Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H]12N([CH2:10][CH2:11][NH:12][C@:13]34[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:14]3[C@@H:15]3[C@@:28]([CH3:31])([CH2:29][CH2:30]4)[C@@:27]4([CH3:32])[C@@H:18]([C@:19]5([CH3:44])[C@@H:24]([CH2:25][CH2:26]4)[C:23]([CH3:34])([CH3:33])[C:22]([C:35]4[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=4)=[CH:21][CH2:20]5)[CH2:17][CH2:16]3)[C@@H](CCC1)COC2.[C@@H:51]12[O:58][C@@H:55]([CH2:56][CH2:57]1)[CH2:54][NH:53][CH2:52]2>>[CH:55]12[O:58][CH:51]([CH2:57][CH2:56]1)[CH2:52][N:53]([CH2:10][CH2:11][NH:12][C@:13]13[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:14]1[C@@H:15]1[C@@:28]([CH3:31])([CH2:29][CH2:30]3)[C@@:27]3([CH3:32])[C@@H:18]([C@:19]4([CH3:44])[C@@H:24]([CH2:25][CH2:26]3)[C:23]([CH3:33])([CH3:34])[C:22]([C:35]3[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=3)=[CH:21][CH2:20]4)[CH2:17][CH2:16]1)[CH2:54]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3[C@@H]4CCC[C@H]3COC4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C1C[C@H]2CNC[C@@H]1O2
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CC4CCC(C3)O4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1R,5S)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using (1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane as the alkylating amine in step 3. The product was isolated as a white solid (8 mg, 28%). LCMS: m/e 669.7 (M+H)+, 2.11 min (method 4). 1H NMR (500 MHz, ACETONITRILE-d3) δ 8.17-7.83 (m, 2H), 7.43-7.12 (m, 2H), 5.32 (dd, J=6.2, 1.8 Hz, 1H), 4.80 (d, J=1.7 Hz, 1H), 4.72 (d, J=1.4 Hz, 1H), 4.37 (br. s., 2H), 3.14 (br. s., 4H), 2.99 (br. s., 4H), 2.92-2.81 (m, 1H), 2.68-2.44 (m, 2H), 2.27-1.15 (m, 24H), 1.75 (s, 3H), 1.21 (s, 3H), 1.09 (s, 3H), 1.05 (s, 3H), 0.98 (s, 3H), 0.96 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1Cl)=[O:5])[CH3:2].[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)=[O:5])[CH3:2]
Reactant: NCc1ccccn1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Product: CCOC(=O)c1cnc(Cl)cc1NCc1ccccn1

Procedure:
From 4,6-dichloropyridine-3-carboxylic acid ethyl ester synthesized according to the method described in US2006/0217417 and 2-(aminomethyl)pyridine in a manner similar to Example 339, the title compound was obtained as a colorless crystalline powder (yield 71%).
Reaction SMILES: [C:1]1(=[CH:5][C:6]([OH:8])=O)[CH2:4][CH2:3][CH2:2]1.[CH3:9][C:10]1[C:11]([O:18][CH3:19])=[CH:12][CH:13]=[C:14]([C:16]=1[CH3:17])[NH2:15].CN(C)CCCN=C=NCC.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl.C(N(CC)CC)C>[C:1]1(=[CH:5][C:6]([NH:15][C:14]2[CH:13]=[CH:12][C:11]([O:18][CH3:19])=[C:10]([CH3:9])[C:16]=2[CH3:17])=[O:8])[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(O)C=C1CCC1
Reactant: COc1ccc(N)c(C)c1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)C=C2CCC2)c(C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
Cyclobutylideneacetic acid (3.8 g), 5,6-dimethyl-4-methoxyaniline (5 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (4.7 g), 1,3-dicyclohexylcarbodiimide (DCC) (2.4 g), 4-dimethylaminopyridine (DMAP) (805 mg) and triethylamine (TEA) (7.3 g) were dissolved in dichloromethane (80 mL). The mixture was stirred at room temperature overnight, concentrated, and the residue dissolved in ethyl acetate. The organic phase was washed with water (3×20 mL) and 1M HCl (3×20 mL), and a white solid was filtered out. The organic solution was then dried out by evaporation giving 2-cyclobutylidene-N-(4-methoxy-2,3-dimethylphenyl)acetamide as a brown solid (5.3 g). The product was used in the next step without further purification. MS: (m/z)=246 (100, M+H+).
Reaction SMILES: C(N(CC)CC)C.Cl.[C:9]1([C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH:20]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[C:22]([O:24][CH3:25])=[O:23]>C(Cl)Cl>[CH3:25][O:24][C:22]([N:18]1[CH2:17][CH:16]=[C:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:20][CH2:19]1)=[O:23]
Reactant: COC(=O)Cl
Reactant: C1=C(c2ccccc2)CCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CC=C(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 105.2 %

Procedure:
Triethylamine (2.6 mL, 19.15 mmol) was added to a suspension of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (1.50 g, 7.66 mmol) in DCM (30 mL). The resulting mixture was stirred for 5 minutes until complete dissolution of the solids, then was cooled to 0° C., and methyl chloroformate (0.65 mL, 8.43 mmol) was added dropwise. A thick white precipitate formed. The reaction mixture was warmed to room temperature and stirred for 1 hour, then was quenched by addition of water, and extracted with DCM. The combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure to give 1.75 g of 4-phenyl-3,6-dihydro-2H-pyridine-1-carboxylic acid methyl ester as a pale yellow oil. This crude product (7.66 mmol) was dissolved in chloroform (30 mL) and 3-chloroperoxybenzoic acid (77%, 2.22 g, 9.95 mmol) was added. The resulting solution was stirred at room temperature for 18 hours. An aqueous solution of Na2SO3 (20%, 30 mL) was added and the resulting mixture was vigorously stirred for 1 hour. The phases were separated and the aqueous layer was extracted with DCM. The combined organic extracts were washed with a saturated aqueous solution of NaHCO3, dried over MgSO4, filtered and evaporated under reduced pressure to give a pale yellow oil. This crude oil was purified by flash chromatography (10% to 20% of EtOAc in hexane) to give 1.68 g (94% 2 steps yield) of 6-phenyl-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid methyl ester as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[CH:16][C:15]=2[C:22](=[O:33])[NH:23][C:24]2[CH:32]=[C:31]3[C:27]([CH:28]=[N:29][NH:30]3)=[CH:26][CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:34]([C:37]1[C:42]([CH3:43])=[CH:41][CH:40]=[CH:39][N:38]=1)=[C:35]=S>C(Cl)CCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([C:22](=[O:33])[NH:23][C:24]3[CH:32]=[C:31]4[C:27]([CH:28]=[N:29][NH:30]4)=[CH:26][CH:25]=3)=[CH:16][C:17]3[N:21]=[C:35]([NH:34][C:37]4[C:42]([CH3:43])=[CH:41][CH:40]=[CH:39][N:38]=4)[NH:20][C:18]=3[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccnc1N=C=S
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(N)c(N)cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1
Solvent: ClCCCl
Product: Cc1cccnc1Nc1nc2cc(C(=O)Nc3ccc4cn[nH]c4c3)c(N3CCN(C(=O)OC(C)(C)C)CC3)cc2[nH]1

Procedure:
4-[4,5-Diamino-2-(1H-indazol-6-ylcarbamoyl)-phenyl]piperazine-1-carboxylic acid tert-butyl ester (see Example 87) was reacted with 2-isothiocyanato-3-methylpyridine (0.3 mmol; prepared from 3-methylpyridin-2-ylamine following general procedure A) followed by cyclization using EDC as described in general procedure B to obtain 4-[6-(1H-indazol-6-ylcarbamoyl)-2-(3-methylpyridin-2-ylamino)-3H-benzimidazol-5-yl]-piperazine-1-carboxylic acid tert-butyl ester. MS: m/z 568 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[CH:2].I[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1>>[C:19]1([CH3:23])[CH:20]=[CH:21][CH:22]=[CH:17][C:18]=1[C:2]#[C:1][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1
Reactant: C#Cc1ccc(OCC(=O)OCC)cc1
Reactant: Cc1cccc(I)c1
Product: CCOC(=O)COc1ccc(C#Cc2ccccc2C)cc1

Procedure:
The title compound was prepared from ethyl (4-ethynylphenoxy)acetate (42 mg, 0.21 mmol) and iodo-3-methylbenzene (0.03 mL, 0.20 mmol) according to the general procedure ID to give 43 mg (72%) of an orange oil after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:10). Rf: 0.22 (EtOAc:hexanes, 1:10); 1HNMR (CDCl3) δ 7.49-7.46 (m, 3H), 7.26-7.12 (m, 3H), 6.90-6.87 (m, 2H), 4.64 (s, 2H), 4.30-4.27 (dq, 2H, J=7.2 Hz, 2.1 Hz), 2.50 (s, 3H), 1.33-1.28 (tt, 3H, J=7.2 Hz, 1.5 Hz); 13CNMR (CDCl3) δ 168.6, 157.7, 140.0, 133.0, 131.7, 129.4, 128.1, 125.5, 123.2, 116.9, 114.7, 93.0, 87.4, 65.4, 61.5, 20.7, 14.1; EI-MS m/z 294 (M+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][C:27]1[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][C:28]=1[C:29](O)=[O:30]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:29]([C:28]4[CH:32]=[C:33]([O:36][C:37]([F:38])([F:39])[F:40])[CH:34]=[CH:35][C:27]=4[CH3:26])=[O:30])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: Cc1ccc(OC(F)(F)F)cc1C(=O)O
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OC(F)(F)F)ccc4C)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2-methyl-5-(trifluoromethoxy)benzoic acid (compound F5) as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[CH2:24]([N:31]=[C:32]=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]1[C:4](=[O:5])[C:6]2[CH:7]=[N:8][C:9]3[C:10]([O:22][CH3:23])=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]=2[N:16]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:32]1=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: O=C=NCc1ccccc1
Product: COc1cccc2c1ncc1c(=O)n(Cc3ccccc3)c(=O)n(C3CCCC3)c12
Yield: 69.7 %

Procedure:
3-Benzyl-1-cyclopentyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (28 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.10 mmol) and benzyl isocyanate (0.4 mmol) following general procedure C. LCMS: m/z 402 [M+1]+.
Reaction SMILES: [NH:1]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:22][C:23]([CH3:29])([CH3:28])[CH2:24][C:25](Cl)=[O:26]>>[CH3:22][C:23]([CH3:29])([CH3:28])[CH2:24][C:25]([N:1]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:26]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: C1COCCOCCOCCOCCOCCOCCN1
Product: CC(C)(C)CC(=O)N1CCOCCOCCOCCOCCOCCOCC1

Procedure:
Analogously to Example 14 from 1-aza-4,7,10,13,16,19-hexaoxacycloheneicosane and 3,3-dimethylbutyryl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.O[CH:10]1[CH2:14][CH2:13][O:12][CH2:11]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:10]2[CH2:14][CH2:13][O:12][CH2:11]2)=[N:6][CH:7]=1
Reactant: Oc1ccc(Br)cn1
Reactant: OC1CCOC1
Product: Brc1ccc(OC2CCOC2)nc1

Procedure:
The title compound was prepared from 5-bromo-2-hydroxypyridine and rac-3-hydroxy-tetrahydrofuran in analogy to Example 9c): colorless solid.
Reaction SMILES: [OH:1][CH:2]([C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:19])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.Cl>C(Cl)Cl.CS(C)=O>[CH3:12][O:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([C@@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[O:19])=[O:1])=[CH:10][CH:9]=1
Reactant: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)NCc2ccccc2)cc1
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccc(OCC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)NCc2ccccc2)cc1
Temperature: -18 °C
Reaction time: 1.5 h
Yield: 76.9 %

Procedure:
(S)-2-[[(S)-2-[1-Hydroxy-2-(p-methoxyphenoxy)ethyl]-1-pyrrolidinyl]carbonyl]-N-(phenylmethyl)-1-pyrrolidinecarboxamide (5.00 g) was dissolved in methylene chloride (40 ml) and DMSO (20 ml). The mixture was cooled to -18° C. and added with diphosphorus pentaoxide (6.09 g). After stirring for 90 minutes, the reaction mixture was poured into 1.5N aqueous solution of hydrochloric acid and extracted with methylene chloride. The extract was washed with a saturated aqueous solution of sodium bicarbonate and water in order, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in ethyl acetate and the mixture was left standing at room temperature for a day to give the title compound (3.83 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C@@H:8]([CH2:28]Cl)[CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[SH:38].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:30])[NH:7][C@H:8]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:28][S:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[NH2:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCl)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: Nc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CSc1ccccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.2 %

Procedure:
A solution of tert-butyl[(2R)-1-{[tert-butyl(diphenyl)silyl]oxy}-3-chloropropan-2-yl]carbamate (58, 390 mg, 0.87 mmol) in dry DMF (2.5 ml) was treated with neat 2-aminobenzenethiol (351 mg, 2.8 mmol) followed by cesium carbonate (560 mg, 1.72 mmol). The mixture was stirred at room temperature for 3 h, diluted with DCM and washed with 1M NaOH followed by saturated NaHCO3, dried over MgSO4, filtered and concentrated to afford the title compound (482 mg) as an oil, which was submitted without further purification to the next synthetic step. MS: m/z=537.2 (MH+).
Reaction SMILES: [CH3:1]/[C:2](/[C:9]1[S:10][C:11]([CH2:14][CH:15](OS(C2C=CC(C)=CC=2)(=O)=O)[CH3:16])=[CH:12][CH:13]=1)=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N-:28]=[N+:29]=[N-:30].[Na+]>CS(C)=O>[N:28]([CH:15]([CH3:16])[CH2:14][C:11]1[S:10][C:9](/[C:2](/[CH3:1])=[CH:3]/[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:13][CH:12]=1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)/C=C(\C)c1ccc(CC(C)OS(=O)(=O)c2ccc(C)cc2)s1
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)/C=C(\C)c1ccc(CC(C)N=[N+]=[N-])s1

Procedure:
5-[(RS)-2-hydroxyprpyl]-2-thienyl methyl ketone and triethyl phosphonoacetate were reacted in alcohol in the presence of sodium ethylate to give ethyl (E)-5-[(RS)-2-hydroxypropyl]-β-methyl-2-thiopheneacrylate. With p-toluenesulphochloride there was obtained therefrom ethyl (E)-β-methyl-5-[(RS)-2-[(p-toluenesulphonyl)oxy]propyl]-2-thiopheneacrylate (melting point 121°, from methylene chloride/alcohol). Reaction of this ester with sodium azide in dimethyl sulphoxide gave ethyl (E)-5-[(RS)-2-azidopropyl]-β-methyl-2-thiopheneacrylate. Reduction of the latter ester with triphenylphosphine and hydrolysis led to ethyl (E)-5-[(RS)-2-aminopropyl]-β-methyl-2-thiopheneacrylate; ε320 =17970.
Reaction SMILES: [NH2:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[CH:11]1[C:20]2[C:15](=[C:16]([CH2:21][C:22](O)=[O:23])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1>>[CH:11]1[C:20]2[C:15](=[C:16]([CH2:21][C:22]([NH:1][C:2]3[S:6][CH:5]=[N:4][C:3]=3[C:7]([O:9][CH3:10])=[O:8])=[O:23])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1
Reactant: COC(=O)c1ncsc1N
Reactant: O=C(O)Cc1cccc2cnccc12
Product: COC(=O)c1ncsc1NC(=O)Cc1cccc2cnccc12

Procedure:
Methyl 5-(2-(isoquinolin-5-yl)acetamido)thiazole-4-carboxylate was prepared from methyl 5-aminothiazole-4-carboxylate (0.132 g, 0.834 mmol) and 2-(isoquinolin-5-yl)acetic acid (0.163 g, 0.834 mmol) according to protocol A. Retention time (min)=2.400, method [3], MS(ESI) 328.0 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[NH:21][C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]=2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][O:33][C:32]([CH3:37])([CH3:36])[CH2:31]1>>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][O:33][C:32]([CH3:36])([CH3:37])[CH2:31]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Reactant: CC1(C)CC(CCCCBr)CCO1
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCCCC3CCOC(C)(C)C3)c2n1

Procedure:
Prepared similarly to Intermediate 223 from N2-butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate and 4-(4-bromobutyl)-2,2-dimethyltetrahydro-2H-pyran but conducting the alkylation over 1.5 hours at 60° C.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15].[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[N+:14]([C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[N:4]([CH3:3])[S:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:25])=[O:24])([O-:16])=[O:15]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
To a suspension of sodium hydride (60%, 0.12 g (3.00 mmol)) in DMF (4.0 ml), N-methyl-2,4-dinitroaniline (0.39 g (1.98 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, benzenesulfonyl chloride (0.38 ml (2.98 mmol)) was added dropwise. After two hours' stirring at room temperature, the reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography with ethyl acetate-hexane (1:2) as eluent, to give 0.52 g (78%) of the title compound as pale yellow crystals.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.[OH:33][CH:34]1[CH2:37][NH:36][CH2:35]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:36]4[CH2:37][CH:34]([OH:33])[CH2:35]4)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: OC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(O)C4)c(Cl)c32)c(F)cc1F
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
To 3.5 g of N,N-dimethylformamide were added 2.00 g of 1-(6-amino-3,5-difluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1.00 g of 3-hydroxyazetidine hydrochloride, and 2.00 g of N-methylpyrrolidine together with 0.2 ml of ethanol, and the mixture was stirred at 85° C. for 10 minutes. The solvent and the like were distilled off under reduced pressure. After adding 10 ml. of ethanol to the residue, the mixture was heated under reflux for 10 minutes and allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 2.10 g of the title compound as a pale yellow powder.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([Sn](CCCC)(CCCC)CCCC)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:41]1[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][N:42]=1>>[Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([C:41]2[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][N:42]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: Fc1ccnc(Cl)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Product: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2cc(F)ccn2)o1
Yield: 51 %

Procedure:
The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (130 mg, 0.196 mmol) and 2-chloro-4-fluoropyridine following General Procedure A. Flash chromatography (10% EtOAc/hexanes) yielded the title compound as a thick oil (48 mg, 51%): 1H NMR (CDCl3, 400 MHz) δ 8.59 (dd, 1H, J=8.5, 5.6 Hz), 7.69 (s, 1H), 7.38 (dd, 1H, J=9.4, 2.3 Hz), 7.28-7.24 (m, 2H), 7.18-7.15 (m, 3H), 6.96 (ddd, 1H, J=8.2, 5.6, 2.4 Hz), 4.87 (dd, 1H, J=7.0, 6.2 Hz), 2.60 (t, 2H, J=7.6 Hz), 1.96 (m, 2H), 1.62 (m, 2H), 1.36 (m, 4H), 0.91 (s, 9H), 0.11 (s, 3H), 0.01 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 170.4, 167.8, 166.1, 152.4 (d, J=7.6 Hz), 150.2, (d, J=7.6 Hz), 149.8 (d, J=4.6 Hz), 142.7, 128.3, 128.2, 126.2, 125.5, 110.5 (d, J=15.2 Hz), 106.9 (d, J=18.2 Hz), 68.7, 36.4, 35.9, 31.4, 29.1, 25.7, 25.7, 25.1, 18.2, −5.0, −5.2.
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.CS([Cl:35])(=O)=O>ClCCl.N1C=CC=CC=1>[Cl:35][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3ccccc32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(Cl)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-Hydroxy-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (3.57 g) is dissolved in dichloromethane (30 ml) and pyridine (1.1 ml), and thereto is added dropwise methanesulfonyl chloride (0.9 ml) in small portions at 0° C. Then, the mixture is stirred at room temperature for 3 days. The solvent is distilled off and the resulting residue is poured into ice-water. The precipitated crystal is collected by filtration, washed with water, and dried to give 5-chloro-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (3.10 g) as light yellow powder.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([O:20][CH2:21][CH3:22])[CH:19]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=1.[CH2:23]([O:25][P:26]([O:30]CC)[O:27][CH2:28][CH3:29])[CH3:24]>>[CH2:21]([O:20][C:18]1[CH:19]=[C:3]([CH:4]=[C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[CH:17]=1)[CH2:2][P:26](=[O:30])([O:27][CH2:28][CH3:29])[O:25][CH2:23][CH3:24])[CH3:22]
Reactant: CCOP(OCC)OCC
Reactant: CCOc1cc(CCl)cc(Oc2ccc(C(F)(F)F)cn2)c1
Product: CCOc1cc(CP(=O)(OCC)OCC)cc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
2-(3-(Chloromethyl)-5-ethoxyphenoxy)-5-(trifluoromethyl)pyridine from Step 3 was treated neat with triethylphosphite (0.30 mL, 1.75 mmol) and heated to 150° C. After 16 h, the reaction mixture was cooled and purified by silica gel chromatography (0-50%, EtOAc:CH2Cl2) to afford the title compound (400 mg, 82% yield) as a thick oil.