Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:16][CH3:17])[C:9](Br)=[CH:10][C:11]=2[O:13][CH3:14])[C:6]([O:18][CH3:19])=[CH:5][C:4]=1Br.C([Sn](CCCC)(CCCC)[C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:16][CH3:17])[C:9]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[CH:10][C:11]=2[O:13][CH3:14])[C:6]([O:18][CH3:19])=[CH:5][C:4]=1[C:28]1[S:27][CH:26]=[CH:30][CH:29]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: COc1cc(Br)c(OC)c2c(OC)cc(Br)c(OC)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1cc(-c2cccs2)c(OC)c2c(OC)cc(-c3cccs3)c(OC)c12
Yield: 96 %

Procedure:
1,4,5,8-Tetramethoxy-2,6-dibromonaphthalene (7.80 g., 0.019 mol.) and 2-(tributylstannyl)thiophene (18.00 g., 0.048 mol.) were dissolved in 200 mL dry toluene under argon atmosphere. Pd(PPh3)4 (100 mg.) was introduced into the reaction flask using a Schlenk tube under argon. The resultant mixture was subsequently refluxed for 18 hrs. The brownish black solution was cooled and poured into 500 mL of petroleum ether to afford crude yellow solid. Upon recrystallization from CH2Cl2/petroleum ether (1:3) the desired product was obtained as a light yellow solid. Yield: 96%. M.p. 233.5-237° C. Anal. Calcd. for C22H20O4S2: C, 64.06%; H, 4.89%; S, 15.54%. Found: C, 64.12%; H, 4.90%; S, 15.12%. Mass spectrum: 411.84 (M+). 1H-NMR (CDCl3; in ppm.): 3.73 (s, 3H), 4.05 (s, 3H), 7.13 (dd, 2H), 7.19 (s, 2H), 7.41 (dd, 2H), 759 (dd, 2H,). 13C-NMR (CDCl3; in ppm.): 56.7, 61.7, 107.5, 122.5, 124.4, 125.7, 126.6, 126.9, 139.1, 146.5, 152.5.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH:5](O)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.S(Cl)([Cl:19])=O>C(Cl)Cl.N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH:5]([Cl:19])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1
Reactant: OC(c1ccc(Cl)cc1)c1cccc(Br)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Clc1ccc(C(Cl)c2cccc(Br)c2)cc1
Reaction time: 8 h
Yield: 103 %

Procedure:
A solution of the above benzhydryl alcohol (13.0 g, 43 mmol) in 100 mL of methylene chloride and 5 mL of pyridine was stirred at room temperature during dropwise addition of 4.7 mL (64 mmol) of thionyl chloride in 20 mL of methylene chloride. After stirring overnight, the reaction solution was washed with two 60 mL portions of 1M hydrochloric acid and 50 mL of water and dried over magnesium sulfate. Evaporation of the solvent gave 14.0 g of 3-bromo-4'-chlorobenzhydryl chloride as a pale yellow oil. A portion was purified by chromatography on silica gel with hexane to give a colorless oil. Calc. for C13H9BrCl2 : C, 49.41; H, 2,87; Br, 25.28; Cl, 22.44. Found: C, 49.50; H, 2.82; Br, 25.27; Cl, 22.48.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[C:26](Cl)(=[O:28])[CH3:27]>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH2:21][N:22]([C:26](=[O:28])[CH3:27])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: CC(=O)Cl
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(F)cc2CN(CC)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-4′-fluoro-6-methoxy-biphenyl-3-yl)-acetic acid ethyl ester and acetyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:31][CH:32]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:33](Cl)=[O:34]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:31][CH:32]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:33]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1)=[O:34]
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)C(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.9 %

Procedure:
To a solution of 0.61 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 8 ml of methylene chloride is added 0.30 g of triethylamine followed by 0.47 g of (±)-2-chloro-2-phenylacetyl chloride in 2 ml of methylene chloride. The mixture is stirred at room temperature for 1 hour and then diluted with 10 ml of 50% NaHCO3. The methylene chloride is evaporated and the residue is extracted with ethyl acetate. The separated organic layer is washed with saturated NaHCO3 and brine and then dried with Na2SO4 followed by filtering through a pad of hydrous magnesium silicate. The filtrate is evaporated to a residue which is stirred with ether-hexane to give 0.98 g of pink solid. MS(CI):456(M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])[C:23]([Cl:38])=[CH:22][N:21]=1>>[Cl:38][C:23]1[C:24]([NH:26][C:27]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])=[N:25][C:20]([NH:1][C:2]2[CH:18]=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12](=[O:13])[N:14]([CH3:15])[CH3:16])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:21][CH:22]=1
Reactant: CN(C)C(=O)CN1CCc2ccc(N)cc2CC1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)CCN(CC(=O)N(C)C)CC3)ncc1Cl

Procedure:
2-[5-Chloro-2-(3-dimethylcarbamoylmethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide was prepared from 2-(7-amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 308c. Product isolated as a yellow foam (91 mg, 43%). LCMS (m/e) 526 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.73 (s, 1H), 8.07 (s, 1H), 7.35-7.25 (m, 3H), 7.15 (s, 1H), 7.10 (d, 1H, J=8.3 Hz), 6.89 (d, 1H, J=8.3 Hz), 6.83 (s, 1H), 6.17-6.10 (m, 1H), 3.28 (s, 2H), 3.15 (s, 3H), 2.99 (s, 3H), 2.92 (d, 3H, J=4.8 Hz), 2.89-2.83 (m, 2H), 2.79-2.73 (m, 2H), 2.69-2.61 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:22])[CH2:11][C:12]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])=[O:13])=[CH:4][CH:3]=1.[C:23]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:22])[CH:11]([CH3:23])[C:12]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])=[O:13])=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(C(=O)CC(=O)CCc2ccc(F)cc2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CC(C(=O)CCc1ccc(F)cc1)C(=O)c1cccc(C#N)c1
Temperature: 60 °C
Yield: 60.1 %

Procedure:
A mixture of 3-[5-(4-fluorophenyl)-3-oxo-pentanoyl]-benzonitrile (Example 6 Step 1) (1.0 g, 3.39 mmol), K2CO3 (469 mg, 3.39 mmol), MeI (264 μL, 4.23 mmol) and acetone (25 mL) was heated at 60° C. for 36 hours and then concentrated under reduced pressure. The residue was partitioned between H2O (20 mL) and Et2O (80 mL) and acidified to pH=3 using 2 M HCl solution. The organics were separated and concentrated under reduced pressure. The residue was purified by column chromatography on silica using 30% EtOAc/iso-hexanes to yield the alkylated product (0.63 g, 60%). 1H NMR (CDCl3, 360 MHz) δ 8.14 (1H, s), 8.04 (1H, d, J=8.0 Hz), 7.83 (1H, d, J=7.7 Hz), 7.57 (1H, J=7.8 Hz), 7.08-7.00 (2H, m), 6.87 (2H, t, J=8.6 Hz), 4.38 (1H, q, J=7.0 Hz), 2.85-2.70 (4H, m), 1.43 (3H, d, J=7.0 Hz). MS (ES−) C19H16FNO2 requires: 309, found: 308 (M+H+, 100%).
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:27]1[CH:28]=[CH:29][C:30]2[N:31]([N:33]=[CH:34][N:35]=2)[N:32]=1.C(N(C(C)C)C(C)C)C>C(O)CCC>[C:20]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([N:33]=[CH:34][N:35]=4)[N:32]=3)[CH2:11][CH2:10]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Clc1ccc2ncnn2n1
Reactant: NCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: c1ccc(C(OC2CCN(CCCCNc3ccc4ncnn4n3)CC2)c2ccccc2)cc1
Yield: 9.1 %

Procedure:
4-(Diphenylmethoxy)-1-piperidinebutanamine (1.83 g) and 6-chloro[1,2,4]triazolo[1,5-b]pyridazine (557 mg) were dissolved in 1-butanol (30 ml), followed by addition of N-ethyldiisopropylamine (931 mg). The mixture was refluxed under heating for 14 hours. After being cooled, the mixture was concentrated under reduced pressure, followed by addition of ice-water and extraction with ethyl acetate. The extract was washed with an aqueous sodium chloride saturated solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography and eluted with a mixture of ethyl acetate, methanol and triethylamine (45:5:1). Fractions containing the objective compound were collected and concentrated. The resulting crystals were collected, washed with ethyl ether and dried to yield the title compound (149 mg).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:11])=[N:8][CH:9]=2)[N:4]([CH3:12])[N:3]=1.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([F:20])[CH:19]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[F:13][C:14]1[CH:15]=[C:16]([C:2]2[C:10]3[C:5](=[N:6][C:7]([NH2:11])=[N:8][CH:9]=3)[N:4]([CH3:12])[N:3]=2)[CH:17]=[C:18]([F:20])[CH:19]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: Cn1nc(Br)c2cnc(N)nc21
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1nc(-c2cc(F)cc(F)c2)c2cnc(N)nc21

Procedure:
3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Intermediate 3) (0.05 g, 0.22 mmol) is suspended in 1,4-dioxane (1 ml). The reaction mixture is sonicated to give a very fine suspension and placed in a microwave vial containing 3,5-difluoro phenylboronic acid (38 mg, 0.24 mmol). To this is added a solution of tris(dibenzylileneacetone) di palladium(0) (0.002 g, 0.0022 mmol) in 1,4-dioxane (0.5 ml) followed by a solution of tricyclohexyl phosphine (0.0015 g, 0.0053 mmol) in 1,4-dioxane (0.5 ml) and 1.27M aqueous potassium phosphate solution (0.294 ml, 0.374 mmol). The resulting mixture is flushed with argon and heated using microwave radiation at 150° C. for 30 minutes. The reaction mixture is treated with DMSO (2 ml) and filtered through a 2 g silica cartridge washing with EtOAc:MeOH (10:1, 4 ml). The filtrate is concentrated in vacuo and the resulting residue is dissolved in NMP (4 ml) and loaded onto an Isolute™ SCX column (silica based cation exchange sorbent) eluting with MeOH (4 ml) and 1M NH3 in MeOH (6 ml). The appropriate fractions are combined and concentrated in vacuo to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(=S)=S.O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:13](=[O:14])[CH2:12][CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:19][CH:18]=1
Reactant: O=C(Cl)CCCc1ccc([N+](=O)[O-])cc1
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O
Product: O=C(CCCc1ccc([N+](=O)[O-])cc1)c1ccc(F)cc1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A solution of 4-(4-nitrophenyl)butyryl chloride (5.4 g, 23.7 mmol) and 4-fluorobenzene (2.6 mL, 26.2 mmol) dissolved in carbon disulfide (25 mL) was treated in portions with aluminum chloride (4.1 g, 30.75 mmol) under a nitrogen atmosphere. After the addition was complete, the reaction mixture was heated to 60-70° C. for about 12 hours. The resulting mixture was cooled in an ice bath, treated with concentrated hydrochloride acid (12 mL), and stirred for 30 minutes. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with 1 N aqueous sodium hydroxide, water, and brine, dried and evaporated in vacuo. Purification by silica gel chromatography, eluting with 5% ethyl acetate/hexane gave the title compound as a white solid (3.81 g, 56%). The product was used in the next step.
Reaction SMILES: [F:1][C:2]1[C:3]([O:24]COC)=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([Si](CC)(CC)CC)[O:8][C:5]2=[N:6][CH:7]=1.C1C(=O)N([I:35])C(=O)C1>CN(C=O)C>[F:1][C:2]1[CH:7]=[N:6][C:5]2[O:8][C:9]([I:35])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[C:3]=1[OH:24]
Reactant: CC[Si](CC)(CC)c1oc2ncc(F)c(OCOC)c2c1-c1ccccc1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Oc1c(F)cnc2oc(I)c(-c3ccccc3)c12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The mixture of 5-fluoro-4-methoxymethoxy-3-phenyl-2-(triethylsilanyl)-furo[2,3-b]pyridine (4) (0.10 g, 0.26 mmol) and NIS (0.07 g, 0.31 mmol) in DMF (1.5 mL) was stirred at 50° C. overnight. The reaction mixture was purified by preparative HPLC to give the title compound 5.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[C:6]2[C:10]=1[O:9][CH:8]([CH2:11][N:12]([CH3:14])[CH3:13])[CH2:7]2.Cl[C:26]1[N:35]=[CH:34][C:33]2[N:32]([CH3:36])[C:31](=[O:37])[C@@H:30]([CH2:38][CH3:39])[N:29]([CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[C:28]=2[N:27]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C>[CH:40]1([N:29]2[C:28]3[N:27]=[C:26]([NH:1][C:2]4[CH:3]=[CH:4][C:5]([C:15]([O:17][CH2:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)=[O:16])=[C:6]5[C:10]=4[O:9][CH:8]([CH2:11][N:12]([CH3:14])[CH3:13])[CH2:7]5)[N:35]=[CH:34][C:33]=3[N:32]([CH3:36])[C:31](=[O:37])[C@H:30]2[CH2:38][CH3:39])[CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Reactant: CN(C)CC1Cc2c(C(=O)OCc3ccccc3)ccc(N)c2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Solvent: O
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)OCc4ccccc4)c4c3OC(CN(C)C)C4)nc2N1C1CCCC1
Yield: 34.2 %

Procedure:
Benzyl 7-amino-2-(dimethylaminomethyl)-2,3-dihydrobenzofuran-4-carboxylate 29g (212 mg, 0.65 mmol) was dissolved in 20 mL of 4-methyl-2-pentanol followed by the addition of (7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7H-pteridin-6-one 1o (230 mg, 0.78 mmol) and p-toluenesulfonic acid monohydrate (198 mg, 1.04 mmol). The reaction solution was heated to reflux for 3 hours with stirring and concentrated under reduced pressure. The resulting residue was added with 30 mL of saturated sodium bicarbonate solution and extracted with dichloromethane (50 ml×3). The combined organic phase was washed with water (30 mL) and saturated sodium chloride solution (30 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound benzyl 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2-(dimethylaminomethyl)-2,3-dihydrobenzofuran-4-carboxylate 29h (0.13 g, yield: 34.2%) as a white solid.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:7])[CH2:5][Cl:6].[CH2:8]([C:11]1[CH:12]=[C:13]([N:17]=[C:18]=[O:19])[CH:14]=[CH:15][CH:16]=1)[CH:9]=[CH2:10]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C1C=CC=CC=1>[Cl:6][CH2:5][C:4]([O:7][C:18](=[O:19])[NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:8][CH:9]=[CH2:10])[CH:12]=1)=[N:3][O:2][CH3:1]
Reactant: C=CCc1cccc(N=C=O)c1
Reactant: CONC(=O)CCl
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: c1ccccc1
Product: C=CCc1cccc(NC(=O)OC(CCl)=NOC)c1
Temperature: 25 °C

Procedure:
N-Methoxychloroacetamide (12.3 grams; 0.1 mole), benzene (80 ml) and dibutyltin dilaurate (1 drop) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. 3-Allylphenylisocyanate (16 grams; 0.1 mole) dissolved in benzene (30 ml) is incrementally added to the reaction mixture, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 2 hours. After this time the reaction mixture is distilled to remove benzene and unreacted starting material thereby yielding the desired product 1-chloro-2-(N-3-allylphenylcarbamoyloxy)-2-methoxyiminoethane.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:45]([O:47]CC)=[CH2:46])CCC>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[C:45]([C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1)(=[O:47])[CH3:46]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
A mixture of tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (5.0 g, 14.6 mmol), palladium diacetate (240 mg, 1.46 mmol), triphenylphosphine (376 mg, 2.92 mmol) and tributyl(1-ethoxyvinyl)stannane (5.3 mL, 16.1 mL) in dioxane (100 mL) was degassed with nitrogen for three times, and the reaction mixture was stirred at 80° C. overnight. The reaction was cooled to RT and diluted with THF (100 mL), followed by the addition of 2 N HCl (100 mL). The mixture was stirred at RT for 30 mins, and LCMS showed the reaction was completed. The reaction mixture was diluted with ethyl acetate (200 mL). The organic phase was separated, washed with water (3×100 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to afford the title compound (3.0 g, 67%). MS (ES+) C15H22N4O3 requires: 306. found: 251 [M−56+H]+.
Reaction SMILES: [ClH:1].[N:2]1([C:8]2[S:9][CH2:10][C:11](=[NH:13])[N:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[NH:14]=[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=N)[NH:16]1>CO>[ClH:1].[NH:14]=[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[C:10]2[S:9][C:8]([N:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[N:12][C:11]2=[NH:13])[NH:16]1
Reactant: N=C1NC(=N)c2ccccc21
Reactant: N=C1CSC(N2CCCCC2)=N1
Agent: Cl
Solvent: CO
Product: N=C1N=C(N2CCCCC2)SC1=C1NC(=N)c2ccccc21
Temperature: 0 °C

Procedure:
To a solution of 21.9 parts of 2-piperidino-4-imino-2-thiazoline hydrochloride in 240 parts of methyl alcohol there was added 14.5 parts of 1,3-diiminoisoindoline. The resultant mixture was heated at reflux for six hours, then chilled to 0° C and filtered. The collected solid was washed with methyl alcohol and dried at 50° C to obtain 27 parts of 1-imino-3-(2-piperidino-4-imino-2-thiazolin-5-ylidene)isoindoline hydrochloride melting at 320°-321° C (dec). The assigned chemical structure was completely corroborated by a concordant nuclear magnetic resonance spectrum. The hydrochloride salt is readily converted to the free base, a colorless solid melting at 226°-227°C, by treatment with dilute ammonium hydroxide. This compound, which corresponds to Formula VIII wherein R, R1, R2 and R3 are each hydrogen and N=B is piperidino, was found on testing in vitro by standard serial dilution procedures to be bacteriostatic versus: Staphylococcus aureus 209 at a minimal concentration of 6.3 parts per million; Esherichia coli at 62.5 parts per million; Pseudomonas aeruginosa 211 at 125 parts per million; and fungicidal versus Tricophyton mentogrophytes at 62.5 parts per million; Aspergillus niger at > 125 parts per million; and Candida albicans at 125 parts per million.
Reaction SMILES: [C:1](O)(=O)/C=C\C(O)=O.[C:9]([O:16][CH3:17])(=[O:15])/[CH:10]=[CH:11]\[C:12]([O-:14])=[O:13].C1(=O)OC(=O)C=C1>CO.O>[C:12]([O:14][CH3:1])(=[O:13])/[CH:11]=[CH:10]\[C:9]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)/C=C\C(=O)[O-]
Reactant: O=C(O)/C=C\C(=O)O
Agent: O=C1C=CC(=O)O1
Solvent: CO
Solvent: O
Product: COC(=O)/C=C\C(=O)OC

Procedure:
This example also refers to FIG. 1. A butane oxidation reactor (not shown) produces 100 moles per hour of maleic anhydride, of which 40 kmols are condensed by cooling the gases in condensers (not shown). The remaining 60 moles per hour are recovered as a 50 wt % aqueous solution of maleic acid from an absorber (2) in line 5 and mixed together with the crude maleic anhydride from the partial condensers (line 8). The aqueous maleic acid is fed to the mono-ester reaction column (9). Recycle methanol from the refining section is fed (line 16a) to the bottom of the column (9). More than 80% of the maleic acid is converted to mono-methyl maleate and the bottom product (line 17) contains less than 20 mol % water. Mainly water and methanol and a small amount of maleic acid in the overhead are fed (line 14) to the methanol column (25). The bottom product from the mono-ester reaction column (9) is fed to a reaction column (19) to react the mono-methyl maleate with methanol to produce di-methyl maleate. 300 moles per hour of methanol are fed (line 24) to the bottom of the reaction column (19). Essentially water free, fully converted di-methyl maleate is fed (line 26) to hydrogenation. Recycle methanol from the refining section is fed to the top of the reaction column as wash (line 16b) to minimise the di-methyl maleate and maleic acid in the overhead of the column. Methanol and water from the overhead (line 31) of the reaction column is fed to the methanol column (25) where the methanol is separated and recycled to the reaction column (line 24). Water and a small amount of recovered maleic acid and di-methyl maleate from the bottom of the methanol column are recycled to the absorber (2) in line 3. Thus in this arrangement the evaporator and the mono-ester reaction column duties are combined in a single unit which will reduce the equipment costs by eliminating the evaporation equipment.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH2:9]=[CH:10][CH:11]=[CH2:12]>CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH:10]([CH:11]1[CH2:12][CH:3]1[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH2:9]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=CC=C
Agent: [Rh]
Solvent: CC(=O)O
Product: C=CC1CC1C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
Butadiene (200 mL) was liquified at -70° C. and added to ethyl diazoacetate (20 g, 175 mmol) in a pressure vessel. The catalyst, rhodium (II) acetate dimer (300 mg, 0.7 mmol), was added and the reaction vessel sealed. The reaction mixture was allowed to warm to ambient temperature and the reaction vessel was shaken for 24 h at ambient temperature. The reaction mixture and the ethanol rinse of the reaction vessel were combined and this blue solution was filtered through 50 g of silica gel. The silica gel was washed with 2% diethyl ether in pentane until the blue color was eluted. The blue solution was then concentrated in vacuo at 0° C. and filtered through CeliteR filter aid to remove any remaining catalyst. The filtrate was distilled under reduced pressure (approximately 15 mm) to yield 18.6 g (76% yield) of ethyl 2-ethenylcyclopropane carboxylate as a clear colorless liquid, b.p. 22°-26° C.