Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].S(=O)(=O)(O)O.C(O)=O.[NH2:13][NH:14][C:15]([NH2:17])=[O:16]>O.C(O)=O.O>[NH2:13][NH:14][C:15]([NH2:17])=[O:16].[N:4]1[C:2](=[O:3])[N:1]=[CH:15][N:14]=1
Reactant: NC(N)=O
Agent: NNC(N)=O
Agent: O=S(=O)(O)O
Solvent: O=CO
Solvent: O
Product: O=C1N=CN=N1
Temperature: 10 °C
Yield: 43.1 %

Procedure:
Aqueous semicarbazide free base feedstock (523.8 grams) was prepared from 64 percent N2H4 (4.18 moles) and urea (4.17 moles) by the method of Example 1. Ninety-eight percent sulfuric acid (99.8 grams, 0.998 mole) and 90 percent formic acid (510.6 grams, 9.99 moles) were successively added to the aqueous semicarbazide free base. After reflux at 108°-110° C. for four hours, a formic acid/H2O azeotrope was stripped, H2O (160 ml) was added to the concentrate and stripping resumed at 118°-125° C. to give 595 grams of combined distillate. The reaction mixture was cooled to 10° C. and the mother liquor was siphoned (58 grams). Crude 1,2,4-triazol-5-one was recrystallized from H2O (725 ml), the supernatant liquid was siphoned (930 grams), and 200 ml H2O was added for product filtration. Vacuum-drying gave 152.6 grams of 1,2,4-triazol-5-one (1.80 moles, 43.1 percent yield based on N2H4 charged), m.p. 234°-236° C. (Cl-, 0.02 percent).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=O)=[N:6][CH:7]=1>C1COCC1>[NH3:6].[N:10]1([CH2:8][C:5]2[N:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C(c1ccc(O)cn1)N1CCCCC1
Solvent: C1CCOC1
Product: N
Product: Oc1ccc(CN2CCCCC2)nc1
Temperature: 60 °C
Yield: 4 %
Yield: 37.1 %

Procedure:
To a solution of (5-hydroxy-pyridin-2-yl)-piperidin-1-yl-methanone (1.30 g, 6.31 mmol) in THF (100 mL) was added borane-dimethylsulfide complex (1.75 mL, 18.9 mmol). After 18 h the solvent was removed and the residue was diluted with MeOH (50 mL) and heated to 60° C. After 2 h the solvent was evaporated and chromatography of the residue (SiO2: 4-8% 2 M NH3 in MeOH/DCM) gave the title compound as an oil (0.225 g, 17%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[N:20]=[C:19]3[N:21]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=4)[O:23][C:18]3=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:32][N:33]([CH3:43])[C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[N:20]=[C:19]3[N:21]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:37](=[O:38])[C:36]5[CH:40]=[CH:41][CH:42]=[C:34]([N:33]([CH3:32])[CH3:43])[CH:35]=5)[CH:25]=4)[O:23][C:18]3=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cccc(C(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc3oc(-c4cccc(N)c4)nc3n2)CC1
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)c1cccc(C(=O)Nc2cccc(-c3nc4nc(CN5CCN(C(=O)OC(C)(C)C)CC5)ccc4o3)c2)c1
Temperature: 160 °C
Yield: 22.5 %

Procedure:
4-[2-(3-Amino-phenyl)-oxazolo[4,5-b]pyridin-5-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester (83 mg, 0.2 mmol) was dissolved in 1 mL of pyridine along with 1 eq of 3-dimethylamino benzoyl chloride hydrochloride (44 mg, 0.2 mmol). The reaction mixture was heated in a Biotage microwave reactor (160° C.) for min. It was then cooled to room temperature and concentrated. The resulting residue was purified by chromatography (Isco, gradient elution, CH2Cl2 to 95% CH2Cl2, 4% MeOH and 1% Et3N) to afford 25 mg of 4-{2-[3-(3-dimethylamino-benzoylamino)-phenyl]-oxazolo[4,5-b]pyridin-5-ylmethyl}-piperazine-1-carboxylic acid tert-butyl ester (23% yield).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:18]1([CH2:21][CH2:22][CH3:23])[O:20][CH2:19]1.B(F)(F)F.CCOCC>C(OCC)C>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:18]([O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[F:1])([CH2:21][CH2:22][CH3:23])[CH2:19][OH:20]
Reactant: OCc1ccccc1F
Reactant: CCCC1(c2ccc(Cl)cc2Cl)CO1
Agent: FB(F)F
Solvent: CCOCC
Product: CCCC(CO)(OCc1ccccc1F)c1ccc(Cl)cc1Cl
Yield: 9 %

Procedure:
A mixture of 11.6 g (92 mmoles) of 2-fluorobenzyl alcohol and 21.9 g (92 mmoles) of 2-(2,4-dichlorophenyl)-1,2-epoxypentane is added dropwise at 0°-2° C. to a solution of 2.0 ml (16.5 mmoles) of boron trifluoride ethyl etherate in 10 ml of diethyl ether. The solution is allowed to react further overnight at +7° C. and is worked up as in Example I by extraction and column chromatography. 2.95 g of the pure product are obtained in the form of a colourless oil. 100 MHz-1H-NMR (CDCl3): δ=6.8-7.7 ppm (m, 7H aromatic); 4.5 ppm (s, 2H, ##STR27## 3.9-4.4 ppm (m, 2H, --CH2OH); 1.7-2.3 ppm (m, 3H, --CH2CH2CH3 and OH); 0.7-1.4 ppm (m, 5H, --CH2CH3).
Reaction SMILES: C[C:2]([CH3:5])([O-:4])C.[Na+].[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:10]=2[CH2:9][CH2:8]1.[C:18](O)(=[O:20])[CH3:19].O>C1(C)C=CC=CC=1>[O:7]1[C:11]2[CH:12]=[CH:13][C:14](/[CH:16]=[CH:19]/[C:18]([O:4][CH2:2][CH3:5])=[O:20])=[CH:15][C:10]=2[CH2:9][CH2:8]1
Reactant: O=Cc1ccc2c(c1)CCO2
Reactant: CC(=O)O
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)/C=C/c1ccc2c(c1)CCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 369.3 %

Procedure:
To an ice-cooled suspension of sodium t-butoxide (90.4 g, 941 mmols) in toluene (1 L) was added dropwise triethyl phosphonoacetate (211.0 g, 941 mmols) followed by 2,3-dihydrobenzofuran-5-carbaldehyde (115.9 g 782 mmols). The mixture was stirred for 1 hour and then acetic acid (12 g, 200 mmols) and water (604 mL) was added. The separated organic layer was washed with water (525 mL) followed by a saturated aqueous solution of sodium bicarbonate (263 mL) and concentrated under reduced pressure. Methanol (525 mL) and water (525 mL) were added to the residue and the mixture was stirred for 30 minutes. Crystals precipitated were collected by filtration to obtain 161.2 g (yield: 94%) of the title compound.
Reaction SMILES: C[Mg]I.[Mg].[CH3:5]I.[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12](=[O:18])[C:13](=[O:17])[NH:14]2)=[CH:10][CH:9]=1>C(OCC)C.C1COCC1>[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([OH:18])([CH3:5])[C:13](=[O:17])[NH:14]2)=[CH:10][CH:9]=1
Reactant: O=C1Nc2cc(Br)ccc2C1=O
Reactant: CI
Agent: C[Mg]I
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(O)C(=O)Nc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.1 %

Procedure:
To a ice-cold solution of methyl magnesium iodide prepared from magnesium (1.7 g, 70.78 mmoles) and methyl iodide (4.40 ml, 70.78 mmoles) in diethyl ether (60 ml), 6-bromoisatin (4 g, 17.69 mmoles) in THF (120 ml) was added and warmed to room temperature. After 12 h, the reaction mixture was cooled to 0° C., quenched with dilute HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as brown solid (4.2 g, 93% yield). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 10.34 (s, 1H), 7.23 (t, J=7.9 Hz, 1H), 7.14 (dd, J=7.9, 1.7 Hz, 1H), 6.93 (d, J=1.6 Hz, 1H), 5.92 (s, 1H), 1.33 (s, 3H).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[C@H:16]12[CH2:22][C@H:19]([NH:20][CH2:21]1)[CH2:18][N:17]2C(OC(C)(C)C)=O.[ClH:30].N1(C(=O)CC2C=NC(N3C=NN=N3)=CC=2)CCNCC1>>[ClH:30].[C@H:16]12[CH2:22][C@H:19]([NH:20][CH2:21]1)[CH2:18][N:17]2[C:13](=[O:15])[CH2:12][C:9]1[CH:10]=[N:11][C:6]([N:1]2[CH:5]=[N:4][N:3]=[N:2]2)=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1ccc(-n2cnnn2)nc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: Cl
Agent: O=C(Cc1ccc(-n2cnnn2)nc1)N1CCNCC1
Product: O=C(Cc1ccc(-n2cnnn2)nc1)N1C[C@@H]2C[C@H]1CN2

Procedure:
1-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl]-2-[6-(1H-tetrazol-1-yl)pyridin-3-yl]ethanone hydrochloride was prepared in two steps starting from [6-(1H-tetrazol-1-yl)pyridin-3-yl]acetic acid and commercially available tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate in an analogous fashion as described for the synthesis of 1-(piperazin-1-yl)-2-[6-(1H-tetrazol-1-yl)pyridin-3-yl]ethanone hydrochloride. MS m/z 286 (M+1)+.
Reaction SMILES: [CH3:1][C:2]([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][C:4]#[CH:5].N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:29]([SnH:33]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH3:32]>>[CH3:1][C:2]([O:12][Si:13]([CH3:14])([CH3:15])[CH3:16])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3]/[CH:4]=[CH:5]/[Sn:33]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCC(C)(CCCCCC)O[Si](C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCCCC(C)(C/C=C/[Sn](CCCC)(CCCC)CCCC)O[Si](C)(C)C
Temperature: 25 °C

Procedure:
A solution of 30 g of 4-methyl-4-trimethylsilyloxy-1-decyne, 150 mg of azobisisobutyronitrile, and 35 ml of tri-n-butyltin hydride was magnetically stirred under an argon atmosphere at 130°-135° C. for about 2 hours (exothermic), then cooled to ambient temperature. The product was distilled to provide 60 g of (E)-4-methyl-4-trimethylsilyloxy-1-tri-n-butylstannyl-1-decene (b.p. 156°-158° at 0.03 mm).
Reaction SMILES: [S:1](Cl)(Cl)(=[O:3])=[O:2].[C:6]1([C:12]2[N:13]=[CH:14][S:15][C:16]=2[N:17]2C(=O)C3=CC=CC=C3C2=O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH3:28]>ClCCl.CO>[NH2:17][C:16]1[S:15][C:14]([S:1]([NH2:28])(=[O:3])=[O:2])=[N:13][C:12]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:17][C:16]1[S:15][CH:14]=[N:13][C:12]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: N
Reactant: O=C1c2ccccc2C(=O)N1c1scnc1-c1ccccc1
Solvent: CO
Solvent: ClCCl
Product: Nc1sc(S(N)(=O)=O)nc1-c1ccccc1
Product: Nc1scnc1-c1ccccc1
Reaction time: 15 h
Yield: 36 %
Yield: 16 %

Procedure:
The crude mixture of sulfonyl chloride with 4-phenyl-5-phthalimido-thiazole (231 mg) in dichloromethane (10 ml) was treated with ammonia in methanol (900 μl, 2.0 M) dropwise at ambient temperature. After 10 min the mixture was concentrated in vacuo. The residue was suspended in ethanol (10 ml), treated with ethanolic hydrazine (660 μl, 1.0 M, 660 μl mol) and heated to reflux. After 1.5 hr a further portion of ethanolic hydrazine was added (660 μl, 1.0 M, 660 μmol) and reflux continued for 15 hr. The cooled mixture was filtered and concentrated in vacuo. Flash chromatography on silica gel (ethyl acetate/hexanes) yielded pure 5-amino-2-(aminosulfonyl)-4-phenylthiazole (56 mg, 36% for 3 steps) and 5-amino-4-phenylthiazole (17 mg, 16% for 3 steps).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[NH2:33][C@@H:34]([CH2:37][CH3:38])[CH2:35][OH:36]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][NH:33][C@H:34]([CH2:35][OH:36])[CH2:37][CH3:38])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: CC[C@H](N)CO
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Product: CC[C@@H](CO)NCCCS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 242) and (S)-2-amino-1-butanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C24H36N6O5SF [(M+H)+]539.2447, observed 539.2449.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[CH:13][C:14](=[O:17])[NH:15][CH:16]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:18]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([C:11]3[CH:12]=[CH:13][C:14](=[O:17])[N:15]([CH3:18])[CH:16]=3)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1.[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[N:15][CH:16]=3)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: O=c1ccc(C2CCC3(CC2)OCCO3)c[nH]1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(C2CCC3(CC2)OCCO3)cn1
Product: Cn1cc(C2CCC3(CC2)OCCO3)ccc1=O
Temperature: 70 °C

Procedure:
A solution of 5-(1,4-dioxa-spiro[4.5]dec-8-yl)-1H-pyridin-2-one (as prepared in the previous step, 750 mg, 3.19 mmol) in DMF (5 mL) was treated with Cs2CO3 (Aldrich, 1.56 g, 4.80 mmol) at room temperature for 10 min. MeI (Aldrich, 330 μL, 4.80 mmol) was added into the reaction solution and heated at 70° C. for 6 hours. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give yellow oil, which was then purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid along with O-alylated product, 5-(1,4-dioxa-spiro[4.5]dec-8-yl)-2-methoxy-pyridine.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:11]2[C:20]3[C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[S:23][C:19]=3[CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][CH:15]=[CH:16]3)[CH:5]=[C:6](I)[C:7]=1[O:8][CH3:9].[Cu][C:29]#[N:30].O.Cl.[CH3:33][N:34]1CCCC1=O>>[CH:27]1[C:21]2[C:20]3[C:11]([C:4]4[CH:5]=[C:6]([C:29]#[N:30])[C:7]([O:8][CH3:9])=[C:2]([CH:3]=4)[C:33]#[N:34])=[C:12]4[C:17](=[CH:18][C:19]=3[S:23][C:22]=2[CH:24]=[CH:25][CH:26]=1)[CH:16]=[CH:15][CH:14]=[CH:13]4
Reactant: N#C[Cu]
Reactant: CN1CCCC1=O
Reactant: COc1c(I)cc(-c2c3ccccc3cc3sc4ccccc4c23)cc1I
Agent: Cl
Solvent: O
Product: COc1c(C#N)cc(-c2c3ccccc3cc3sc4ccccc4c23)cc1C#N
Temperature: 150 °C
Yield: 82 %

Procedure:
A suspension of 11-(3,5-diiodo-4-methoxy-phenyl)-benzo[b]naphtho[2,3-d]thiophene (4.55 g, 7.68 mmol) and copper (I) cyanide 3.13 g, 38.4 mmol) in 1-methyl-2-pyrrolidinone (18 mL) was heated in an 150° C. oil bath under a dry nitrogen atmosphere. After 1 h the solution was added to water (200 mL) and acidified with 10% aqueous HCl. The solid was filtered and flash chromatographed (silica gel: eluent: methylene chloride) to provide the title compound as a yellow solid (2.47 g, 82%): mp 214-215° C.: MS (EI): [M+], 390 (100%, MI); Anal. Calc. for C25H14N2OS: C, 76.90, H, 3.61, N, 7.17. Found: C, 76.48, H, 3.46, N, 7.17.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.I[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C(OC(C)(C)C)=O>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:3][CH:4]=1)#[N:7]
Reactant: CC(C)(C)OC(=O)N1CCC(I)CC1
Reactant: N#Cc1ccc(Br)nc1
Agent: CC(C)(C)OC=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cn2)CC1
Yield: 27 %

Procedure:
This compound was synthesized from 6-bromonicotinonitrile and tert-butyl 4-iodopiperidine-1-carboxylate as described for example 49 step 1 (150 mg, yield 27%). 1H NMR (400 MHz, CDCl3) δ 8.82 (d, J=2.0 Hz, 1H), 7.91 (dd, J=8.2 Hz, 2.1 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 4.28 (m, 2H), 2.97-2.81 (m, 3H), 1.91 (m, 2H), 1.78-1.67 (m, 2H), 1.48 (s, 9H). MS (ESI) m/z: Calculated for C16H21N3O2: 287.16. found: 188.2 (M+H-Boc)+
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[CH:4]([C:3]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:2]=1[O:1][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(OC)ccc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-hydroxy-4-methoxybenzaldehyde (1 g; 6.58 mmol), BrCH2CO2Et (0.806 ml; 7.24 mmol) and K2CO3 (1 g, 7.24 mmol) in anhydrous DMF (5 ml) was stirred overnight at room temperature. The mixture was diluted with EtOAc (100 ml) and H2O (100 ml). The organic layer was separated and dried over MgSO4, and filtrate evaporated, to give the product (1.29 g; 97%), as colourless solid. 1H-NMR (CDCl3) 1.28 (tr, 3H, J=7.11 Hz); 3.84 (s, 3H); 4.25 (q, 2H, J=7.14, 14.28 Hz); 4.69 (s, 2H); 6.30 (d, 1H, J=2.16 Hz); 6.58 (dd, 1H, J=1.77, 8.73 Hz); 7.83 (d, 1H, J=8.7 Hz); 10.36 (s, 1H).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[N:5]=[C:6]([C:9]2([C:19]#[N:20])[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH2:10]2)[S:7][CH:8]=1.CC(=O)[O:23]CC.C1CCCCC1>O.C(O)C>[CH3:3][C:4]1[N:5]=[C:6]([C:9]2([C:19]([NH2:20])=[O:23])[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH2:10]2)[S:7][CH:8]=1
Reactant: CCOC(C)=O
Reactant: Cc1csc(C2(C#N)CCC3(CC2)OCCO3)n1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCCCC1
Solvent: O
Solvent: CCO
Product: Cc1csc(C2(C(N)=O)CCC3(CC2)OCCO3)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of KOH (12.9 g, 230 mmol) in water (200 ml) was added to 8-(4-methyl-thiazol-2-yl)-1,4-dioxa-spiro[4.5]decane-8-carbonitrile (15.2 g, 58 mmol), dissolved in ethanol (200 ml), and the mixture was stirred at RT for 48 h. Since according to TLC (EA/cyclohexane 4:1) educt was still present, the mixture was subsequently stirred at 80° C. for a further 3 h.
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:10][CH2:9][C:6]([C:11]3[NH:19][C:18]4[C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH3:23])[C:15](=[O:24])[N:14]([CH2:25][CH2:26][CH3:27])[C:13]=4[N:12]=3)([CH2:7][CH2:8]1)[CH2:5][CH2:4]2.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[O:24]=[C:15]1[N:14]([CH2:25][CH2:26][CH3:27])[C:13]2[N:12]=[C:11]([C:6]34[CH2:7][CH2:8][C:3]([CH2:2][O:1][S:29]([CH3:28])(=[O:31])=[O:30])([CH2:10][CH2:9]3)[CH2:4][CH2:5]4)[NH:19][C:18]=2[C:17](=[O:20])[N:16]1[CH2:21][CH2:22][CH3:23]
Reactant: CS(=O)(=O)Cl
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(CO)(CC3)CC4)nc2n(CCC)c1=O
Solvent: c1ccncc1
Product: CCCn1c(=O)c2[nH]c(C34CCC(COS(C)(=O)=O)(CC3)CC4)nc2n(CCC)c1=O

Procedure:
To a mixture of 8-(4-hydroxymethylbicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydropurine-2,6-dione (X, Example 86) in pyridine at 0° is added methanesulfonyl chloride (1.2 equivalents) in pyridine. The mixture is stirred at 0° until complete conversion is achieved and then the solvent removed under reduced pressure.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14](Cl)=[C:15]([F:20])[CH:16]=2)[N:11]([CH:22]2[CH2:24][CH2:23]2)[C:10]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:30][C:31](=[O:37])[NH:32][CH:33]1[CH2:36][NH:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27].C(N(CC)CC)C>CC(N(C)C)=O.O>[C:26]([O:30][C:31](=[O:37])[NH:32][CH:33]1[CH2:36][N:35]([C:14]2[CH:13]=[C:12]3[C:17]([C:18](=[O:19])[N:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:10](=[O:25])[N:11]3[CH:22]3[CH2:24][CH2:23]3)=[CH:16][C:15]=2[F:20])[CH2:34]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: O=c1c2cc(F)c(Cl)cc2n(C2CC2)c(=O)n1OCc1ccccc1
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CN(c2cc3c(cc2F)c(=O)n(OCc2ccccc2)c(=O)n3C2CC2)C1
Temperature: 80 °C
Yield: 47.6 %

Procedure:
A solution of 3-benzyloxy-7-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione (Example E-3, 0.20 g, 0.55 mmol) in DMA (3.0 mL) was reacted with azetidin-3-yl-carbamic acid tert-butyl ester (0.286 g, 1.66 mmol), triethylamine (0.76 mL, 5.5 mmol) and heated to 80° C. for 2 days. The mixture was then cooled, diluted with H2O, and extracted with ethyl acetate. The organic layers were combined, dried with sodium sulfate, and concentrated. The residue was purified by column chromatography (silica gel, 3:1 hexanes/ethyl acetate to 1:1 hexanes/ethyl acetate) to provide 0.13 g of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N+:11]([O-])=O.C(O)(=O)C.C(N)=N.[H][H]>[Ni].CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH2:11]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Ni]
Agent: N=CN
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccc(Cl)c(N)c1

Procedure:
40.8 g of 1-chloro-2,4-dinitrobenzene, 2 g of Raney nickel (60%, aqueous), 1.5 g of formamidine acetate and 120 ml of methanol are introduced in an autoclave equipped with gas introduction stirrer. The air in the autoclave is then displaced by nitrogen and then by hydrogen. The hydrogenation is carried out at a pressure of 10 bar and a temperature of 60° C. The hydrogenation time is 11/4 hours. 1-Chloro-2,4-diaminobenzene, 99% pure (analysed as 1-Chloro-2,4-acetamidobenzene by liquid chromatography), is obtained in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([NH2:17])=[CH:4][N:3]=1.[C:18]([N:25]1[CH2:31][CH2:30][CH2:29][C@H:26]1[CH:27]=O)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[C:21]([O:20][C:18]([N:25]1[CH2:31][CH2:30][CH2:29][C@H:26]1[CH2:27][NH:17][C:5]1[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: COc1ccc(Oc2nc(Cl)ncc2N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc(Oc2nc(Cl)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of Compound 1c (4.45 g, 17.7 mmol) in 1,2-dichloroethane (80 mL) was added Boc-L-prolinal (Compound 1d) (5.0 g; 24.4 mmol) and glacial acetic acid (4.5 mL) at ambient temperature, and the mixture was stirred under a nitrogen atmosphere for 3 h. The mixture was then treated with NaB(OAc)3H (9.37 g; 44.2 mmol) and continually stirred at room temperature for 20 h. The resultant mixture was diluted with CH2Cl2, and washed with saturated NaHCO3(aq) and H2O. The organic phase was washed sequentially with H2O and brine, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a Et2O—CH2Cl2 gradient to afford Compound 1e (6.54 g; 85% yield) as a pale-yellow solid. 1H-NMR (400 MHz, CDCl3): δ 7.73-7.79 (m, 1H), 7.07-7.14 (m, 2H), 6.91-6.98 (m, 2H), 5.73 (br. s, 0.6H), 4.77 (br. s, 0.4H), 4.20-4.30 (m, 1H), 3.85 (s, 3H), 3.21-3.58 (m, 4H), 1.81-2.11 (m, 4H), 1.46-1.49 (m, 9H); MS: m/z 435.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[C:19]1([N:25]2[C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=[N:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:30]([C:29]4[N:25]([C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:26]=[CH:27][CH:28]=4)=[O:31])[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: O=C(Cl)c1ccnn1-c1ccccc1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1ccnn1-c1ccccc1
Yield: 17 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 1-phenyl-1H-pyrazole-5-carbonyl chloride to afford the title compound (15 mg, 17%). 1H-NMR (δ, ppm, DMSO-d6): 6.47 (d, 1H, HPy,5, J=6.0 Hz), 6.89 (d, 1H, Harom, J=8.0 Hz), 7.06 (d, 1H, Hpyrrazole, J=2.1 Hz), 7.37-7.49 (m, 7H, Harom), 7.53 (d, 1H, Harom, J=8.0 Hz), 7.78-7.81 (m, 2H, Hpyrrazole+Py,6), 10.64 (s, 1H, NHamide), 11.16 (s, 1H, NHPy3), 11.37 (s, 1H, NHPy2). HRMS (EI): m/z [M+H] calcd for C22H17N6O3: 413.1362; found: 413.1366.