown oil. Chromatography on silica gel (3% MeOH-DCM increasing to 5% MeOH-DCM) to provide the title compound as a faint amber solid. MS m/e 558.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 8.15 (d, J=2.0 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.54-7.47 (m, 3H), 7.40 (d, J=8.1 Hz, 2H), 7.14 (s, 1H), 4.35 (s, 2H), 4.10 (s, 3H), 4.03 (s, 1H), 3.92 (s, 3H), 2.40 (s, 3H), 1.54 (s, 3H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]3[S:13][CH:12]=[C:11]([C:14]([NH:16][C:17]4[CH:22]=[C:21]([C:23](=[O:37])[NH:24][C:25]5[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:26]=5)[CH:20]=[CH:19][C:18]=4[CH3:38])=[O:15])[C:7]=3[N:8]=[CH:9][N:10]=2)[CH2:3][CH2:2]1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([O:32][CH2:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:23](=[O:37])[C:21]2[CH:20]=[CH:19][C:18]([CH3:38])=[C:17]([NH:16][C:14]([C:11]3[C:7]4[N:8]=[CH:9][N:10]=[C:5]([NH:4][CH:1]5[CH2:3][CH2:2]5)[C:6]=4[S:13][CH:12]=3)=[O:15])[CH:22]=2)=[CH:26][C:27]=1[C:33]([F:35])([F:34])[F:36])(=[O:42])=[O:41]
Reactant: Cc1ccc(C(=O)Nc2ccc(CO)c(C(F)(F)F)c2)cc1NC(=O)c1csc2c(NC3CC3)ncnc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(COS(C)(=O)=O)c(C(F)(F)F)c2)cc1NC(=O)c1csc2c(NC3CC3)ncnc12
Reaction time: 6 h

Procedure:
4-(Cyclopropylamino)-N-(5-(4-(hydroxymethyl)-3-(trifluoromethyl)phenylcarbamoyl)-2-methylphenyl)thieno[3,2-d]pyrimidine-7-carboxamide (300 mg, 0.554 mmol) was dissolved in DCM (2.5 mL), and TEA (0.15 mL, 1.11 mmol) was added thereto. Methanesulfonyl chloride (66 μL, 0.83 mmol) was added to the reaction mixture at 0° C. The reaction mixture was stirred for 6 hours and diluted with DCM (10 mL). The organic layer was washed with brine, dried with MgSO4, filtered and concentrated under reduced pressure to obtain the title compound without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:10])=O)[C:4]([CH3:11])=[N:3]1.S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[O:31]=[C:27]1[CH2:26][C:25]2[C:29](=[CH:30][C:22]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:8]([C:5]4[C:4]([CH3:11])=[N:3][N:2]([CH3:1])[C:6]=4[CH3:7])=[O:10])[CH:34]=[CH:33][CH:32]=3)=[O:21])=[CH:23][CH:24]=2)[NH:28]1
Reactant: Cc1nn(C)c(C)c1C(=O)O
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cc1nn(C)c(C)c1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
A dry flask was charged with 1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid (0.122 g, 0.791 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (8 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.200 g, 0.793 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and subsequently vacuum filtered. The solid was washed with 0° C. THF (˜5 mL) and collected to afford the 1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.169 g, 0.440 mmol, 56%).
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=3[C:8]=2[C:7]([CH:20]=[O:21])=[CH:6][CH:5]=1.CC(C)=[O:25].[Mn]([O-])(=O)(=O)=O.[K+]>O>[F:22][CH:2]([F:1])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=3[C:8]=2[C:7]([C:20]([OH:25])=[O:21])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OC(F)F)c2oc3ccc([N+](=O)[O-])cc3c12
Reactant: CC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(OC(F)F)c2oc3ccc([N+](=O)[O-])cc3c12
Temperature: 72.5 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
In a 20 L 4 necked RB flask, fitted with a mechanical stirrer, reflux condenser, add 4-difluoro methoxy-8-nitro-1-formyl dibenzo[b,d]furan (1 kg, 3.25 M), acetone (7.2 L) and heat to temp. 70-75° C. under stirring. Add a slurry of potassium permanganate (0.48 kg) in water (3 L) to the reaction mixture at 70-75° C. under stirring and maintain for 1 hr. After 1 hr maintenance, the second lot of potassium permanganate (0.120 kg) in water (400 ml) was added at 70-75° C. under stirring and maintain for 1 hr. After 2 hr maintenance, the third lot of potassium permanganate (0.120 kg) in water (400 ml) was added at 70-75° C. under stirring and maintain for 1 hr. The progress of the reaction was monitored by HPLC. After ascertaining the completion of the reaction, acetone (7.2 L) was added at temp. of 70-75° C. under stirring and maintained for 30 min. The reaction mixture was brought to 25-35° C., filtered. The inorganic salt cake was washed with acetone (2 L) collect and combine all the acetone washings. The acetone MLS were distilled at temp. below 75° C. under vacuum, cool the residue to 25-35° C. and maintain under stirring for 30 min. The precipitated product was filtered, dried and the wet cake was subjected to reflux with a solvent mixture of (5 L acetone and 1.25 L water) and maintained for 3 h. Cool the reaction mass to 10-15° C. maintain for 30 min under stirring, filter the precipitated product, wash the product with water (1 L). The wet cake was subjected to azeotropic removal of water by refluxing with toluene (10 L) After complete removal of water, the reaction mixture was brought to 25-35° C., maintained for 30 min, filtered and dried in vacuum oven below 70° C. till LOD<1%. The dried product appears as cream color, solid, weighs about 840-850 g, yield 80-81%, purity˜95% by HPLC, m.p.>270° C. The IR (KBr) spectrum shows 3100 (C—H str), 1695 (—COOH str), 1100 (C—F str) cm−1. The 1H-NMR spectrum shows δ 9.8 (s, 1H), 8.6 (d, 1H), 8.2 (m, 2H), 7.3 (m, 3H), 7.6 (m, 1H). The CI mass shows m/z 322 (M+) The elemental analysis shows calculated % C, 52.03; % H, 2.18; % N, 4.33. Observed % C, 52.04; % H, 2.03; % N, 4.45%.
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]([C:10]([C:13]2[NH:17][CH:16]=[N:15][N:14]=2)([CH3:12])[CH3:11])[N:3]=1.Br[CH:19]([CH3:21])[CH3:20].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.O>[CH:19]([C:13]1([C:10]([N:4]2[CH:5]=[C:6]([N+:7]([O-:9])=[O:8])[C:2]([CH3:1])=[N:3]2)([CH3:12])[CH3:11])[N:17]=[CH:16][NH:15][NH:14]1)([CH3:21])[CH3:20]
Reactant: Cc1nn(C(C)(C)c2nnc[nH]2)cc1[N+](=O)[O-]
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: Cc1nn(C(C)(C)C2(C(C)C)N=CNN2)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
To a solution of 3-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-4H-1,2,4-triazole (1.3 g, 5.5 mmol) in CH3CN (30 mL) was added 2-bromopropane (813 mg, 6.60 mmol) and Cs2CO3 (1.79 g, 5.50 mmol). The mixture was stirred at 50° C. overnight. After cooling down, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated to afford the title compound (1.06 g, 70%). LC-MS (ESI): m/z=279 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1)([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][CH3:7])C.[C:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:37]S(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:48][C:32]1[O:31][C:30]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:34][C:33]=1[CH2:35][CH2:36][O:37][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([CH2:6][CH3:7])[C:4]([OH:23])=[O:3])=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(CC)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Product: CCC(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)(Oc1ccccc1)C(=O)O

Procedure:
The Standard Procedure (B) was utilized to prepare the title compound from 2-(4-hydroxybenzyl)-2-phenoxybutyric acid ethyl ester and toluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3) δ 7.99-7.94 (m, 2H), 7.44-7.40 (m, 3H), 7.32-7.28 (m, 2H), 7.07 (t, 1H, J=7.4 Hz), 7.02-6.97 (m, 4H), 6.79-6.74 (m, 2H), 4.18 (t, 2H, J=6.6 Hz), 3.29 (s, 2H), 2.98 (t, 2H, J=6.6 Hz), 2.37 (s, 3H), 2.14 (qd, 1H, J=14.8, 7.6 Hz), 2.07 (qd, 1H, J=14.8, 7.6 Hz), 0.91 (t, 3H, J=7.6 Hz).
Reaction SMILES: [CH3:1][C@:2]([N+:8]([O-])=O)([C@@H:5]([OH:7])[CH3:6])[CH2:3][OH:4].[C:11]([OH:14])(=[O:13])[CH3:12]>CCO.[Pd]>[C:11]([OH:14])(=[O:13])[CH3:12].[NH2:8][C@@:2]([CH3:1])([C@H:5]([OH:7])[CH3:6])[CH2:3][OH:4]
Reactant: C[C@H](O)[C@@](C)(CO)[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: C[C@@H](O)[C@](C)(N)CO
Reaction time: 48 h

Procedure:
To a solution of (+-)(2R*,3R*)-2-methyl-2-nitro-1,3-butanediol (2B, 22.1 g, 0.148 mol) in 95% EtOH (150 mL) was added glacial acetic acid (25 mL) and 10% Pd/C (MCB, 2.0 g). The reduction was carried out in a Parr apparatus at 50 psi of H2 during a 48 h period at RT. The catalyst was removed by filtration through a Millipore® filter, and the solvent removed under vacuum (2 days). The viscous, colorless syrup was dissolved in abs. EtOH (30 mL). Dilution with abs. Et2O (300 mL) gave a cloudy liquid which was placed in a refrigerator for two days. During this time, colorless crystals formed. They were washed with Et2O and dried in a vacuum oven at RT for two days. The yield of (+-)(2R*,3R*)-2-amino-2-methyl-1,3-butanediol acetate was 25.6 g (97%) mp 117°-121°, (C,H,N).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([OH:25])[C@@:10]2([N:22]=[N+:23]=[N-:24])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:30][CH:31]=[CH2:32].S(O)(C(F)(F)F)(=O)=O>C1CCCCC1.CCOCC>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([O:25][CH2:32][CH:31]=[CH2:30])[C@@:10]2([N:22]=[N+:23]=[N-:24])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@@H]2C[C@@H](O)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOCC
Solvent: C1CCCCC1
Product: C=CCO[C@@H]1C[C@H]2[C@H](C(=O)OCC)[C@H]2[C@]1(N=[N+]=[N-])C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 13.9 %

Procedure:
To a solution of (1S,2R,3R,5R,6S)-2-azido-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (VII) (200 mg, 0.58 mmol) and allyl 2,2,2-trichloroacetimidate (0.18 mL, 1.16 mmol) in cyclohexane (0.7 mL) was added TfOH (29 □L), whereupon the solution became hot and stirring was continued at 23° C. for 1 h. The reaction mixture was poured on ice, diluted with ether, washed with sat. NaHCO3 -sol., brine and dried over MgSO4. The crude product was purified by silica gel column chromatography with hexane/EtOAc 4:1 to give (1S,2R,3R,5R,6S)-3-allyloxy-2-azido-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXIII-2) (31 mg, 14%) as a yellow oil. 1H-NMR (250 MHz, CDCl3) □1.26 (3H, t, J=7.1 Hz), 1.76 (1H, t, J=3.5 Hz), 2.03-2.26 (3H, m), 2.32 (1H, dd, J=12, 7 Hz), 3.58 (1H, dd, J=9, 7 Hz), 3.92 (1H, m), 4.02 (1H, m), 4.13 (2H, q, J=7.1 Hz), 5.10-5.22 (2H, m), 5.25 (1H, d,J=12 Hz), 5.34 (1H, d,J=12 Hz), 5.75 (1H, m), 7.30-7.42 (5H, m);MS[EI] 284 [(M-CO2Et-N2)+ ]; □D20 17.85° (c=0.50, CHCl3).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[C:22]([C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1)#[N:23]>CC(N(C)C)=O.C(Cl)Cl>[C:22]([C:24]1[CH:25]=[C:26]([NH:30][C:31](=[O:32])[NH:1][C:2]2[CH:21]=[CH:20][C:5]([C:6]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][CH:11]=3)=[O:7])=[CH:4][CH:3]=2)[CH:27]=[CH:28][CH:29]=1)#[N:23]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: Nc1ccc(C(=O)NCc2ccc(S(N)(=O)=O)cc2)cc1
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: N#Cc1cccc(NC(=O)Nc2ccc(C(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Temperature: 0 °C
Yield: 75.9 %

Procedure:
4-Amino-N-(4-sulfamoylbenzyl)-benzamide (2.13 g, 1 eq.) was dissolved anhydrous in DMA (10 ml) under inert atmosphere, anhydrous DCM (30 ml) was added and the solution was cooled to 0° C. A solution of 3-cyanophenylisocyanate (1.9 g, 1.9 eq.) in anhydrous DCM (10 ml) was added and the mixture stirred over night. The resulting precipitate was filtered off, washed with methanol and dried in vacuo to yield 2.38 g (76%) 4-[3-(3-cyanophenyl)-ureido]-N-(4-sulfamoylbenzyl)-benzamide.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17]Cl)[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:20]([OH:25])[CH2:21][CH:22]([CH3:24])[CH3:23].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17][O:25][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Cc1cc(CCl)c(O)c(-n2nc3ccccc3n2)c1
Reactant: CC(C)CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cc(COCCC(C)C)c(O)c(-n2nc3ccccc3n2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
2-(2H-Benzotriazol-2-yl)-6-chloromethyl-4-methyl-phenol (10.0 g, 33 mmol) is suspended in a mixture of isoamyl alcohol (35 g, 0.4 mol) and acetone (5 g) and stirred at 80° C. for 30 minutes. Sodium carbonate (4.7 g, 44 mmol) is added and the slightly yellow reaction mixture is stirred at 80° C. for 30 minutes. Acetone is removed under vacuum, salts are filtered off and the reaction mixture is evaporated to dryness. The residue is dissolved in ethyl acetate and extracted with aqueous citric acid (5%) and brine. The organic layer is dried over sodium sulphate, filtered and evaporated to dryness. The crude product is purified by column chromatography (ethyl acetate/heptane 1:12) to yield 7.0 g of 2-(2H-Benzotriazol-2-yl)-6-(3-methyl-butoxymethyl)-4-methyl-phenol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:23][C:24]1[CH:33]=[C:32]([CH3:34])[C:31]2[C:26](=[CH:27][C:28]([OH:35])=[CH:29][CH:30]=2)[N:25]=1>>[CH3:23][C:24]1[CH:33]=[C:32]([CH3:34])[C:31]2[C:26](=[CH:27][C:28]([O:35][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]5[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:29][CH:30]=2)[N:25]=1
Reactant: Cc1cc(C)c2ccc(O)cc2n1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Product: COc1cc2c(Oc3ccc4c(C)cc(C)nc4c3)ncnc2cc1OCC1CCN(C)CC1
Yield: 33.3 %

Procedure:
Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (0.13 g, 0.4 mmol), (prepared as described for the starting material in Example 10), was reacted with 2,4-dimethyl-7-hydroxyquinoline (87 mg, 0.5 mmol), (Chem. Berichte, 1903, 36, 4016), to give 4-(2,4-dimethylquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (61 mg, 33%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].Cl[C:9]1[N:14]=[C:13]([Cl:15])[N:12]=[C:11]2[N:16]([CH3:19])[N:17]=[CH:18][C:10]=12>>[Cl:15][C:13]1[N:12]=[C:11]2[N:16]([CH3:19])[N:17]=[CH:18][C:10]2=[C:9]([N:5]([CH3:6])[CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[N:14]=1
Reactant: CNCCN(C)C
Reactant: Cn1ncc2c(Cl)nc(Cl)nc21
Product: CN(C)CCN(C)c1nc(Cl)nc2c1cnn2C

Procedure:
Reaction of N,N,N′-trimethylethylene diamine with 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 5 by General Procedure B gave N-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N,N′,N′-trimethyl-ethane-1,2-diamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[O:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([CH2:19][NH2:20])[CH2:15][CH2:14]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[F:54][C:55]1[CH:63]=[CH:62][C:58]([C:59](O)=[O:60])=[CH:57][CH:56]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[O:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([CH2:19][NH:20][C:59](=[O:60])[C:58]2[CH:62]=[CH:63][C:55]([F:54])=[CH:56][CH:57]=2)[CH2:17][CH2:18]1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: NC[C@H]1CC[C@H](Oc2ccnc3c(F)cccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC[C@H]1CC[C@H](Oc2ccnc3c(F)cccc23)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{trans-4-[(8-Fluoroquinolin-4-yl)oxy]cyclohexyl}methylamine (1.82 g mg, 6.63 mmol) was dissolved in tetrahydrofuran (415 mL). After adding HATU (2.78 g, 7.30 mmol), diisopropylethylamine (1.30 mL, 7.30 mmol) and 4-fluorobenzoic acid (1.02 g, 7.30 mmol), the reaction mixture was stirred overnight at room temperature. After chromatography, the desired product was obtained at 71% yield (1.96 g).