Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Si:3]([C:8]#[CH:9])([CH2:6]C)[CH2:4]C)C.[Li]CCCC.CCCCCC.CON(C)[C:24]([CH:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25]>C1COCC1>[CH:26]1([C:24](=[O:25])[C:9]#[C:8][Si:3]([CH3:1])([CH3:4])[CH3:6])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CON(C)C(=O)C1CCCCCC1
Reactant: C#C[Si](CC)(CC)CC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC(=O)C1CCCCCC1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of triethylsilylacetylene (4.78 ml, 14 mmol) in THF (10 ml) at −78° C. was added dropwise a solution of BuLi in hexane (8 ml, 13 mmol). After 30 minutes, the mixture was warmed to −10° C. and a solution of N-methoxy-N-methylcycloheptanecarboxamide (2 g, 10.8 mmol) in THF (10 ml) was added. The mixture was stirred for 30 minutes at −10° C., quenched by addition of aqueous saturated ammonium chloride, allowed to warm up to room temperature and diluted with ether. The layers were separated and the aqueous phase was extracted with ether. Combined organic layers were washed with brine, dried over Na2SO4 and concentrated. After purification by chromatography on silica gel (hexane/CH2Cl2 90/10), the 1-cycloheptyl-3-(trimethylsilyl)-2-propyn-1-one 28 was obtained as a colorless liquid (1.74 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:16][C:15]3[C:10](=[N:11][C:12]([O:17][CH3:18])=[CH:13][CH:14]=3)[CH:9]=2)[C:5]([OH:19])=[CH:4][CH:3]=1.[C:20]([O-])([O-])=O.[Cs+].[Cs+].ClCI>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:19][CH2:20][N:16]3[C:15]4[CH:14]=[CH:13][C:12]([O:17][CH3:18])=[N:11][C:10]=4[CH:9]=[C:8]3[C:6]=2[N:7]=1
Reactant: COc1ccc2[nH]c(-c3nc(Cl)ccc3O)cc2n1
Reactant: O=C([O-])[O-]
Agent: ClCI
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(cc3n2COc2ccc(Cl)nc2-3)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
To a stirring solution of 6-chloro-2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)pyridin-3-ol (200 mg, 0.727 mmol) and Cs2CO3 (472 mg, 1.45 mmol) in DMF (15 mL) was added chloroiodomethane (192 mg, 1.09 mmol) in DMF (2 mL) dropwise at 100° C. under N2. The mixture was stirred at 100° C. for 1 hour. The mixture was diluted with H2O and extracted with EtOAc. The organics were washed with brine and dried over Na2SO4. After concentrated, the resulting residue was purified using Pre-TLC to provide 2-chloro-10-methoxy-6H-pyrido[2,3-e]pyrido[2′,3′:4,5]pyrrolo[1,2-c][1,3]oxazine (110 mg, yield: 52%). 1H-NMR (CDCl3, 400 MHz) 7.44 (d, J=8.8 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.16 (s, 1H), 7.10 (d, J=8.8 Hz, 1H), 6.63 (d, J=8.8 Hz, 1H), 5.81 (s, 2H), 3.95 (s, 3H). MS (M+H)+: 288/290.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:17](O)([CH:19]([CH3:21])[CH3:20])[CH3:18])[CH:14]=[CH:15][CH:16]=1)[CH3:9].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:1][C:2]([CH3:23])([CH3:24])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([CH:19]([CH3:20])[CH3:21])=[CH2:18])[CH:12]=1)[CH3:9]
Reactant: CC(C)C(C)(O)c1cccc(CN(C)C/C=C/C#CC(C)(C)C)c1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: C=C(c1cccc(CN(C)C/C=C/C#CC(C)(C)C)c1)C(C)C
Temperature: 25 °C
Yield: 57.1 %

Procedure:
Compound 20 (0.76 g; 2.32 mmol) was dissolved in pyridine (35 ml). While the solution was stirred at room temperature, phosphorus oxychloride (3.71 g; 24.2 mmol) was added dropwise. The mixture was heated for 3 hours at 100° C. while being stirred, and brought to room temperature. The mixture was poured into ice+saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 0.41 g of the target compound (yield: 56.9%).
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:4]=[CH:3]1.C([Li])CCC.[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1>C1COCC1.CCCCCC>[CH:20]1([C:23]([C:3]2[N:2]([CH3:1])[C:14]3[C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[N:7]=[CH:6][C:5]=3[N:4]=2)=[O:24])[CH2:22][CH2:21]1
Reactant: Cn1cnc2cnc3ccccc3c21
Reactant: O=C(Cl)C1CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1c(C(=O)C2CC2)nc2cnc3ccccc3c21
Temperature: 25 °C
Yield: 36.5 %

Procedure:
In the same manner as in Ex. 1, to a solution containing 550 mg of 1-methyl-1H-imidazo[4,5-c]quinoline (II-2) in 25 ml of THF and a mixture of 2.2 ml of 1.6M solution of n-butyl lithium in hexane-2 ml of THF was added 0.75 g of cyclopropanecarbonyl chloride. The reaction mixture was gradually warmed to room temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and aqueous ammonia. The organic layer was washed with water and brine, and then dried. The ethyl acetate was removed by evaporation, and the residue was chromatographed on a column of silica gel for purification. The fraction eluted with ethyl acetate was concentrated and the residue was crystallized from n-hexane to give 275 mg (yield: 36%) of the titled compound (Ia-1). This was recrystallized from ethyl acetate n-hexane to give colorless crystals melting at 156°~158° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[NH:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[C:6]=2[N:22]=1.[OH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]([C:34]2[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=2)=[O:33])[CH2:28][CH2:27]1>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:7]1[CH2:8][CH2:9][CH2:10][NH:11][C:5]2[N:4]=[CH:3][C:2]([C:38]3[CH:39]=[C:34]([C:32]([N:29]4[CH2:28][CH2:27][N:26]([CH2:25][CH2:24][OH:23])[CH2:31][CH2:30]4)=[O:33])[CH:35]=[CH:36][CH:37]=3)=[N:22][C:6]1=2
Reactant: O=C(c1cccc(B(O)O)c1)N1CCN(CCO)CC1
Reactant: Fc1ccc(F)c(CN2CCCNc3ncc(Br)nc32)c1Cl
Product: O=C(c1cccc(-c2cnc3c(n2)N(Cc2c(F)ccc(F)c2Cl)CCCN3)c1)N1CCN(CCO)CC1

Procedure:
The entitled compound can be prepared from 2-Bromo-9-(2-chloro-3,6-difluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b][1,4]diazepine and 3-(4-(2-hydroxyethyl)piperazine-1-carbonyl)phenylboronic acid as described in example 1 or 30.
Reaction SMILES: [NH2:1][C@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=[O:24].C(N(CC)CC)C>C(Cl)Cl>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@H:2]([NH:1][C:23](=[O:24])[C:22]([CH3:27])([CH3:26])[CH3:21])[C:3]1=[O:20]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CN1C(=O)[C@@H](N)N=C(c2ccccc2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C(=O)[C@@H](NC(=O)C(C)(C)C)N=C(c2ccccc2)c2ccccc21
Reaction time: 0.17 h

Procedure:
Equimolar amounts of 3(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, trimethylacetylchloride and triethylamine were mixed in CH2Cl2 at room temperature and stirred 10 minutes. Flash chromatography of the reaction solution on silica gel (10% Et2O in CH2Cl2) provided the title compound as a white foam after removal of the solvent: m.p. 85°-94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[CH:4](Br)Br.C(O)=[O:13].Cl>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[CH:4]=[O:13]
Reactant: Fc1ccc(C(Br)Br)c(Cl)c1
Reactant: O=CO
Agent: Cl
Product: O=Cc1ccc(F)cc1Cl
Temperature: 25 °C
Yield: 107.2 %

Procedure:
In a flask were placed 30.25 g (0.100 mole) of 2-chloro-4-fluorobenzal bromide, 45 ml (1.2 mole) of formic acid, and 15 ml of concentrated hydrochloric acid. This mixture was heated at 100°-105° C. overnight. After cooling to room temperature, the reaction mixture was poured into 200 ml of an ice/water mixture which was then extracted twice with diethyl ether. The combined extracts were washed successively with a saturated, aqueous, sodium bicarbonate solution and water. After being dried over anhydrous magnesium sulfate, the extract was filtered, and the solvent was evaporated under reduced pressure,, leaving 17 g of 2-chloro-4-fluorobenzaldehyde as a residue.
Reaction SMILES: [C:1](Cl)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:10]1[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)[C:2]1[CH:9]=[CH:8][C:5]([O:6][CH3:7])=[CH:4][CH:3]=1.[O:25]([C@H:33]([CH3:56])[C@H:34]([CH2:37][N:38]1[CH:46]=[N:45][C:44]2[C:39]1=[N:40][CH:41]=[N:42][C:43]=2[NH:47][C:48](=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:35][OH:36])[Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>N1C=CC=CC=1>[O:25]([C@H:33]([CH3:56])[C@H:34]([CH2:37][N:38]1[CH:46]=[N:45][C:44]2[C:39]1=[N:40][CH:41]=[N:42][C:43]=2[NH:47][C:48](=[O:55])[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[CH2:35][O:36][C:1]([C:2]1[CH:9]=[CH:8][C:5]([O:6][CH3:7])=[CH:4][CH:3]=1)([C:10]1[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[Si:26]([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:28])[CH3:27]
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)Cn1cnc2c(NC(=O)c3ccccc3)ncnc21
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@@H](Cn2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@@H](C)O[Si](C)(C)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 20 h
Yield: 88 %

Procedure:
DMTCl (0.8 g. 2.37 mmol) was added in one portion to a stirred solution of 12 (0.82 g, 1.8 mmol) in 20 ml of anhydrous pyridine. The reaction was kept at room temperature for 20 hrs, concentrated and partitioned between ethyl acetate and 10% citric acid. The organic phase was washed with saturated NaCl, dried over Na2SO4 and concentrated. The resultant crude product was chromatographed on silica eluting with 50% ethyl acetate in hexane. Concentration of the pure product fractions afforded 1.2 g (88%) of 13 as a white amorphous solid. 1H NMR (DMSO-d6): δ 11.12 (s, 1H), 8.70 (s, 1H), 8.38 (s, 1H), 8.05 (d, J=8.7 Hz, 2H), 7.65 (m, 1H), 7.55 (t, J=7.5 Hz. 2H), 7.18 (m, 5H), 7.04 (t, J=8.7, 4H), 6.77 (m, 4H), 4.36 (m, 1H), 4.24 (m, 1H), 4.02 (m, 1H), 3.60 (s, 6H), 3.12 (m, 1H), 2.95 (m, 1H), 2.39 (m, 1H), 1.14 (d, J=6.6 Hz, 3H), 0.74 (s, 9H), 0.00 (s, 3H), −0.10 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:64])([CH3:63])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[N:56]([CH3:57])[C:55]3[CH:58]=[CH:59][CH:60]=[CH:61][C:54]=3[N:53]=2)[C:47]1=[O:62])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:64])([CH3:63])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[N:56]([CH3:57])[C:55]3[CH:58]=[CH:59][CH:60]=[CH:61][C:54]=3[N:53]=2)[C:47]1=[O:62])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: Cn1c(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)nc2ccccc21
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2nc3ccccc3n2C)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.9 %

Procedure:
A solution containing the product from Example 2C (0.025 g, 0.047 mmol) in THF (0.5 mL) was treated with the product from Example 59F (0.020 g, 0.061 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine (0.041 mL, 0.235 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The reaction was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The residue was partitioned between ethyl acetate and saturated NaHCO3, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (0.006 g, 14% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.83 (s, 9 H), 0.89 (s, 9 H), 1.26 (m, 1 H), 1.52 (m, 2 H), 2.32 (m, 1 H), 2.70 (m, 4 H), 2.98 (m, 1 H), 3.09 (m, 2 H), 3.46 (s, 1 H), 3.50 (s, 3 H), 3.81 (s, 3 H), 4.15 (m, 3 H), 4.53 (dd, J=11.40, 3.68 Hz, 2 H), 4.70 (d, J=15.44 Hz, 1 H), 6.63 (d, J=9.56 Hz, 1 H), 6.93 (m, 3 H), 7.07 (d, J=6.62 Hz, 2 H), 7.24 (m, 6 H), 7.59 (m, 3 H), 7.88 (m, 4 H), 8.63 (d, J=3.31 Hz, 1 H).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[S:12][C:13]([C:17]([O:19]CC)=O)=[C:14]([CH3:16])[N:15]=1>C(O)C>[CH3:16][C:14]1[N:15]=[C:11]([C:6]2[C:5]([O:4][CH3:3])=[CH:10][CH:9]=[CH:8][CH:7]=2)[S:12][C:13]=1[C:17]([NH:2][CH3:1])=[O:19]
Reactant: CN
Reactant: CCOC(=O)c1sc(-c2ccccc2OC)nc1C
Solvent: CCO
Product: CNC(=O)c1sc(-c2ccccc2OC)nc1C
Yield: 72 %

Procedure:
Into a mixed solvent of 80 ml of 40% methylamine and 600 ml of ethanol, 13.9 g of ethyl 2-(2-methoxyphenyl)-4-methylthiazole-5-carboxylate was dissolved. Then, in a similar manner in Example 1, the object was obtained as colourless aciculate melting at 167.5° to 168.5° C. in an amount of 9.4 g corresponding to the yield of 72%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].Br[C:25]([CH3:30])([CH3:29])[C:26]([NH2:28])=[O:27].[OH-].[Na+].Cl>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11])[O:23][C:25]([CH3:30])([CH3:29])[C:26]([NH2:28])=[O:27]
Reactant: CC(C)(Br)C(N)=O
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: CC(c1ccc(OC(C)(C)C(N)=O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
3-Chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (Example 133, 200 mg) and 2-bromo-2-methyl-propionamide (272 mg) in dimethyl acetamide (1 mL) were treated with sodium hydroxide (66 mg) and stirred at r.t. for 17 h. A second portion of 2-bromo-2-methyl-propionamide (272 mg) followed by sodium hydroxide (66 mg) was added and the reaction mixture further stirred for 2 h at r.t. This process was repeated a last time and the reaction mixture was diluted with ice-water (10 mL), neutralized with 1N aqueous HCl, extracted with ethyl acetate (2×), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (20 g silica gel, ethyl acetate/heptane 1:2) to give the title compound as off-white waxy solid (170 mg). MS (m/e)=451.0 (MH+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([O:11]C)=O)[CH:4]=1.[Cl-].[NH4+:14].CCOC(C)=O.O>N>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH2:14])=[O:11])[CH:4]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cc(Cl)ccn1
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 214.4 %

Procedure:
To a stirred mixture of methyl 4-chloro-2-pyridinecarboxylate hydrochloride (1.0 g, 4.81 mmol) dissolved in conc. aqueous ammonia (32 mL) was added ammonium chloride (96.2 mg, 1.8 mmol, 0.37 equiv.), and the heterogeneous reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was poured into EtOAc (500 mL) and water (300 mL). The organic layer was washed with water (2×300 mL) and a saturated NaCl solution (1×300 mL), dried (MgSO4), concentrated in vacuo to give 4-chloro-2-pyridinecarboxamide as a beige solid (604.3 mg, 80.3%): TLC (50% EtOAc/hexane) Rf 0.20; 1H-NMR (DMSO-d6) δ 8.61 (d, J=5.4 Hz, 1H), 8.20 (broad s, 1H), 8.02 (d, J=1.8 Hz, 1H), 7.81 (broad s, 1H), 7.76 to 7.73 (m, 1H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17](OC)[CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][N:5]=1)C.B(Br)(Br)Br.[C:25]([O-])(O)=[O:26].[Na+]>ClCCl>[CH3:25][O:26][C:16]1[CH:17]=[CH:18][C:12]2[S:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([NH:3][CH3:1])=[N:5][CH:6]=3)=[N:14][C:13]=2[CH:15]=1
Reactant: O=C([O-])O
Reactant: CCNc1ccc(-c2nc3ccc(OC)cc3s2)cn1
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: ClCCl
Product: CNc1ccc(-c2nc3cc(OC)ccc3s2)cn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To N-ethyl-5-(6-methoxy-1,3-benzothiazol-2-yl)pyridin-2-amine (52.8 mg, 0.185 mmol) in dichloromethane (2 mL) was added BBr3 in dichloromethane (1 M, 925 μL) at 0° C. under an argon atmosphere. The reaction was then stirred at 0° C. for 3 h before it was neutralized with NaHCO3 (sat aq). The precipitated product was filtered off, washed with water and DCM and dried. Recrystallization from (MeOH/toluene) gave the title compound (11 mg) as a white solid. 1H NMR δ ppm 9.75 (br s, 1 H) 8.58 (d, 1 H) 7.93 (dd, 1 H) 7.73 (d, 1 H) 7.34 (d, 1 H) 7.19 (t, 1 H) 6.92 (dd, 1 H) 6.56 (d, 1 H) 3.32-3.38 (m, 2 H) 1.16 (t, 3 H); MS m/z (M+H) 272.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:20]([O:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O=C(Oc1ccc(O)c([N+](=O)[O-])c1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Oc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1)c1ccccc1
Yield: 90 %

Procedure:
A mixture of benzoic acid 4-hydroxy-3-nitro-phenyl ester (Tapia, R.; Torres, G. and Valderrama, J. A. Synth. Commun. 1986, 16, 681) (20.7 g, 80 mmol), benzyl bromide (42.75 g, 250 mmol), potassium carbonate (48.3 g, 350 mmol) and DMF (300 mL) was stirred at room temperature for 2 days. After removing the solvent the residue was dissolved in water and extracted with CH2Cl2. The organic extracts were dried (MgSO4) and concentrated. The product was purified by flash silica gel chromatography eluting with CH2Cl2 to give the title compound as a pale yellowish solid (25.1 g, 90%); 1H NMR (300 MHz, CDCl3) δ 5.27(s, 2 H), 7.17(d, J=9.1 Hz, 1 H), 7.30–7.55(m, 8 H), 7.60–7.70(m, 1 H), 7.80(d, J=2.9 Hz, 1 H), 8.15–8.25(m, 2 H); MS (ES) m/z: 345.0 (MH+, 100%); HRMS Calcd. for C20H15NO5(M+): 349.0951. Found: 349.0952.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:8][CH2:7]1.CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[C:36]([NH:2][CH2:3][CH2:4][N:5]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:10][CH2:11]1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: C=CCOC(=O)N1CCC(N(CCN)CCc2ccc(Cl)cc2)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)N1CCC(N(CCNC(=O)c2ccccc2)CCc2ccc(Cl)cc2)CC1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
Allyl 4-((2-aminoethyl)(4-chlorophenethyl)amino)piperidine-1-carboxylate hydrochloride obtained in Step 2 was suspended in dichloromethane (4 mL/mmol), the suspension was cooled to −15° C. and DIPEA (2.2 equiv) followed by benzoyl chloride (1.05 equiv) were added dropwise over 5 minutes. The cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature. After 2 h TLC revealed no presence of starting material. The reaction mixture was diluted with EtOAc (10 mL/mmol of starting material), washed with 1 M NaOH (2×), water (2×) and brine (2×) and dried over anhydrous MgSO4. After filtration of the drying agent the solvent was stripped off and the crude product was purified by column chromatography.
Reaction SMILES: [Na].[CH2:2]1[O:26][C:5]2([CH2:22][CH2:21][C@@:20]3([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@@H:19]3[CH2:18][CH2:17][C@@:15]3([CH3:16])[C@H:11]4[CH2:12][C@H:13]([OH:25])[C@H:14]3[NH2:24])[CH2:6]2)[O:4][CH2:3]1.[CH:27](OCC)=[O:28]>C(O)C>[CH2:3]1[O:4][C:5]2([CH2:22][CH2:21][C@@:20]3([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@@H:19]3[CH2:18][CH2:17][C@@:15]3([CH3:16])[C@H:11]4[CH2:12][C@H:13]([OH:25])[C@H:14]3[NH:24][CH:27]=[O:28])[CH2:6]2)[O:26][CH2:2]1
Reactant: C[C@]12CCC3(C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@H](N)[C@@H](O)C[C@@H]12)OCCO3
Reactant: CCOC=O
Agent: [Na]
Solvent: CCO
Product: C[C@]12CCC3(C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@H](NC=O)[C@@H](O)C[C@@H]12)OCCO3

Procedure:
Sodium (0.37 g) was added to a stirred suspension of 17α-amino-16β-hydroxy-5α-androstan-3-one ethylene acetal (5.5 g) in ethyl formate (55 ml) and ethanol (27.5 ml) and the stirred mixture was heated under reflux for 11/2 h. After removal of the solvent, the residue was dissolved in chloroform and the solution was washed with water and dried (MgSO4). Evaporation of the solvent and crystallisation of the product from chloroform-ethyl acetate gave 17α-formamido-16β-hydroxy-5α-androstan-3-one ethylene acetal (4.5 g). A second recrystallisation furnished an analytical sample m.p. 277°-280° C., [α]DDMSO +58° (C 1.0).
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(OC([NH:41][C:42]1[S:46][C:45]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[C:49]([O:54][CH3:55])[C:48]=2[F:56])=[N:44][C:43]=1[C:57]([OH:59])=O)=O)(C)(C)C.[NH2:60][C:61]1[CH:62]=[N:63][N:64]([CH3:81])[C:65]=1[N:66]1[CH2:71][CH2:70][CH:69]([CH2:72][NH:73]C(=O)OC(C)(C)C)[CH2:68][CH2:67]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:41][C:42]1[S:46][C:45]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[C:49]([O:54][CH3:55])[C:48]=2[F:56])=[N:44][C:43]=1[C:57]([NH:60][C:61]1[CH:62]=[N:63][N:64]([CH3:81])[C:65]=1[N:66]1[CH2:71][CH2:70][CH:69]([CH2:72][NH2:73])[CH2:68][CH2:67]1)=[O:59]
Reactant: COc1ccc(F)c(-c2nc(C(=O)O)c(NC(=O)OC(C)(C)C)s2)c1F
Reactant: Cn1ncc(N)c1N1CCC(CNC(=O)OC(C)(C)C)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(F)c(-c2nc(C(=O)Nc3cnn(C)c3N3CCC(CN)CC3)c(N)s2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.4 %

Procedure:
A solution of PyBOP (211 mg, 0.406 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluoro-3-methoxyphenyl)thiazole-4-carboxylic acid (118 mg, 0.31 mmol) in DCM (3 mL) was stirred at room temperature for 30 min. A solution of tert-butyl (1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate (89 mg, 0.29 mmol) and DIPEA (81 μL, 0.46 mmol) in DCM (3 mL) was added and the mixture stirred at room temperature for 16 hr. The mixture was diluted with DCM and washed with water. The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (0-100% EtOAc/isohexane). The isolated intermediate was re-dissolved in DCM (10 mL) and TFA (2 mL) added. The mixture was stirred at room temperature for 3 hr. The mixture was concentrated under reduced pressure and the residue purified by preparative HPLC to yield 354 as a white solid (31 mg, 42%). 1H NMR (400 MHz, d4-MeOD) δ 7.58 (s, 1H), 7.37-6.99 (m, 1H), 7.06 (t, J=10.0 Hz, 1H), 3.93 (s, 3H), 3.73 (s, 3H), 3.29-3.04 (m, 4H), 2.65 (d, J=6.5 Hz, 2H), 1.85 (d, J=12.4 Hz, 2H), 1.70-1.42 (m, 1H), 1.48-1.21 (m, 2H). LCMS (ES+) m/z 478 (M+1).