Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12](=[O:25])[C:13]3[C:17]=2[C:16](=[O:18])[NH:15][C:14]=3[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(C1C=CC(C)=CC=1)(O[CH3:30])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:30][N:15]1[C:16](=[O:18])[C:17]2=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[O:11][C:12](=[O:25])[C:13]2=[C:14]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1NC(c2ccccc2)=C2C(=O)OC(c3ccc([N+](=O)[O-])cc3)=C12
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)C2=C(c3ccc([N+](=O)[O-])cc3)OC(=O)C2=C1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
A mixture of furopyrrole 12 (0.9 g, 2.7 mmol), methyl tosylate (750 mg, 4.04 mmol), potassium carbonate (1 g, 7.2 mmol) and dimethyl formamide was stirred at room temperature overnight. Water was then added, and the organic component extracted with DCM. The solvent was removed, and washing with water then methanol gave the methylated compound 13 as a red solid (0.652 g, 70%), m.p. 253-255° C. δH (CDCl3) 8.55 and 8.38 (4H, AA′BB′, Ar), 7.88-7.84 (2H, m, o-Ph), 7.65-7.60 (3H, m, m/p-Ph) and 3.49 (3H, s, NCH3). λmax (abs) (DCM)/nm 482 ( 17,462)
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[F:21])=[O:13])=[CH:10][N:11]=2)[N:5]=[C:6](Cl)[CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][N:24]=1.CC(C)([O-])C.[K+].[C@H:39]1([NH2:46])[CH2:44][CH2:43][C@H:42]([NH2:45])[CH2:41][CH2:40]1>C1COCC1.CN(C=O)C>[NH2:45][C@H:42]1[CH2:43][CH2:44][C@H:39]([NH:46][C:6]2[CH:7]=[C:2]([NH:22][C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][N:24]=3)[C:3]3[N:4]([C:9]([C:12](=[O:13])[NH:14][C:15]4[CH:20]=[CH:19][N:18]=[CH:17][C:16]=4[F:21])=[CH:10][N:11]=3)[N:5]=2)[CH2:40][CH2:41]1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Reactant: N[C@H]1CC[C@H](N)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N[C@H]1CC[C@H](Nc2cc(Nc3ccc(C(=O)O)cn3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 5A (0.050 g, 0.153 mmol) and methyl 6-aminonicotinate (0.028 g, 0.184 mmol) in THF (0.767 mL) at room temperature was added potassium tert-butoxide (0.337 mL, 0.337 mmol). The resulting suspension was stirred 2 h at room temperature. The solvent was then removed via a stream of nitrogen. The solid was taken up in NMP (0.767 mL), (trans)-cyclohexane-1,4-diamine (0.210 g, 1.840 mmol) was added, and the mixture was heated to 110° C. in a CEM Discover 300 W microwave for 20 min. The mixture was diluted with DMF and purified via preparatory HPLC using a YMC ODS C-18 column (30×250 mm), 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 60 min, flow rate 25 mL/min. Rt=48.545 min. The appropriate fractions were concentrated and lyophilized overnight, and 6-(6-((trans)-4-aminocyclohexylamino)-3-(3-fluoropyridin-4-ylcarbamoyl)imidazo[1,2-b]pyridazin-8-ylamino)nicotinic acid (7.4 mg, 8.29 μmol, 5.41% yield) was obtained as a white lyophile. HPLC: Rt=3.466 min. YMC S5 ODS-A column (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.2% H3PO4). Solvent A: (10% MeOH, 90% H2O, 0.2% H3PO4). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% 1 min, flow rate 4 mL/min. MS: [M+H]=506.1. 1H NMR (400 MHz, DMSO-D6) δ ppm 11.20 (1H, s), 10.31 (1H, s), 8.85 (1H, d, J=2.27 Hz), 8.70 (1H, d, J=1.26 Hz), 8.45-8.51 (1H, m), 8.43 (1H, s), 8.12-8.19 (1H, m), 8.07 (1H, s), 7.93 (2H, s), 7.58 (1H, d, J=8.56 Hz), 7.24 (1H, s), 7.11 (1H, s), 6.99 (1H, s), 3.79-3.93 (1H, m), 3.00-3.13 (1H, m), 2.05-2.18 (2H, m), 1.97 (2H, s), 1.47 (2H, s), 1.33 (2H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([OH:18])(=[O:17])[CH2:13][C:14]([CH3:16])=O.[NH2:19]/[C:20](/[CH:26]([O:29][CH3:30])[O:27][CH3:28])=[CH:21]\[C:22]([O:24][CH3:25])=[O:23]>C(O)(C)(C)C>[CH3:25][O:24][C:22]([C:21]1[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:13]([C:12]([OH:18])=[O:17])=[C:14]([CH3:16])[NH:19][C:20]=1[CH:26]([O:29][CH3:30])[O:27][CH3:28])=[O:23]
Reactant: CC(=O)CC(=O)O
Reactant: COC(=O)/C=C(\N)C(OC)OC
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CC(C)(C)O
Product: COC(=O)C1=C(C(OC)OC)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Yield: 109.7 %

Procedure:
A solution of 3-nitrobenzaldehyde (3.02 g), 3-nitrooxy-2,2-bis(nitrooxymethyl)propyl ester of acetoacetic acid (7.10 g) and methyl 3-amino-4,4-dimethoxycrotonate (3.50 g) dissolved in tert-butyl alcohol (12 ml) was refluxed for 15 hours. The resulting mixture was cooled and concentrated under reduced pressure. The residue obtained was subjected to column chromatography on silica gel (200 g) and eluted with a mixture of toluene and ethyl acetate (10:1 by volume). The fractions containing the desired compound were collected and evaporated under reduced pressure to give a viscous oil of 3-nitrooxy-2,2-bis(nitrooxymethyl)propyl ester of 5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (8.60 g).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:13]([CH3:15])([CH3:14])[N+:12]([O-])=[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10]2)=[CH:5][CH:4]=1.C(O)C>[Zn].C(O)=O>[CH3:1][N:2]([CH3:23])[C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:10][C@H:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:12][C:13]2([CH3:14])[CH3:15])=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(C2CC(c3ccccc3)=[N+]([O-])C2(C)C)cc1
Agent: [Zn]
Solvent: CCO
Solvent: O=CO
Product: CN(C)c1ccc([C@H]2C[C@H](c3ccccc3)NC2(C)C)cc1

Procedure:
47 G. of 4-(p-dimethylaminophenyl)-5,5-dimethyl-2-phenyl-1-pyrroline 1-oxide are dissolved in a mixture of 400 ml. of ethanol and 400 ml. of formic acid and treated portionwise while stirring with 80 g. of zinc powder. The temperature is held at 43° C. during this addition. Subsequently, the mixture is stirred for a further 2 hours, the zinc sludge is then filtered off and the filtrate evaporated under reduced pressure. The residue is taken up in water, neutralized with 3-N sodium hydroxide and extracted with ether. The ether phase is then dried over sodium sulfate and evaporated under reduced pressure. The residue is chromatographed on silica gel, elution being carried out first with pure benzene and then with benzene/acetone mixtures with increasing acetone content (up to 50% acetone). There is thus obtained trans-3-(p-dimethylaminophenyl)-2,2-dimethyl-5-phenyl-pyrrolidine which melts at 108°-109° C. after crystallization from n-hexane.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH:25][C:27](=[O:34])[C:28]5[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: C[C@H](Nc1cncc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Agent: Cl
Product: C[C@H](Nc1cncc(-n2cnc3cc(NC(=O)c4cccnc4)ccc32)n1)c1ccccc1
Yield: 39 %

Procedure:
In a procedure analogous to example 32, reaction of 1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-5-amine (33 mg, 0.10 mmol) and nicotinoyl chloride hydrochloride (20 mg, 0.11 mmol) furnished the product (17 mg, 39%) after chromatography.
Reaction SMILES: CN(C=O)C.[Cl:6][CH:7](Cl)[CH3:8].C(Cl)(=O)C(Cl)=O.[N:16]1[C:21]2[CH:22]=[CH:23][S:24]C=2C(=O)[NH:18][CH:17]=1>O>[Cl:6][C:7]1[C:8]2[S:24][CH:23]=[CH:22][C:21]=2[N:16]=[CH:17][N:18]=1
Reactant: O=c1[nH]cnc2ccsc12
Reactant: CC(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncnc2ccsc12
Reaction time: 0.17 h
Yield: 82 %

Procedure:
To a solution of DMF (170.3 μL, 2.2 mmol) and dichloroethane (1.2 mL) at 0° C. under N2, oxalyl chloride (279.2 mg, 3.2 mmol) is added slowly and stirred for 10 min. 3H-thieno[3,2-d]pyrimid-4-one (152.2 mg, 1.0 mmol) is added and refluxed for 5 h. The reaction mixture is poured into water and extracted with CH2Cl2. The organic layer is stripped under reduced pressure to yield 4-chlorothieno[3,2-d]pyrimidine (140 mg, 82%) as a yellow solid. 1H NMR (DMSO) δ 9.05 (1H, s), 8.62 (1H, d, J=5 Hz), 7.79 (1H, d, J=5 Hz)
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[S:10][C:9]=2[C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.Cl[C:29]1[O:30][C:31]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:32][C:33](=[O:35])[CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[S:10][C:9]=2[C:8]([C:29]2[O:30][C:31]([N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)=[CH:32][C:33](=[O:35])[CH:34]=2)=[CH:7][CH:6]=1
Reactant: O=c1cc(Cl)oc(N2CCOCC2)c1
Reactant: COCOc1ccc(B2OC(C)(C)C(C)(C)O2)c2c1Sc1ccccc1S2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COCOc1ccc(-c2cc(=O)cc(N3CCOCC3)o2)c2c1Sc1ccccc1S2
Temperature: 90 °C
Yield: 101.6 %

Procedure:
2-(4-Methoxymethoxy-thianthren-1-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (6.23 g, 17.14 mmol), 2-chloro-6-morpholin-4-yl-pyran-4-one (3) (6.99 g, 17.40 mmol) and powdered potassium carbonate (7.20 g, 52.20 mmol) were suspended in anhydrous dioxane (60 ml) under a nitrogen atmosphere. The mixture was degassed for 15 minutes before the addition of tetrakis(triphenylphosphino)palladium (1.2 g, 5% eq) and then degassed for a further 15 minutes after addition. The reaction was then heated at 90° C. for 24 hours. Water (60 ml) was added and the mixture extracted with EtOAc (3×30 ml). The organic extracts were then dried using MgSO4, filtered and concentrated in vacuo to yield a dark yellow oil. The crude residue was then purified by flash chromatography (SiO2) (9:1—EtOAc/MeOH) to give the title compound (7.93 g, 79%) as a green powder. m/z (LC-MS, ESP): RT=4.39 min, (M++1)=456
Reaction SMILES: [NH2:1][CH:2]1[CH2:14][CH2:13][C:12]2[NH:11][C:10]3[CH:9]=[CH:8][C:7]([C:15]#[N:16])=[CH:6][C:5]=3[C:4]=2[CH2:3]1.C(N(CC)CC)C.Cl[C:25]([O:27][CH3:28])=[O:26]>CS(C)=O>[CH3:28][O:27][C:25](=[O:26])[NH:1][C@H:2]1[CH2:3][C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[C:7]([C:15]#[N:16])[CH:6]=3)[NH:11][C:12]=2[CH2:13][CH2:14]1
Reactant: N#Cc1ccc2[nH]c3c(c2c1)CC(N)CC3
Reactant: COC(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)N[C@@H]1CCc2[nH]c3ccc(C#N)cc3c2C1

Procedure:
Combine 6-amino-6,7,8,9-tetrahydro-5H-carbazole-3-carbonitrile (2.4 mmol, 0.5 g) and triethylamine (4.7 mmol, 0.66 mL) in DMSO (10 mL) with 15 stirring. Add methyl chloroformate (3.6 mmol, 275 μL) and stir the resulting mixture at room temperature for 5-10 min. Quench with water (35 mL) and dilute the reaction mixture with ethyl acetate (200 mL). Separate the layers and wash the organic layer with with brine (100 mL). Back wash the brine layer with ethyl acetate (2×100 mL) and dry the combined organic layers with magnesium sulfate. Filter and concentrate in vacuo to provide crude product that is used without further purification. LCMS of the reaction mixture prior to workup gave masses 270.0 (APCI-pos) and 268.0 (APCI-neg) for the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[C:8]2[CH3:23])=[CH:4][CH:3]=1.IC.[C:28](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH2:19][C:20]([O:22][CH3:28])=[O:21])=[C:8]2[CH3:23])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(CCC(=O)O)c(C)n2Cc1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CCc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.2 %

Procedure:
To a 0° C. solution of the acid from Example 1, Step 2 (900 mg, 2.24 mmol) in 10 mL of DMF was added iodomethane (0.18 mL, 2.89 mmol) followed by potassium carbonate (326 mg, 2.36 mmol). The mixture was warmed to room temperature, stirred 3 h, then poured into water and extracted with ether. The organic extracts were washed with water and brine, dried over Na2SO4 and evaporated to give 953 mg of the title compound.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C@H:24]2[CH2:29][CH2:28][C@H:27]([CH3:30])[CH2:26][CH2:25]2)[C:13]([NH:15][C:16]2[S:17][C:18]([S:21]C#N)=[CH:19][N:20]=2)=[O:14])[CH2:8][CH2:7]1)(=[O:5])[CH2:2][CH2:3][CH3:4].SC[C@@H]([C@@H](CS)O)O.[N:39](=[CH:47][CH2:48]Cl)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]Cl>>[N:39]1([CH2:47][CH2:48][S:21][C:18]2[S:17][C:16]([NH:15][C:13](=[O:14])[N:12]([CH:9]3[CH2:8][CH2:7][N:6]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH2:11][CH2:10]3)[C@H:24]3[CH2:29][CH2:28][C@H:27]([CH3:30])[CH2:26][CH2:25]3)=[N:20][CH:19]=2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: ClCC=NCCCCCCCl
Reactant: CCCC(=O)N1CCC(N(C(=O)Nc2ncc(SC#N)s2)[C@H]2CC[C@H](C)CC2)CC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: CCCC(=O)N1CCC(N(C(=O)Nc2ncc(SCCN3CCCCCC3)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
Prepared as described in general procedures (H) and (I) using 1-(1-butyryl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 2-(hexamethyleneimino)ethylchloride
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[OH:31])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.Br[CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[F:40][C:2]([F:1])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:37])([F:36])[F:38])[CH:34]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[O:31][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:10][N:9]=1
Reactant: CCOC(=O)CCCBr
Reactant: Oc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-{[(3,5-Bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenol (150 mg) is dissolved in N,N-dimethylformamide (4 ml), and thereto are added ethyl 4-bromo-butyrate (74 μl) and potassium carbonate (71 mg) and the mixture is stirred at 80° C. overnight. To the reaction solution are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=22:3→7:3) to give ethyl 4-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenoxy)-butyrate (123 mg). MS (m/z): 695 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]([CH3:17])[CH3:16])[CH:8]=2)[N:3]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][NH2:24]>O>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:24][CH2:23][C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]([CH3:17])[CH3:16])[CH:8]=2)[N:3]=1
Reactant: CN(C)c1ccc2nc(N)c(C#N)c(Cl)c2c1
Reactant: NCc1cccs1
Solvent: O
Product: CN(C)c1ccc2nc(N)c(C#N)c(NCc3cccs3)c2c1

Procedure:
3 g of 2-amino-3-cyano-4-chloro-6-dimethylaminoquinoline and 6 mL of 2-thienylmethylamine are stirred at 125° C. for 3 hours. The reaction mixture is poured onto 30 mL of water. The precipitated material is filtered off, washed with 20 mL of water. After drying 1.9 g of the title compound is obtained, m.p.: 211° C.
Reaction SMILES: ICCI.[Sm].C(=O)=O.CC(C)=O.[CH2:13]([CH:15]1[CH:41]=[C:40]([CH3:42])[CH2:39][CH:38]([CH3:43])[CH2:37][CH:36]([O:44][CH3:45])[CH:35]2[O:46][C:31]([OH:50])([CH:32]([CH3:49])[CH2:33][CH:34]2[O:47][CH3:48])[C:30](=[O:51])[C:29](=[O:52])[N:28]2[CH:23]([CH2:24][CH2:25][CH2:26][CH2:27]2)[C:22](=[O:53])[O:21][CH:20]([C:54]([CH3:74])=[CH:55][CH:56]2[CH2:61][CH2:60][CH:59]([C:62]3[CH:71]=[CH:70][C:69]4[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=4)[CH:63]=3)[CH:58]([O:72][CH3:73])[CH2:57]2)[CH:19]([CH3:75])[CH:18]([OH:76])[CH2:17][C:16]1=[O:77])[CH3:14]>C1COCC1.C1COCC1.CO>[CH2:13]([CH:15]1[CH:41]=[C:40]([CH3:42])[CH2:39][CH:38]([CH3:43])[CH2:37][CH:36]([O:44][CH3:45])[CH:35]2[O:46][C:31]([OH:50])([CH:32]([CH3:49])[CH2:33][CH:34]2[O:47][CH3:48])[CH:30]([OH:51])[C:29](=[O:52])[N:28]2[CH:23]([CH2:24][CH2:25][CH2:26][CH2:27]2)[C:22](=[O:53])[O:21][CH:20]([C:54]([CH3:74])=[CH:55][CH:56]2[CH2:61][CH2:60][CH:59]([C:62]3[CH:71]=[CH:70][C:69]4[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=4)[CH:63]=3)[CH:58]([O:72][CH3:73])[CH2:57]2)[CH:19]([CH3:75])[CH:18]([OH:76])[CH2:17][C:16]1=[O:77])[CH3:14]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(c4ccc5ccccc5c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: ICCI
Agent: O=C=O
Agent: [Sm]
Solvent: CO
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(C)CC2OC)C(O)C(=O)N2CCCCC2C(=O)OC(C(C)=CC2CCC(c3ccc4ccccc4c3)C(OC)C2)C(C)C(O)CC1=O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 22.3 %

Procedure:
A solution of 1,2-diiodoethane (42 mg, 0.15 mmol) in dry THF (1 mL) was added dropwise to a stirred mixture of samarium metal (46.5 mg, 0.31 mmol) in dry THF (1 mL) and stirred for 1.5 hours. The reaction mixture was then cooled to -78° C. (dry ice/acetone) and treated with a solution of 17-ethyl- 1,14-dihydroxy-12-[2'-(4"-(naphth-2-yl)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.109 mmol) in 1:1 THF/CH3OH. The mixture was maintained at -78° C. for 15 minutes then allowed to warm to room temperature. The reaction was quenched with cold saturated aqueous K2CO3 and quickly extracted with CH2Cl2. The extracts were combined, dried with Na2SO4, filtered and concentrated in vacuo. Purified by preparative TLC on silica gel (eluted with 7% CH3OH in CH2Cl2) to give 22 mg of 17-ethyl-1,2,14-trihydroxy-12-[2'-(4"-(naphth-2-yl)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.04,9 ]octacos-18-ene-3,10,16-trione (1H NMR and mass spectral analysis are consistent with the desired structure).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=O)[NH:8][C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:7]1[NH:8][C:4]2[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: Cc1ccc2[nH]c(=O)[nH]c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc2nc(Cl)[nH]c2c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
5-Methyl-1,3-dihydro-2H-benzimidazol-2-one (13.1 g, 88.5 mmol) and phosphorus oxychloride (130 ml, freshly distillated) was charged into three-neck round-bottom flask. The mixture was heated up to boiling point till homogeneous solution was formed. After that the dried hydrogen chloride was bubbled through inlet gas-pipe into the reaction mixture. The mixture was boiled for 15 hours. Excess of phosphorus oxychloride was distillated in vacuo. Mixture of ice and water (250 ml) was added to residue. The obtained suspension was cooled to the room temperature and filtered. Filtrate was alkalinized by aqueous ammonia solution till pH 8, cooled by cold water and filtered crude 2-chloro-6-methyl-1H-benzimidazole. White powder was crystallized from aqueous methanol (water-methanol: 1:1, 200 ml), washed by aqueous methanol and dried in a desiccator under phosphorous oxide in vacuo. Yield: 8.17 g (55%).
Reaction SMILES: C(O)(C)C.[Cl:5][C:6]1[CH:12]=[C:11]([N+:13]([O-])=O)[C:10]([CH3:16])=[CH:9][C:7]=1[NH2:8].[OH-].[K+]>C1(=O)C=CC=CC1=O.O>[Cl:5][C:6]1[CH:12]=[C:11]([NH2:13])[C:10]([CH3:16])=[CH:9][C:7]=1[NH2:8]
Reactant: Cc1cc(N)c(Cl)cc1[N+](=O)[O-]
Agent: O=C1C=CC=CC1=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1cc(N)c(Cl)cc1N
Yield: 91.4 %

Procedure:
A reaction vessel was charged with 60 g of isopropyl alcohol, 50 g of water, 37.3 g of 2-chloro-5-methyl-p-nitroaniline, 5 g of potassium hydroxide and 0.6 g of 1,2-benzoquinone, and then the same procedure as in Example 1 was followed, to obtain 28.6 g of 2-chloro-5-methyl-p-phenylenediamine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[CH2:34]1[NH:39][CH2:38][CH2:37][N:36]2[CH2:40][CH2:41][CH2:42][C@H:35]12>ClCCl.CN(C)C=O.ClCCl>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]([N:39]2[CH2:38][CH2:37][N:36]3[CH2:40][CH2:41][CH2:42][C@@H:35]3[CH2:34]2)=[O:7])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: Nc1cc(C(=O)O)ccc1F
Reactant: C1C[C@@H]2CNCCN2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: Nc1cc(C(=O)N2CCN3CCC[C@@H]3C2)ccc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 3-amino-4-fluorobenzoic acid (0.621 g, 4 mmol) and 1-hydroxybenzotriazole hydrate (0.613 g, 4 mmol) in dichloromethane/N,N-dimethylformamide (10:1, 60 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, 0.621 g, 4 mmol). After 5 minutes, (R)-octahydropyrrolo[1,2-a]pyrazine (0.505 g, 4 mmol) in dichloromethane (1 mL) was added. The mixture was stirred at room temperature overnight. Then the mixture was concentrated. The residue was purified by chromatography on silica gel (dichloromethane, then methanol/dichloromethane=1:10) to give (R)-(3-amino-4-fluorophenyl)(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methanone: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.25 (m, 1H), 1.60-2.10 (m, 6H), 2.70-3.10 (m, 4H), 3.55-3.70 (m, 1H), 4.40-4.60 (m, 1H), 5.30 (s, 2H), 6.50 (m, 1H), 6.77 (m, 1H), 7.00 (m, 1H); MS (ESI) m/z 264 (M+H)+.