Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CO.[CH:4]1([NH2:8])[CH2:7][CH2:6][CH2:5]1.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=1[CH:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:25][CH:26]=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([BH3-])#N.[Na+]>CO>[CH:4]1([NH:8][CH2:26][CH2:25][CH:24]([C:18]2[CH:19]=[C:20]([Br:23])[CH:21]=[CH:22][C:17]=2[O:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:7][CH2:6][CH2:5]1
Reactant: O=CCC(c1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Reactant: NC1CCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Brc1ccc(OCc2ccccc2)c(C(CCNC2CCC2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5 M HCl-methanol (3.50 mL, 17.71 mmol) was added to a solution of cyclobutylamine (4.50 mL, 53.15 mmol) in methanol (14 mL). The mixture was added to 3-(2-benzyloxy-5-bromophenyl)-3-phenylpropanal (Example 20.1), (3.50 g, 8.86 mmol), followed by sodium cyanoborohydride (0.389 g, 6.20 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was chromatographed on silica (toluene-ethyl acetate-triethylamine 92:4:4). Yield 2.61 g (65%); 1H NMR (CDCl3) δ1.57 (m, 5H), 2.14 (m, 4H), 2.47 (t, 2H), 3.16 (m, 1H), 4.45 (t, 1H), 5.00 (s, 2H), 6.75 (d, 1H), 7.10-7.47 (m, 12H).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]=2[CH:8]=[CH:9][C:10]([NH:16][C@H:17]2[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18]2)=[N:11]3)=O)[CH2:3][CH2:2]1.Cl.[NH2:27][OH:28].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[CH:1]1([C:4]([C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]=2[CH:8]=[CH:9][C:10]([NH:16][C@H:17]2[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18]2)=[N:11]3)=[N:27][OH:28])[CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C(c1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12)C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C(c1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12)C1CC1
Reaction time: 2 h
Yield: 45.6 %

Procedure:
A stirred suspension of cyclopropyl-[2-((R)-indan-1-ylamino)-quinolin-5-yl]-methanone (example 30) (150 mg, 0.46 mmol), hydroxylamine hydrochloride (95 mg, 1.37 mmol) and sodium carbonate (145 mg, 1.37 mmol) in ethanol (5 ml) was heated under reflux conditions for 18 h, the reaction mixture was poured into water (5 ml) and the mixture was stirred for 2 h. The precipitate was collected by filtration and further purified by flash chromatography on silica gel (heptane/ethyl acetate) to yield the title compound as off-white solid (72 mg, 46%). M.p. 151° C.; MS: m/e=344.1 (M+H+).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:14]([CH:15]=O)=[C:13]([Cl:17])[N:12]=[CH:11][N:10]=1.Cl.Cl.[CH2:20]([NH:27][NH2:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:20]([N:27]1[C:9]2=[N:10][CH:11]=[N:12][C:13]([Cl:17])=[C:14]2[CH:15]=[N:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1c(Cl)ncnc1Cl
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Clc1ncnc2c1cnn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.3 %

Procedure:
Triethylamine (1.181 mL, 8.48 mmol) was added to 4,6-dichloropyrimidine-5-carbaldehyde (CAS no. 5305-40-8) (500 mg, 2.83 mmol) and benzylhydrazine dihydrochloride (CAS no. 20570-96-1) (551 mg, 2.83 mmol) in THF (15 mL) at room temperature under nitrogen. The resulting suspension was stirred at room temperature for 10 minutes and then heated at 65° C. for 50 mins. Silica was added to the reaction mixture and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford the product (500 mg, 72.3%). 1H NMR (400 MHz, CDCl3) 5.67 (2H, s), 7.28-7.38 (5H, m), 8.16 (1H, s), 8.79 (1H, s); m/z (ES+) (M+H)+=245; HPLC tR=2.29 min.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[O:21])=[CH:15][CH:14]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[C:29]1[CH:37]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[NH:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[C:29]1[CH2:37][N:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[O:21])=[CH:15][CH:14]=1)[CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: O=C(Nc1ccc(CNC2CCCc3cccnc32)cc1)c1ccccn1
Reactant: O=Cc1nc2ccccc2[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=C(Nc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1)c1ccccn1

Procedure:
Using general procedure B: Reaction of pyridine-2-carboxylic acid {4-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-phenyl}-amide (AMD9409) (67 mg, 0.19 mmol), 1H-benzoimidazole-2-carbaldehyde (30 mg, 0.21 mmol), and NaBH(OAc)3 (119 mg, 0.50 mmol) for 0.5 h at 60° C. followed by purification of the crude product by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH 198:1:1) gave AMD9413 (48 mg, 53%) as a white foam. 1H NMR (300 MHz, CDCl3) δ 1.62-1.75 (m, 1H), 1.96-2.07 (m, 2H), 2.23-2.30 (m, 1H), 2.68-2.91 (m, 2H), 3.74 (br s, 2H), 3.98 (d, 1H, J=16.8 Hz), 4.09 (m, 1H), 4.19 (d, 1H, J=16.5 Hz), 7.16-7.20 (m, 3H), 7.41-7.46 (m, 4H), 7.53 (d, 1H, J=6.0 Hz), 7.64-7.67 (m, 3H), 7.87 (ddd, 1H, J=7.5, 7.5, 1.5 Hz), 8.26 (d, 1H, J=7.8 Hz), 8.58 (d, 1H, J=3.9 Hz), 8.70 (d, 1H, J=3.3 Hz), 9.94 (br s, 1H); 13C NMR (75.5 MHz, CDCl3) δ 21.39, 23.41, 29.22, 48.54, 53.54, 60.11, 119.57, 121.50, 122.25, 122.36, 126.37, 129.28, 134.71, 135.33, 136.73, 137.21, 137.62, 146.93, 147.93, 149.80, 157.47, 161.84. ES-MS m/z 489 (M+H). Anal. Calcd. for C30H28N6O.0.5H2O.0.3CHCl3: C, 68.23; H, 5.54; N, 15.76. Found: C, 68.06; H, 5.54; N, 15.46.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[C:28]([CH:29]=[O:30])=[CH:27][N:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:15]1([C:11]2[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]3[CH:21]=[CH:22][C:3]([CH2:2][O:23][C:24]4[C:28]([CH:29]=[O:30])=[CH:27][N:26]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:25]=4)=[CH:4][CH:5]=3)[N:10]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
A mixture of 4-[(4-chloromethylphenoxy)methyl]-2-phenyl-5-methyl-1,3-oxazole (2.85 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (1.64 g), potassium carbonate (1.20 g) and N,N-dimethylformamide (100 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-({4-[(2-phenyl-5-methyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde as colorless crystals (3.49 g, 86%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 152-153° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([C:16]#[N:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].[NH4+].C(Cl)Cl>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([C:16]2[NH:20][N:19]=[N:18][N:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CC1CCN(C(=O)OCc2ccccc2)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC(c2nnn[nH]2)C1
Temperature: 105 °C
Reaction time: 8 h
Yield: 31.4 %

Procedure:
A mixture of 1.8 g (7.8 mmol) of (R/S)-1-benzyloxycarbonyl-3-cyano pyrrolidine (from Step A), 1.5 g (23 mmol) of sodium azide and 1.25 g (23 mmol) of ammonium chloride in 70 mL of DMF was stirred at 105° C. overnight. After cooling to rt, the reaction was poured into 150 mL of CH2Cl2 and washed with 150 mL of 1N HCl and 2×150 mL of H2O. The organic phase was dried over MgSO4 and concentrated. The residue was purified on a 40M Biotage column using 80:20:1 v/v/v CH2Cl2/EtOAc/HOAc as the eluant to afford 670 mg (31%) of the title compound: RF: 0.23 (80:20:1 v/v/v CH2Cl2/EtOAc/HOAc); 1H-NMR (500 MHz) δ 2.29, 2.48 (2m, 2H), 3.54-4.03 (m, 5H), 5.14-5.24 (m, 2H), 7.30-7.37 (m, 5H), 10.43 (br, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:17](I)=[CH:16][N:15]([CH2:19][C:20]3[C:25]([CH3:26])=[C:24]([O:27][CH3:28])[C:23]([CH3:29])=[CH:22][N:21]=3)[C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=1.[C:30]([Si:32]([CH3:35])([CH3:34])[CH3:33])#[CH:31]>>[Cl:1][C:2]1[C:3]2[C:17]([C:31]#[C:30][Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:16][N:15]([CH2:19][C:20]3[C:25]([CH3:26])=[C:24]([O:27][CH3:28])[C:23]([CH3:29])=[CH:22][N:21]=3)[C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=1
Reactant: COc1c(C)cnc(Cn2cc(I)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Reactant: C#C[Si](C)(C)C
Product: COc1c(C)cnc(Cn2cc(C#C[Si](C)(C)C)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C

Procedure:
The title compound was prepared by Sonogashira coupling of N-[4-chloro-5-iodo-7-(4-methoxy -3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide (see Example 1) with ethynyl-trimethylsilane according to the General Procedure A. tR=7.48 min. 1H NMR (CDCl3) δ 8.18 (s, 2H), 7.38 (s, 1H), 5.49 (s, 2H), 3.74 (s, 3H), 2.24 (s, 6H), 1.35 (s, 9H), 0.24 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([O:14]C)=O)[NH:9]2)=[CH:5][CH:4]=1.[NH3:16]>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([NH2:16])=[O:14])[NH:9]2)=[CH:5][CH:4]=1
Reactant: N
Reactant: COC(=O)c1cc2ccc(OC)cc2[nH]1
Product: COc1ccc2cc(C(N)=O)[nH]c2c1
Temperature: 50 °C

Procedure:
A suspension of 4 g (19.49 mmol) of methyl 6-methoxy-2-indolecarboxylate in 60 ml of 28% aqueous ammonia is heated at 50° C. for 14 h in an autoclave. After filtration of the mixture over sintered glass, the white solid obtained is washed with water and dried, and is then added to a hot mixture of ethyl acetate/cyclohexane (100 ml/10 ml). The medium is cooled in a water/ice bath and filtered over sintered glass, to give 1.05 g of 6-methoxy-1H-indole-2-carboxamide in the form of a white solid.
Reaction SMILES: Br[CH2:2][C:3]([OH:19])([C:15]([F:18])([F:17])[F:16])[CH:4]([NH:12][CH:13]=[S:14])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CC(C)=O>[C:8]([O:7][C:5]([C@@H:4]1[C@@:3]([OH:19])([C:15]([F:18])([F:17])[F:16])[CH2:2][S:14][CH:13]=[N:12]1)=[O:6])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)C(NC=S)C(O)(CBr)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)[C@H]1N=CSC[C@]1(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a solution of 3.67 gms of (2R,3S) and 2S,3R)-t-butyl 4-bromo-3-hydroxy-2-thioformamido-3-trifluoromethylbutyrate in 65 ml acetone was added 4.15 g powdered anhydrous potassium carbonate. The reaction mixture was stirred for 30 minutes at room temperature, filtered and evaporated to dryness under reduced pressure. The crude brown oil was then purified by chromatography on silica gel using 80:20 hexane:ethyl acetate as the eluting, solvent to give 0.781 gms of white solid, (4R,5S) and (4S,5R)-t-butyl-5-hydroxy-5-trifluoromethyl-4,5-dihydro-6H-1,3-thiazine-4-carboxylate (yield 27%) m.p. 126.5°-127.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([C@@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH3:11])=[O:9])=[N:6][CH:7]=1.[CH:26]1([C:29]([N:31]2[CH2:36][CH2:35][CH:34]([C:37](O)=[O:38])[CH2:33][CH2:32]2)=[O:30])[CH2:28][CH2:27]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([C@@H:12]2[CH2:17][CH2:16][N:15]([C:37]([CH:34]3[CH2:33][CH2:32][N:31]([C:29]([CH:26]4[CH2:28][CH2:27]4)=[O:30])[CH2:36][CH2:35]3)=[O:38])[CH2:14][C@H:13]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(O)C1CCN(C(=O)C2CC2)CC1
Reactant: CN(C(=O)c1ccc(Br)cn1)[C@@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)c1ccc(Br)cn1)[C@@H]1CCN(C(=O)C2CCN(C(=O)C3CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
Using the compound obtained in Example 648, step 1 and 1-(cyclopropylcarbonyl)piperidine-4-carboxylic acid, and by the reaction and purification in the same manner as in Example 97, the title compound was obtained.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][C@H:10]([O:19][CH3:20])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:20][O:19][C@H:10]([CH2:11][N:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1)[CH2:9][NH2:8]
Reactant: CO[C@H](CN1CCN(C)CC1)CN(Cc1ccccc1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CO[C@@H](CN)CN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(2S)—N,N-Dibenzyl-2-methoxy-3-(4-methylpiperazin-1-yl)propan-1-amine 38a (500 mg, 1.36 mmol) was dissolved in 20 mL of methanol followed by the addition of palladium/carbon (100 mg, 10%), filled with hydrogen for three times. The reaction mixture was stirred at room temperature for 12 hours and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (2S)-2-methoxy-3-(4-methylpiperazin-1-yl)propan-1-amine 38b (250 mg, as a yellow oil liquid), which was used in the next step without further furification.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([C:24]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]([F:39])([F:38])[F:37])(=[O:29])=[O:28])([CH3:26])[CH3:25])[N:21]=[C:20]([C:40]2[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=2)[N:19]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([C:24]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]([F:37])([F:38])[F:39])(=[O:29])=[O:28])([CH3:25])[CH3:26])[N:21]=[C:20]([C:40]2[CH:41]=[CH:42][C:43]([NH:44][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:45][CH:46]=2)[N:19]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccccc2C(F)(F)F)nc(-c2ccc(N)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccccc2C(F)(F)F)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Phenyl chloroformate (0.542 mL, 4.32 mmol) was added to 4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[2-[2-(trifluoromethyl)phenyl]sulfonylpropan-2-yl]pyrimidin-2-yl]aniline line (1.5 g, 2.88 mmol) and sodium hydrogen carbonate (0.363 g, 4.32 mmol) in dioxane (20 mL) at 5° C. under nitrogen. The resulting mixture was stirred at RT for 2 hours then diluted with ethyl acetate (200 mL), and washed with water (125 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product which was triturated with a mixture of diethyl ether and isohexane to give the desired material as a white solid (1.38 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[CH:11]([O:15][CH3:16])[C:12]([OH:14])=O.[NH2:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>>[C:18]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:12](=[O:14])[CH:11]([C:3]2[C:4]([F:10])=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[O:15][CH3:16])=[CH:21][CH:20]=1)#[N:17]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COc1cc(F)c(C(OC)C(=O)O)c(F)c1
Product: COc1cc(F)c(C(OC)C(=O)NCc2ccc(C#N)cc2)c(F)c1

Procedure:
(RS)-(2,6-Difluoro-4-methoxy-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-4-methoxy-phenyl)-2-methoxy-acetamide. Light yellow amorphous solid. MS 347.1 ([M+H]+)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH2:24]([N:27]([CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])[CH2:25][CH3:26].C(OC)(OC)OC>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[N:32][CH2:31][CH2:30][CH2:29][CH2:28][N:27]([CH2:33][CH2:34][CH3:35])[CH2:24][CH2:25][CH3:26])=[CH:18][CH:17]=1)[CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: CCCN(CCC)CCCCN
Reactant: Cn1ccnc1CN(Cc1ccc(C=O)cc1)Cc1ncc[nH]1
Solvent: CO
Solvent: COC(OC)OC
Product: CCCN(CCC)CCCCN=Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 103.3 %

Procedure:
The compound (210 mg) obtained in Example 84-5 was dissolved in anhydrous methanol (6.3 ml) and added with the compound (117 mg) obtained in Example 1-2. The solution was added with trimethyl orthoformate (297 μl) and the whole was stirred at room temperature for 6.5 hours. After completion of the reaction, the solvent was distilled off, thereby obtaining the subject compound (325 mg) as a brown oily substance.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([NH:14][C:15]1[CH:46]=[CH:45][C:18]([C:19]([N:21]([CH3:44])[C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=3[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([N:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)=[O:36])=[O:20])=[CH:17][C:16]=1[O:47][CH3:48])=[O:13])[CH:8]=[CH:7][CH:6]=2)=O.Cl.[NH2:50][OH:51]>N1C=CC=CC=1>[OH:51][N:50]=[CH:1][C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([NH:14][C:15]1[CH:46]=[CH:45][C:18]([C:19]([N:21]([CH3:44])[C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=3[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([N:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)=[O:36])=[O:20])=[CH:17][C:16]=1[O:47][CH3:48])=[O:13])[CH:8]=[CH:7][CH:6]=2
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(C=O)cc12
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(C=NO)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of 4-[(2-formylindol-4-yl)carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (200 mg) in pyridine (4.0 ml) was added hydroxylamine hydrochloride (21.3 mg), and the solution was stirred at ambient temperature for 1 hour. The resulting solution was concentrated in vacuo and the residue was diluted with chloroform. The organic layer was washed successively with water and brine, dried over magnesium sulfate and concentrate in vacuo to give 4-[(2-hydroxyiminomethylindol-4-yl)carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (203 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH:15]([C:26]([O:28]C)=[O:27])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].CC(C)([O-])C.[K+]>CO>[C:22]([O:21][C:19]([N:17]1[CH2:18][CH:13]([C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([F:11])([F:10])[F:12])=[C:2]([F:1])[CH:3]=2)[CH2:14][CH:15]([C:26]([OH:28])=[O:27])[CH2:16]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)C1CC(c2ccc(OC(F)(F)F)c(F)c2)CN(C(=O)OC(C)(C)C)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(C(=O)O)CC(c2ccc(OC(F)(F)F)c(F)c2)C1

Procedure:
3.72 g (8.82 mmol) of 1-tert-butyl 3-methyl 5-[3-fluoro-4-(trifluoromethoxy)phenyl]piperidine-1,3-dicarboxylate were dissolved in 65 ml of methanol and admixed at RT with 9.90 g (88.2 mmol) of potassium tert-butoxide. After a reaction time of 19 hours, the mixture was concentrated under reduced pressure, taken up in 50 ml of water and adjusted to pH=5 with 1 N hydrochloric acid. The aqueous phase was extracted three times with 50 ml each time of ethyl acetate. The combined organic extracts were dried over sodium sulphate, filtered and concentrated under reduced pressure. Yield: 3.11 g (85% of theory)
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][C:4]([OH:6])=[O:5].[CH2:20](Br)[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22].C(N(CC)CC)C>C(OCC)(=O)C>[OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][C:4]([O:6][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22])=[O:5]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCCCCCCCCCCCCC(O)CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCC(O)CC(=O)OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a suspension of (±)-3-hydroxyhexadecanoic acid (500 mg, 1.84 mmol) in ethyl acetate (3.6 ml) were added phenacyl bromide (421 mg, 2.12 mmol) and triethylamine (294 mg, 2.12 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was washed with water, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and then dried over magnesium sulfate. Magnesium sulfate was filtered off and the filtrate was concentrated under reduced pressure to obtain 678 mg of the title compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][C:5]=1[F:11])[CH3:2].CCN(C(C)C)C(C)C.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:21](=[O:23])[CH3:22])=[CH:6][C:5]=1[F:11])[CH3:2]
Reactant: CCOc1ccc(N)cc1F
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(NC(C)=O)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 41 %

Procedure:
To a solution of 4-ethoxy-3-fluoroaniline SMA 44094 (464 mg, 2.99 mmol) in dry CH2Cl2 (15 mL) in a 50 mL round-bottomed flask equipped with a magnetic stirrer were added DIEA (2.0 mL, 12 mmol), DMAP (87 mg, 0.7 mmol) and acetic anhydride (1.7 mL, 18 mmol) and the mixture was stirred for 5 h at RT. The solution was then diluted with more CH2Cl2 (30 mL), washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 50:50) gave N-(4-ethoxy-3-fluorophenyl)acetamide SMA 44098 as a beige solid (242 mg, 41% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([O:16]CC)=[O:15])[C:9]2=[O:19])=[CH:4][CH:3]=1.[OH-].[Li+]>C(O)C.O>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=[O:15])[C:9]2=[O:19])=[CH:25][CH:24]=1
Reactant: CCOC(=O)CN1CCC(c2ccc(Cl)cc2)(c2ccc(Cl)cc2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CN1CCC(c2ccc(Cl)cc2)(c2ccc(Cl)cc2)C1=O
Reaction time: 3 h

Procedure:
The product from Example 25C (0.95 g, 2.42 mmol) was dissolved in ethanol/water (4:1, 50 mL) and treated with lithium hydroxide (7.85 g, 328.0 mmol). After stirring for 3 hours at reflux, the reaction was concentrated, diluted with ice/water (50 mL) and neutralized with 1 N HCl. The resulting precipitate was collected by filtration, washed with water (50 mL) and air-dried to afford the title compound.